25086856##2014-4-22##Identification and characterization of a novel splice-site mutation in the Wilson disease gene.##This study aimed to identify aberrant transcripts of the new splice-site mutation c.3244-2A>C in the Wilson disease (WD) gene (ATPase, Cu++ transporting, beta polypeptide, ATP7B) and discuss its genotype and clinical phenotype. DNA and RNA were extracted from peripheral blood lymphocytes, amplified by polymerase chain reaction (PCR) and nested reverse transcription PCR (RT-nested PCR) to characterize the aberrant transcripts. RT-nested PCR product sequencing comparison showed that c.3244-2A>C splice-site mutation caused aberrant transcripts and formatted a new splice acceptor. Patient carrying the splice-site mutation c.3244-2A>C presented early onset age, severe clinical manifestations, and poor prognosis. WD patients with the splice-site mutation show severe clinical manifestations, indicating that aberrant transcripts have important implications for WD phenotype.
25288051##2014-10-8##Clinical course and management of acute and chronic viral hepatitis during pregnancy.##
25291347##2014-10-8##Increased Prevalence of Subcutaneous Lipomas in Patients With Wilson Disease.##
25128653##2014-4-18##Does lesioning surgery have a role in the management of multietiological tremor in the era of Deep Brain Stimulation?##
24581591##2013-10-11##Non-cirrhotic portal hypertension - Concept, diagnosis and clinical management.##Non-cirrhotic portal hypertension (NCPH) is mainly related to vascular disorders in the portal system, granuloma formation with periportal fibrosis or genetic alterations affecting the hepatobiliary system. For the diagnosis of the so-called idiopathic NCPH, it is essential to rule out chronic liver diseases associated with progression to cirrhosis as viral hepatitis B and C, alcoholic and non-alcoholic fatty liver, autoimmune disease, hereditary hemochromatosis, Wilson's disease as well as primary biliary cirrhosis and primary sclerosing cholagitis. This mini review will focus on the most common types of NCPH, excluding the idiopathic NCPH. Primary Budd-Chiari syndrome, characterized by obstruction of hepatic venous outflow, must be distinguished from sinusoidal obstruction syndrome, a cause of portal hypertension associated with exposure to toxic plants or therapeutic agents. Noninvasive imaging methods usually help the diagnosis of both Budd-Chiari syndrome and portal thrombosis, the later a relatively frequent cause NCPH. Clinical presentation and management of these vascular disorders are evaluated. Schistosomiasis, a worldwide spread endemic parasitic disease, may evolve to severe forms of the disease with huge spleen and gastroesophageal varices due to presinusoidal portal hypertension. Although management of acute upper gastrointestinal bleeding is similar to that of cirrhosis, prevention of rebleeding differs. Instead of portosystemic shunt procedures, the esophagogastric devascularization with splenectomy is the accepted surgical alternative. Its association with endoscopic therapy is suggested to be the best option for PH due to schistosomiasis. In conclusion, the prompt diagnosis of the disorder leading to non-cirrhotic portal hypertension is essential for its correct management.
24815561##2013-12-23##Chelating polymeric beads as potential therapeutics for Wilson's disease.##Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non-resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease.
24748223##2014-2-20##Biological consequences of zinc deficiency in the pathomechanisms of selected diseases.##From many points of view, zinc is one of the most important trace elements in biological systems. Many articles describe the well-known role of this metal in human physiology and pathophysiology, but in the related literature, there is a lack of current and reliable reviews of the role of zinc deficiency in many diseases. In this article, we describe the role of zinc deficiency in the oxidative stress control, immune response, proliferation, and pathogenesis and pathophysiology of selected diseases such as depression, cardiovascular diseases, diabetes mellitus, Alzheimer's disease, and Wilson's disease.
24663495##2013-10-28##Automation of o-dianisidine assay for ceruloplasmin activity analyses: usefulness of investigation in Wilson's disease and in hepatic encephalopathy.##Ceruloplasmin (Cp) is a serum ferroxidase that plays an essential role in iron metabolism. It is routinely tested by immunoturbidimetric assays that quantify the concentration of the protein both in its active and inactive forms. Cp activity is generally analyzed manually; the process is time-consuming, has a limited repeatability, and is not suitable for a clinical setting. To overcome these inconveniences, we have set the automation of the o-dianisidine Cp activity assay on a Cobas Mira Plus apparatus. The automation was rapid and repeatable, and the data were provided in terms of IU/L. The assay was adapted for human sera and showed a good precision [coefficient of variation (CV) 3.7 %] and low limit of detection (LoD 11.58 IU/L). The simultaneous analysis of Cp concentration and activity in the same run allowed us to calculate the Cp-specific activity that provides a better index of the overall Cp status. To test the usefulness of this automation, we tested this assay on 104 healthy volunteers and 36 patients with Wilson's disease, hepatic encephalopathy, and chronic liver disease. Cp activity and specific activity distinguished better patients between groups with respect to Cp concentration alone, and providing support for the clinical investigation of neurological diseases in which liver failure is one of the clinical hallmarks.
24615184##2013-10-2##Lenticular nucleus hyperechogenicity in Wilson's disease reflects local copper, but not iron accumulation.##In patients with Wilson's disease (WD) transcranial brain sonography typically reveals areas of increased echogenicity (hyperechogenicity) of the lenticular nucleus (LN). Correlation with T2-hypointensity on magnetic resonance images suggested that LN hyperechogenicity in WD is caused by trace metal accumulation. Accumulation of both, copper and iron, in the brain of WD patients has been reported. The present study was designed to elucidate whether LN hyperechogenicity in WD reflects accumulation of copper or iron. Post-mortem brains of 15 WD patients and one non-WD subject were studied with ultrasonography in an investigator-blinded fashion. LN hyperechogenicity was measured planimetrically by manual tracing as well as using digitized image analysis. The putaminal copper content was determined in samples of 11 WD brains and the non-WD brains using inductively coupled plasma mass spectrometry, and iron content was assessed using flame atomic absorption spectroscopy. LN was normal on ultrasonography only in the non-WD brain, but abnormal (hyperechogenic) in all WD brains. Digitized image analysis measures of LN hyperechogenicity and, by trend, manual measures correlated with putaminal copper content (Pearson test; digitized: r = 0.77, p = 0.04; manual: r = 0.57, p = 0.051) but not with iron content (each, p > 0.18). LN hyperechogenicity measures were unrelated to age at death of patients, age at onset of WD, WD duration, age of brain specimen, serum copper or serum ceruloplasmin (each, p > 0.1). We conclude that LN hyperechogenicity in WD reflects copper, but not iron accumulation. Further studies are warranted to elucidate the use of transcranial brain sonography for monitoring therapeutic effects of chelating agents in WD patients.
25112974##2014-3-7##Epidemiology of Wilson's disease in Ireland.##
25089800##2014-8-5##Mutational characterization of ATP7B gene in 103 Wilson's disease patients from Southern China: identification of three novel mutations.##Wilson's disease (WD) is an autosomal recessive inheritance disorder of copper metabolism due to mutations in the ATP7B gene. The distribution of ATP7B gene mutations is diverse in different population. This study aimed to examine the genotypes of the ATP7B mutant alleles in WD patients from Southern China. Genomic DNA was extracted from 103 WD patients and 60 healthy patients. Mutations were screened and detected by DNA sequencing. A total of 51 different ATP7B mutations were identified in WD patients, including six homozygous, 51 compound heterozygous, and 39 single heterozygotes. Three mutations were found to be novel, including one missense mutation (c.2549C>T) and two frameshift mutations (c.3851_3876del and c.1057delC). The most frequent mutations are Arg778Leu (18.93%), Ile1148Thr (8.74%), and Pro992Leu (4.37%). Different from the published results of early studies, Ile1148Thr was found to be the second common mutation in our cohort. The highest mutation detection rate was on exon 8 (43.69%), followed by exon 16 (24.27%), and exon 12 (17.48%). The total mutation detection rate on exon 8, 12, and 16 was 85.44%. No ATP7B gene mutation was found in healthy patients. In conclusion, we identified three novel mutations and Ile1148Thr as another hotspot mutation in WD patients from Southern China. Most of the mutations can be detected by screening exon 8, 12, and 16. Our research has further enriched the mutation spectrum of the ATP7B gene in Chinese and may help to develop genetic screening strategies of WD.
25108317##2014-2-21##Benign Hereditary Chorea: A Case Report and Brief Review of Inherited Choreas.##
25260151##2014-9-27##A calix[2]triazole[2]arene-based fluorescent chemosensor for probing the copper trafficking pathway in Wilson's disease.##
25252715##2014-4-16##Congential scoliosis in Wilson's disease: case report and review of the literature.##
25234939##2013-8-3##A severe case of esophageal ulcer causing a tight stricture despite long-term D-penicillamine treatment.##
25260885##2014-9-28##Impact of the discovery of human zinc deficiency on health.##
25002079##2014-4-21##A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings.##
25199035##2014-9-9##Acute Liver Failure Due to Wilson's Disease With Overlapping Autoimmune Hepatitis Features: The Coexistence of Two Diseases?##
25120201##2014-5-13##Wilson?s disease presenting as rapid eye movement sleep behavior disorder: a possible window to early treatment.##Objective To describe characteristics of REM sleep behavior disorder in Wilson's disease. Method Questionnaire-based interviews (patients and relatives), neurological examinations, two-week prospective dream-diary, video-polysomnography, transcranial sonography, MRI. Results Four Wilson's disease cases with REM sleep behavior disorder were described; three had REM sleep behavior disorder as initial symptom. All showed mesencephalic tegmental/tectal sonographic hyperechogenicities and two presented ponto-mesencephalic tegmental MRI hyperintensities. Conclusion This first description of REM sleep behavior disorder in Wilson's disease in literature documents REM sleep behavior disorder as a possible presenting symptom of Wilson's disease and adds further evidence to the parallelism of Parkinson's disease and Wilson's disease in phenotype and brainstem topography, which ought to be further studied. REM sleep behavior disorder has prognostic relevance for neurodegeneration in α-synucleinopathies. In Wilson's disease, usefulness of early diagnosis and treatment are already well established. REM sleep behavior disorder in Wilson's disease offers a possible theoretical model for potential early treatment in this extrapyramidal and brainstem paradigm syndrome, previewing the possibility of neuroprotective treatment for REM sleep behavior disorder in "pre-clinical" Parkinson's disease.
24972800##2014-3-27##Search for rare liver diseases: The case of glycosylation defects mimicking Wilson Disease ->.##Pediatric hepatology appears to be a very specific field of paediatrics which deals mainly with rare diseases although clinical features can be commonly found - like increased activity of transaminases. Some of these rare diseases like Wilson disease are commonly looked for and recently Wilsonian like phenotypes have been described which additionally presented with abnormal glycosylation of the plasma protein transferrin. In a subgroup of those patients with specific additional clinical symptoms (cleft uvula, low blood sugar, rhabdomyolysis and dilated cardiomyopathy) phosphoglucomutase 1 deficiency was identified. We recommend screening for abnormal glycosylation of the plasma protein transferrin in children with unexplained liver injury.
25010543##2014-7-11##Metalloproteomics: focus on metabolic issues relating to metals.##
25234180##2014-9-20##Wilson's disease: Hepatic manifestations.##
25234179##2014-9-20##Wilson's disease: Neurological and psychiatric manifestations.##
25234178##2014-9-20##Wilson's disease: Etiology, diagnosis, and treatment.##
24878384##2014-1-18##New mutations and polymorphisms of the ATP7B gene in sporadic Wilson disease.##Wilson's disease (WD) is a rare autosomal recessive genetic disorder of copper metabolism resulting in brain damage, liver failure, and neurological impairment and psychiatric disturbances, as a result of excessive copper accumulation in the brain, liver, kidneys and eyes. ATP7B, encoding a copper transporter P-ATPase was identified as the causative gene of WD. Mutations in the ATP7B gene lead to the defection of the transmembrane transporter so that it can not metabolize copper effectively. We reported the clinical and molecular features of three unrelated and non-consanguineous WD patients. We performed molecular genetic analysis of the ATP7B gene in all cases by DNA sequencing, and revealed 7 novel single nucleotide polymorphisms (SNPs) and 8 well known mutations. Among them, that novel SNP (c. -520 C>T) and two well known mutations (c. 2310 C>G/p. Leu700Leu, c. 2333 G>T/A/p. Arg778Leu/Gln) coexisted in all patients and they were heterozygous and homozygous in the youngest case, respectively, indicating that they may be correlated to the pathogenesis and potentially used as a genetic biomarker for early WD diagnosis.
24859463##2014-1-28##Bone mineralization in children with Wilson's disease.##
25003971##2014-2-28##ATP7B activity is stimulated by PKCɛ in porcine liver.##Copper is necessary for all organisms since it acts as a cofactor in different enzymes, although toxic at high concentrations. ATP7B is one of two copper-transporting ATPases in humans, its vital role being manifested in Wilson disease due to a mutation in the gene that encodes this pump. Our objective has been to determine whether pathways involving protein kinase C (PKC) modulate ATP7B activity. Different isoforms of PKC (α, ɛ, ζ) were found in Golgi-enriched membrane fractions obtained from porcine liver. Cu(I)-ATPase activity was assessed in the presence of different activators and inhibitors of PKC signaling pathways. PMA (10(-8)M), a PKC activator, increased Cu(I)-ATPase activity by 60%, whereas calphostin C and U73122 (PKC and PLC inhibitors, respectively) decreased the activity by 40%. Addition of phosphatase λ decreased activity by 60%, irrespective of pre-incubation with PMA. No changes were detected with 2μM Ca(2+), whereas PMA plus EGTA increased activity. This enhanced activity elicited by PMA decreased with a specific inhibitor of PKCɛ to levels comparable with those found after phosphatase λ treatment, showing that the ɛ isoform is essential for activation of the enzyme. This regulatory phosphorylation enhanced Vmax without modifying affinities for ATP and copper. It can be concluded that signaling pathways leading to DAG formation and PKCɛ activation stimulate the active transport of copper by ATP7B, thus evidencing a central role for this specific kinase-mediated mechanism in hepatic copper handling.
25233963##2012-5-15##HDV Seroprevalence in HBsAg Positive Patients.##
25145892##2014-8-23##Psychiatric signs and symptoms in treatable inborn errors of metabolism.##Possible underlying organic causes of psychiatric symptoms can be overlooked in the clinical setting. It is important to increase awareness amongst psychiatric and neurological professionals with regard to certain inborn errors of metabolism as, in some cases, disease-specific therapies are available that can, for instance, treat underlying metabolic causes. The following article describes the basic pathophysiology, clinical and neurological features, and available diagnostic procedures of six treatable metabolic diseases that are associated with neuropsychiatric symptoms: Wilson's disease, cerebrotendinous xanthomatosis, porphyrias, homocysteinemia, urea cycle disorders, and Niemann-Pick disease type C (NP-C). NP-C is taken as a particularly relevant example because, while it is traditionally considered to be a condition that presents with severe neurological and systemic manifestations in children, an increasing number of patients are being detected who have the adolescent- or adult-onset form, which is frequently associated with neuropsychiatric signs. A notable proportion of adult-onset cases have been reported where NP-C has mistakenly been diagnosed and treated as a psychiatric condition, usually based on patients' initial presentation with psychotic or schizophrenia-like symptoms. Underlying organic causes of psychiatric disorders such as psychosis should be considered among patients with atypical symptoms and/or resistance to standard therapy. Alongside improved frameworks for additional multidisciplinary diagnostic work in patients with suspected organic disease, the development of convenient and affordable biochemical screening and/or diagnostic methods has enabled new ways to narrow down differential diagnoses.
25242788##2014-9-23##Liver Transplantation in Neurological Wilson's Disease: Is There Indication? A Case Report.##Wilson's disease (WD) is an autosomal recessive disorder characterized by copper overload. In this disease, inadequate hepatic excretion leads to copper accumulation in the liver, brain, kidney, and cornea. Severe neurological symptoms can develop in patients with WD, often in the absence of relevant liver damage: it is unclear whether liver transplantation (LT) could reverse neurological symptoms, and at present LT is not recommended in this setting. We report a case of regression of neurological symptoms in a patient affected by WD with prevalent neurological involvement. A 19-year-old man with disabling neuropsychiatric symptoms from WD that included frontal ataxia, akinesia, dystonia, tremors, and behavioral disorders in the presence of preserved liver function (Model for End-Stage Liver Disease score = 7; Child-Turcotte-Pugh score = A5) underwent LT in November 2009. At the time of LT, encephalic magnetic resonance imaging (MRI) indicated diffuse neurodegenerative alterations involving subtentorial and supratentorial structures; bilateral Kayser-Fleischer ring was present. Four years after LT, laboratory tests show normalized copper metabolism and excellent liver function test results. Encephalic MRI shows a substantial improvement of already-known signal alterations at nuclei thalamus and putamen, mesencephalon, and pons. Kayser-Fleischer ring disappeared from the right eye, but a little remnant is still visible in the left eye. At neurological examination, all of the previous symptoms and signs are no longer present and behavioral disorders are no longer present; psychosocial functions are completely restored. The present case provides some evidence that LT may be a valid therapeutic option for WD patients with marked neurological impairment, particularly in those no longer responsive to chelation therapy.
25164926##2014-1-22##Screening for Wilson's disease: Which tests are good enough?##
25160780##2014-8-11##No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up.##
25142911##2014-3-17##Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson's disease by laser ablation inductively coupled plasma mass spectrometry.##
25134866##2014-5-5##The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease.##
25128745##2014-3-16##Prognostic Value of Elevated Serum Ceruloplasmin Levels in Patients with Heart Failure.##
25172214##2014-8-31##Determination of the serum metallothionein (MT)1/2 concentration in patients with Wilson's disease and Menkes disease.##
25194954##2014-9-8##The promise of copper lowering therapy with tetrathiomolybdate in the cure of cancer and in the treatment of inflammatory disease.##
24924744##2014-6-12##Carbamoyl phosphate synthetase-1 is a rapid turnover biomarker in mouse and human acute liver injury.##Several serum markers are used to assess hepatocyte damage, but they have limitations related to etiology specificity and prognostication. Identification of novel hepatocyte-specific biomarkers could provide important prognostic information and better pathogenesis classification. We tested the hypothesis that hepatocyte-selective biomarkers are released after subjecting isolated mouse hepatocytes to Fas-ligand-mediated apoptosis. Proteomic analysis of hepatocyte culture medium identified the mitochondrial matrix protein carbamoyl phosphate synthetase-1 (CPS1) among the most readily detected proteins that are released by apoptotic hepatocytes. CPS1 was also detected in mouse serum upon acute challenge with Fas-ligand or acetaminophen and in hepatocytes upon hypoosmotic stress, independent of hepatocyte caspase activation. Furthermore, CPS1 was observed in sera of mice chronically fed the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Mouse CPS1 detectability was similar in serum and plasma, and its half-life was 126 ± 9 min. Immune staining showed that CPS1 localized to mouse hepatocytes but not ductal cells. Analysis of a few serum samples from patients with acute liver failure (ALF) due to acetaminophen, Wilson disease, or ischemia showed readily detectable CPS1 that was not observed in several patients with chronic viral hepatitis or in control donors. Notably, CPS1 rapidly decreased to undetectable levels in sera of patients with acetaminophen-related ALF who ultimately recovered, while alanine aminotransferase levels remained elevated. Therefore, CPS1 becomes readily detectable upon hepatocyte apoptotic and necrotic death in culture or in vivo. Its abundance and short serum half-life, compared with alanine aminotransferase, suggest that it may be a useful prognostic biomarker in human and mouse liver injury.
25003396##2013-8-24##Small fiber dysfunction in patients with Wilson's disease.##
24720933##2013-11-20##[Complexity of the diagnosis of Wilson disease in clinical practice: our experience in 15 patients].##
25137115##2014-8-20##Eating disorders as a public health issue: prevalence and attributable impairment of quality of life in an Italian community sample.##The prevalence of eating disorders (ED) in the community is still under debate, as well as the measure of their impact on the well-being of individuals. It was decided to evaluate the prevalence of eating disorders in an Italian community sample as well as to measure the burden of the quality of life of people and to compare it to those attributable to other chronic illnesses. A community survey of 4,999 people using a questionnaire on health services utilization, the Advanced Neuropsychiatric Tools and Assessment Schedule (ANTAS), a semi-structured clinical interview derived from the non-patient version of the DSM-IV (SCID/NP) and Short Form Health Survey (SF-12) was conducted. A total of 3,398 individuals were interviewed (68% of those recruited). Lifetime prevalence for overall ED was 1.7%; for anorexia 0.7%; for bulimia 0.6% and for binge eating disorder 0.5%. ED was more frequent in women than in men. No cases of anorexia in men were identified. ED showed an attributable burden in impairing quality of life with no statistically significant differences with those due to major depressive disorder, bipolar spectrum disorders and Wilson's disease. Of the pathological conditions considered, only multiple sclerosis showed a worsening attributable burden. ED thus has a non-negligible frequency in Italy, with severe impact on quality of life comparable to that produced by severe chronic psychiatric and general medical conditions. These elements emphasize that ED is a serious public health issue.
24726229##2012-9-18##Delayed appearance of wing-beating tremor after liver transplantation in a patient with Wilson disease.##Orthotopic liver transplantation (OLT) is the sole etiological treatment for Wilson disease (WD), but several neurological complications after OLT have been reported. We report a WD patient who developed a unilateral wing-beating tremor 6years after OLT. New neurological symptoms develop immediately after OLT in most cases. In our patient, the onset of extrapyramidal symptoms was at a prolonged interval after OLT. To our knowledge this is the first patient with delayed extrapyramidal symptoms after OLT in WD where the pathophysiology of these late extrapyramidal symptoms is still unknown.
25252055##2013-3-5##Acute lymphoblastic leukemia in a girl with Wilson's disease.##Wilson's disease (WD) is an autosomal recessive defect in cellular copper transportation. Although acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy, only two cases of ALL associated with WD have been reported to date. One patient died of relapse and infection, and the other died of neutropenic sepsis during the treatment. We here describe the case of a 10-year-old girl with WD and ALL. Adverse events of chemotherapy, including liver toxicity and severe myelosuppression, necessitated adjustments in the chemotherapy doses. After completion of the treatment, the patient has remained in remission from ALL without progression of liver damage for 2 years. Severe treatment-related toxicity should be considered in chemotherapy for patients with WD.
25065347##2014-4-16##Acute liver failure after valproate exposure in patients with POLG1 mutations and the prognosis after liver transplantation.##
25027110##2014-1-27##Bone status and fractures in 85 adults with Wilson's disease.##
25016221##2014-4-1##Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.##
25087157##2014-8-4##A century for progress in the diagnosis of Wilson disease.##
24359125##2014-4-1##Oxidative stress and suicidal erythrocyte death.##
24813262##2013-10-23##Salinity-dependent copper accumulation in the guppy Poecilia vivipara is associated with CTR1 and ATP7B transcriptional regulation.##Copper (Cu) accumulation and regulation of key-genes involved in Cu homeostasis were evaluated in freshwater- and saltwater-acclimated guppies Poecilia vivipara. Fish were exposed (96h) to environmentally relevant concentrations of dissolved Cu (0, 5.0, 9.0 and 20.0μg/L). In freshwater guppies, gill and liver Cu accumulation was dependent on Cu concentration in the exposure medium. In saltwater guppies, this dependence was observed only in the gut. These findings indicate that Cu accumulation was salinity- and tissue-dependent. Key genes involved in Cu metabolism were sequenced for the first time in P. vivipara. Transcripts coding for the high-affinity copper transporter (CTR1) and copper-transporting ATPase (ATP7B) were identified using polymerase chain reaction (PCR) and gene sequencing. The full-length CTR1 open reading frame (1560bp) and a partial ATP7B (690bp) were discovered. Predicted amino acid sequences shared high identities with the CTR1 of Fundulus heteroclitus (81%) and the ATP7B of Sparus aurata (87%). Basal transcriptional levels addressed by RT-qPCR in control fish indicate that CTR1 and ATP7B was highly transcribed in liver of freshwater guppies while CTR1 was highly transcribed in gut of saltwater guppies. This could explain the higher Cu accumulation observed in liver of freshwater guppies and in gut of saltwater guppies, because CTR1 is involved in Cu uptake. Reduced gill mRNA expression of CTR1 was observed in freshwater guppies exposed to 20.0μg/L Cu and in saltwater guppies exposed to 5.0μg/L Cu. In turn, reduced mRNA expression of gut ATP7B was observed in freshwater and salt water guppies exposed to 9.0 and 20.0μg/L Cu. Liver CTR1 and ATP7B transcription were not affected by Cu exposure. These findings suggest that gill CTR1 and gut ATP7B are down-regulated to limit Cu absorption after exposure to dissolved Cu, while liver CTR1 and ATP7B levels are maintained to allow Cu storage and detoxification. In conclusion, findings reported here indicate that Cu accumulation in the euryhaline guppy P. vivipara is tissue specific and dependent on water salinity. They also suggest that Cu homeostasis involves a differential transcriptional regulation of the newly identified Cu transporters, CTR1 and ATP7B.
24650289##2014-3-20##Whom and how to screen for Wilson disease.##Wilson disease is a genetic disorder of hepatic copper excretion leading to copper accumulation in various tissues. The disease expression is highly variable, ranging from totally asymptomatic subjects to patients with severe liver disease or movement disorders. Thus, it is difficult to define in which patient Wilson disease has to be considered as diagnosis. The suspicion should be high in patients presenting with extrapyramidal disorders or with liver diseases or of unknown origin. For diagnosis, in many patients a combination of tests reflecting disturbed copper metabolism may be needed. Not a single test is per se specific and, thus, a range of tests has to be applied (presence or absence of Kayser-Fleischer rings or neurologic symptoms, serum ceruloplasmin, liver copper content, urinary copper excretion, mutation analysis; rated -1 to 4 depending on the test) and clinical symptoms. A diagnostic sum score of ≥ 4 confirms the diagnosis.
24809467##2014-5-10##Kayser-Fleischer ring and sunflower cataract in Wilson disease.##
24797888##2014-2-19##Reply: bilateral pallidal stimulation for Wilson's disease.##
24797718##2013-9-24##Importance of adequate decoppering in Wilson's disease.##
25178601##2014-9-3##Penicillamine Challenge Test in the Diagnosis of Wilson's Disease.##Wilson's disease (WD) is one of the most common metabolic liver diseases encountered in children. Early diagnosis of the disease is essential because specific treatment can be offered, that will prevent further hepatocellular injury and neurologic complications. There is no single diagnostic test that can exclude or confirm the disease with certainty. Penicillamine challenge has proved itself to be a useful diagnostic test in the detection of WD. The main purpose of this study was to observe the reliability of penicillamine challenge test, in the diagnosis of WD. The cross sectional study was done with a case control design in the department of paediatric gastroenterology & Nutrition, BSMMU, Dhaka. The study was carried out on 60 patients of CLD. Along with other physical findings and laboratory investigations, 24 hours urinary copper excretions were estimated before and after penicillamine challenge. Study results were analyzed statistically. Thirty CLD patients who fulfilled the inclusion and exclusion criteria of WD were considered as cases (Group I) and remaining 30 CLD patients were considered as non-Wilsonian CLD and was labeled as control (Group II). Among the control group, 12 CLD patients were found to be HBsAg positive, 1 had hepatitis-C virus infection, 1 had autoimmune hepatitis and the remaining 16 CLD patients were Cryptogenic. The (mean±SD) age of WD patients was 9.90±28 years; male female ratio was 1.5:1. Most common presentation was ascites (70%). K-F ring was found in 86.7% cases. Serum ceruloplasmin level was found significantly lower in WD patients (mean±SD, 0.1197±23g/L, p<0.001). Baseline urinary copper excretion of WD patients differed significantly from controls (Median 219.0μg/24hour, range 35-2018μg/24hour, versus median 44μg/24hour, range 20-238μg/24hour, p<0.001). Baseline urinary copper excretion above 100μg/24hour was observed in 80% WD patients whereas it was 10% in controls. post penicillamine urinary copper excretion was significantly greater in WD patients than controls (Median 2635μg/24hour, range 648-6222μg/24hour, versus median 423μg/24hour, range 91-1250μg/24hour, p<0.001). Post penicillamine urinary copper above 1600μg/24hour observed in 70% of WD patients whereas not a single patient reached the value in control group. Twenty four hours urinary copper estimation after penicillamine challenge was found to be a valuable test in the diagnosis of WD.
25237939##2014-9-20##Characterizing brain mineral deposition in patients with Wilson disease using susceptibility-weighted imaging.##
24170891##2013-10-29##'Face of giant panda': a rare imaging sign in Wilson's disease.##
24980217##2014-2-18##Intrahepatic cholangiocarcinoma in a transplant liver--selective internal radiation therapy followed by right hemihepatectomy: report of a case.##Intra- or extrahepatic cholangiocarcinomas are the second most common primary liver malignancies behind hepatocellular carcinoma. Whereas the incidence for intrahepatic cholangiocarcinoma is rising, the occurrence of extrahepatic cholangiocarcinoma is trending downwards. The treatment of choice for intrahepatic cholangiocarcinoma remains liver resection. However, a case of liver resection after selective internal radiation therapy in order to treat a recurrent intrahepatic cholangiocarcinoma in a transplant liver is unknown in the literature so far. Herein, we present a case of a patient undergoing liver transplantation for Wilson's disease with an accidental finding of an intrahepatic cholangiocarcinoma within the explanted liver. Due to a recurrent intrahepatic cholangiocarcinoma after liver transplantation, a selective internal radiation therapy with yttrium-90 microspheres was performed followed by right hemihepatectomy. Four years later, the patient is tumor-free and in a healthy condition.
24960690##2014-6-25##Copper homeostasis: specialized functions of the late secretory pathway.##Differentiated cells have evolved mechanisms to adapt the functions of the late secretory pathway to the specific needs of the organism. Reporting in this issue of Developmental Cell, Polishchuk et al. (2014) demonstrate that hepatocytes utilize a unique exocytic aspect of the late endosomal/lysosomal compartment to maintain organismal copper homeostasis.
24909901##2013-10-1##Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.##Copper is an essential yet toxic metal and its overload causes Wilson disease, a disorder due to mutations in copper transporter ATP7B. To remove excess copper into the bile, ATP7B traffics toward canalicular area of hepatocytes. However, the trafficking mechanisms of ATP7B remain elusive. Here, we show that, in response to elevated copper, ATP7B moves from the Golgi to lysosomes and imports metal into their lumen. ATP7B enables lysosomes to undergo exocytosis through the interaction with p62 subunit of dynactin that allows lysosome translocation toward the canalicular pole of hepatocytes. Activation of lysosomal exocytosis stimulates copper clearance from the hepatocytes and rescues the most frequent Wilson-disease-causing ATP7B mutant to the appropriate functional site. Our findings indicate that lysosomes serve as an important intermediate in ATP7B trafficking, whereas lysosomal exocytosis operates as an integral process in copper excretion and hence can be targeted for therapeutic approaches to combat Wilson disease.
24907221##2014-6-8##Atypical neuroimaging in Wilson's disease.##Wilson's disease is a rare metabolic disease involving copper metabolism. Neuroimaging plays an important part in evaluation of patients with a neuropsychiatric presentation. We present a case of a 14-year-old girl with atypical confluent white matter disease and cystic degeneration on MRI, with a rapidly progressive course, who succumbed to complications despite treatment with trientine. Wilson's disease should be considered as a differential for leucoencephalopathy in young patients with progressive neurological disease for its early recognition and optimum outcome.
24888462##2014-3-26##Epidermolysis bullosa acquisita-like eruption with anti-collagen VII autoantibodies induced by D-penicillamine in Wilson disease.##
24954801##2014-1-31##The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases.##
24885450##2014-6-3##Diverse Attention Deficits in Patients With Neurologically Symptomatic and Asymptomatic Wilson's Disease.##
24632503##2013-10-23##The plant decapeptide OSIP108 prevents copper-induced apoptosis in yeast and human cells.##We previously identified the Arabidopsis thaliana-derived decapeptide OSIP108, which increases tolerance of plants and yeast cells to oxidative stress. As excess copper (Cu) is known to induce oxidative stress and apoptosis, and is characteristic for the human pathology Wilson disease, we investigated the effect of OSIP108 on Cu-induced toxicity in yeast. We found that OSIP108 increased yeast viability in the presence of toxic Cu concentrations, and decreased the prevalence of Cu-induced apoptotic markers. Next, we translated these results to the human hepatoma HepG2 cell line, demonstrating anti-apoptotic activity of OSIP108 in this cell line. In addition, we found that OSIP108 did not affect intracellular Cu levels in HepG2 cells, but preserved HepG2 mitochondrial ultrastructure. As Cu is known to induce acid sphingomyelinase activity of HepG2 cells, we performed a sphingolipidomic analysis of OSIP108-treated HepG2 cells. We demonstrated that OSIP108 decreased the levels of several sphingoid bases and ceramide species. Moreover, exogenous addition of the sphingoid base dihydrosphingosine abolished the protective effect of OSIP108 against Cu-induced cell death in yeast. These findings indicate the potential of OSIP108 to prevent Cu-induced apoptosis, possibly via its effects on sphingolipid homeostasis.
24745882##2014-1-30##Wilson disease: what is still unclear in pediatric patients?##Since Wilson disease (WD) may not be present with evident clinical symptoms of liver injury and neurological presentation is rare in children, establishing a diagnosis is often challenging, especially in childhood. Increased transaminases can be the only abnormality found in early course of WD. In clinical practice, high suspicion is crucial for early diagnosis and timely treatment to ensure better outcomes. Conventional diagnostic criteria established for adults are commonly agreed for children but may not always be appropriate in very young age. Currently, the best therapeutic approach for each specific presentation of the disease remains controversial and there are no clear indications about how to treat pediatric WD patients with a mild liver disease.
24893241##2014-6-4##Neurologic manifestations of acute and chronic liver disease.##
24934354##2014-4-17##Effects of Iron and Copper Overload on the Human Liver: an Ultrastructural Study.##
23996412##2013-6-20##Plasma exchange for hemolytic crisis and acute liver failure in Wilson disease: correspondence.##
23996411##2013-7-1##Plasma exchange for hemolytic crisis and acute liver failure in Wilson disease: authors' reply.##
24789146##2013-11-6##Cisplatin handover between copper transporters: the effect of reducing agents.##Copper (Cu) transporters emerged as key factors at the basis of the biological response to antitumor platinum (Pt) drugs, which are among the most potent and broadly used chemotherapeutics. ATP7A and ATP7B (the Menkes and Wilson disease proteins, respectively) appear to be implicated in promoting tumor cell resistance to cisplatin. Cu-ATPases could bind the drug and, with the alleged involvement of the chaperone ATOX1, contribute to cell detoxification and survival. Here, we report the spectroscopic characterization of cisplatin binding to ATOX1 and MNK1, the first metal-binding domain of ATP7A, in the presence of the physiological reducing agent glutathione, a sulfur-containing molecule responsible for the majority of Pt detoxification in the cytosol. Under conditions mimicking the cellular environment, we show that cisplatin transfer from ATOX1 to MNK1 does not occur at a detectable rate. These results appear to contradict other literature data which, however, were obtained in the presence of exogenous reducing agents such as tris(2-carboxyethyl)phosphine (TCEP) having good coordinating ability for soft metal ions (such as Pt) and strong trans-labilizing effect. A better understanding of Pt drug processing by Cu trafficking proteins under physiological conditions may help to answer key issues, such as drug availability in tumor cells and resistance.
24894932##2013-9-10##Successful treatment of fulminant Wilson's disease without liver transplantation.##Fulminant Wilson's disease (WD) is life-threatening. The revised WD prognostic index (RWPI) has been used to predict the severity of the disease, with a score ≥11 indicating fatal outcome without liver transplantation (LTx). We here report the case of a 10-year-old female patient with fulminant WD (RWPI, 16) who recovered fully after plasma exchange and continuous hemodiafiltration, followed by treatment with copper chelate agents. To the best of our knowledge, there have been five fulminant WD patients with RWPI ≥ 11 including the present patient, in whom LTx was not done. Based on the therapeutic modalities in these five cases, non-surgical treatment (blood purification and copper chelate agents) may be able to avoid LTx in fulminant WD even with very high RWPI, although preparation for LTx is necessary.
24717435##2012-9-19##Copper is required for oncogenic BRAF signalling and tumorigenesis.##The BRAF kinase is mutated, typically Val 600→Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAF(V600E) inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAF(V600E)-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.
24766067##2014-4-25##D-Penicillamine tripodal derivatives as efficient copper(I) chelators.##New tripodal metal-chelating agents derived from nitrilotriacetic acid (NTA) and extended by three unnatural amino acids D-penicillamine (D-Pen) are presented. D-Pen is actually the drug most extensively used to treat copper (Cu) overload in Wilson's disease and as such is a very attractive building block for the design of chelating agents. D-Pen is also a bulkier analogue of cysteine, with the β-methylene hydrogen atoms replaced by larger methyl groups. The hindrance of the gem-dimethyl group close to the thiol functions is demonstrated to influence the speciation and stability of the metal complexes. The ligands L(4) (ester) and L(5) (amide) were obtained from NTA and commercial D-Pen synthons in four and five steps with overall yields of 14 and 24%, respectively. Their ability to bind Cu(I), thanks to their three thiolate functions, has been investigated using both spectroscopic and analytical methods. UV, CD, and NMR spectroscopy and mass spectrometry evidence the formation of two Cu(I) complexes with L(5): the mononuclear complex CuL(5) and one cluster (Cu2L(5))2. In contrast, the bulkier ethyl ester derivative L(4) cannot accommodate the mononuclear complex in solution and thus forms exclusively the cluster (Cu2L(4))2. Cu K-edge X-ray absorption spectroscopy (XAS and EXAFS) confirms that Cu(I) is bound in trigonal-planar sulfur-only environments in all of these complexes with Cu- - -S distances ranging from 2.22 to 2.23 Å. Such C3-symmetric CuS3 cores are coordination modes frequently adopted in Cu(I) proteins such as metallothioneins. These two ligands bind Cu(I) tightly and selectively, which makes them promising chelators for intracellular copper detoxification in vivo.
24811000##2014-5-10##A heartbreaking case of Wilson's disease: Takotsubo cardiomyopathy complicating fulminant hepatic failure.##
24810691##2014-2-26##Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease.##
24756018##2014-4-24##A modified heterotopic auxiliary living donor liver transplantation: report of a case.##Liver transplantation is regarded as an effective treatment for Wilson's disease (WD), and recently has been shown to improve not only hepatic but also neurologic manifestations. Conventional auxiliary liver transplantation for WD is orthotopic liver transplantation and heterotopic liver transplantation. But the conventional procedure could not avoid the problem of space, functional competition, hemodynamic variation. Here we report a case of heterotopic auxiliary living-donor liver transplantation (HALDLT) to treat WD. We modified the operation to have a splenectomy, implant graft into the splenic fossa. The patient recovered well after the transplantation and has been symptom-free during a 5-year follow-up. This modified operation is more safe and simple. HALDLT might be an effective treatment for WD patients with splenomegaly.
24820353##2014-5-14##Cell therapy to remove excess copper in Wilson's disease.##To achieve permanent correction of Wilson's disease by a cell therapy approach, replacement of diseased hepatocytes with healthy hepatocytes is desirable. There is a physiological requirement for hepatic ATP7B-dependent copper (Cu) transport in bile, which is deficient in Wilson's disease, producing progressive Cu accumulation in the liver or brain with organ damage. The ability to repopulate the liver with healthy hepatocytes raises the possibility of cell therapy in Wilson's disease. Therapeutic principles included reconstitution of bile canalicular network as well as proliferation in transplanted hepatocytes, despite toxic amounts of Cu in the liver. Nonetheless, cell therapy studies in animal models elicited major differences in the mechanisms driving liver repopulation with transplanted hepatocytes in Wilson's disease versus nondiseased settings. Recently, noninvasive imaging was developed to demonstrate Cu removal from the liver, including after cell therapy in Wilson's disease. Such developments will help advance cell/gene therapy approaches, particularly by offering roadmaps for clinical trials in people with Wilson's disease.
24820352##2014-5-14##Liver transplantation for Wilson's disease.##Although Wilsons's disease (WD) may be treated with copper chelation (to remove copper) or zinc salts (to prevent absorption) to alleviate or prevent symptom development in most patients, there are WD patients for whom medical therapy is inadequate and survival would be unlikely without liver transplantation. Liver transplantation is indicated for the ∼5% of WD patients with acute liver failure as the first presentation of disease, most commonly in the second decade of life, or those who present with end-stage liver disease and severe hepatic insufficiency, most commonly in the third and fourth decades. Liver transplantation restores normal biliary copper excretion (thereby preventing disease recurrence) and promotes removal of copper from extrahepatic sites. Outcomes of liver transplantation for WD are excellent, including both cadaveric and living donors.
24754532##2014-4-22##Clinical considerations for an effective medical therapy in Wilson's disease.##Wilson's disease is an autosomal recessively inherited copper overload disorder that leads to hepatic and/or neurologic symptoms. More than a century after the first description of Wilson's disease, the available medical treatment options have not been standardized. The efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in the neurologic patients, including the risk of neurologic deterioration after the initiation of chelation therapy. An approach to overcome this problem is the careful and systematic assessment of biochemical response patterns and the quantitative monitoring of symptoms using validated rating scales. Standardized dosage strategies that address changes in copper pools might improve adherence and reduce side effects. Such an approach may reduce long-term morbidity. In this paper, we discuss considerations for an effective medical treatment and requirements for future studies in Wilson's disease.
24754424##2014-4-22##AP1S1 defect causing MEDNIK syndrome: a new adaptinopathy associated with defective copper metabolism.##MEDNIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia) syndrome has been recently described as a new disorder of copper metabolism. This multisystem disease combines clinical and biochemical signs of both Menkes and Wilson's diseases, in which liver copper overload is treatable using zinc acetate therapy. MEDNIK syndrome is caused by mutation of the AP1S1 gene, which codes for the σ1A subunit of adaptor protein complex 1, and directs intracellular trafficking of copper pumps ATP7A and ATP7B. Adaptor protein complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. A growing number of diseases have been associated with mutations in genes coding for adaptor protein complexes subunits and we propose for them the term adaptinopathies, as a new organic category of disorders of intracellular trafficking, which offers the opportunity to dissect the mechanisms involved in the crosstalk between the Golgi apparatus and the other organelles.
24731025##2014-4-14##Population screening for Wilson's disease.##Wilson's disease is an autosomal recessive disorder of copper transport caused by mutations in the gene encoding an ATPase, ATP7B. Early detection of Wilson's disease is critical because effective medical treatments such as chelating agents and zinc salts are available, which can prevent lifelong neurological disabilities and/or cirrhosis. It is unfortunate that most patients are brought to our attention after they have developed serious complications such as brain damage or cirrhosis, despite the availability of effective treatments. The diagnosis is usually made through copper measurement in the liver tissue, followed by confirmation with genetic testing of the ATP7B gene. Currently, there are no effective biomarkers or methods suitable for newborn screening for Wilson's disease. Ceruloplasmin has been tested for pediatric and newborn screening with limited outcome. Recently, liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) has emerged as a robust technology that may enable multiplex quantification of signature proteotypic peptides with low abundance. The application of this technology may help facilitate the research on Wilson's disease for protein expression, biomarker study, diagnosis, and, hopefully, screening.
24702697##2014-4-4##Modifying factors and phenotypic diversity in Wilson's disease.##Wilson's disease (WD) is a human disorder of copper homeostasis caused by mutations in the copper-transporting ATPase ATP7B. WD is characterized by copper accumulation, predominantly in the liver and brain, hepatic pathology, and wide differences between patients in the age of onset and the spectrum of symptoms. Several factors contribute to the phenotypic variability of WD. The WD-causing mutations produce a wide range of changes in stability, activity, intracellular localization, and trafficking of ATP7B; the nonpathogenic genetic polymorphisms may contribute to the phenotype. In Atp7b(-/-) mice, a mouse model of WD, an abnormal intracellular distribution of copper in the liver triggers distinct changes in the transcriptome; these mRNA profiles might be used to more specifically define disease progression. The major effect of accumulating copper on lipid metabolism and especially cholesterol homeostasis in mice and humans suggests the importance of fat and cholesterol metabolism as modifying factors in WD.
24697840##2014-2-12##Functional understanding of the versatile protein copper metabolism MURR1 domain 1 (COMMD1) in copper homeostasis.##Copper is an important cofactor in numerous biological processes in all living organisms. However, excessive copper can be extremely toxic, so it is vital that the copper level within a cell is tightly regulated. The damaging effect of copper is seen in several hereditary forms of copper toxicity in humans and animals. At present, Wilson's disease is the best-described and best-studied copper-storage disorder in humans; it is caused by mutations in the ATP7B gene. In dogs, a mutation in the COMMD1 gene has been found to be associated with copper toxicosis. Using a liver-specific Commd1 knockout mouse, the biological role of Commd1 in copper homeostasis has been confirmed. Yet, the exact mechanism by which COMMD1 regulates copper homeostasis is still unknown. Here, we give an overview of the current knowledge and perspectives on the molecular function of COMMD1 in copper homeostasis.
24697742##2014-2-12##Structural and metabolic changes in Atp7b-/- mouse liver and potential for new interventions in Wilson's disease.##Wilson's disease (WD) is caused by ATP7B mutations and results in copper accumulation and toxicity in liver and brain tissues. The specific mechanisms underlying copper toxicity are still poorly understood. Mouse models have revealed new insights into pathomechanisms of hepatic WD. Mitochondrial damage is observed in livers of WD patients and in mouse models; copper induces fragmentation of mitochondrial membrane lipids, particularly cardiolipin, with deleterious effects on both mitochondrial integrity and function. Copper accumulation also induces chronic inflammation in WD livers, which is followed by regeneration in parts of the liver and occasionally neoplastic proliferation. Gene expression studies using microarrays have aided our understanding of the molecular basis of these changes. Copper overload alters cholesterol biosynthesis in hepatocytes resulting in reduced liver and serum cholesterol. Experiments are currently underway to elucidate the link between copper and cholesterol metabolism. These findings may facilitate the development of specific therapies to ameliorate WD progression.
24628290##2014-3-14##Positron emission tomography for measurement of copper fluxes in live organisms.##Copper is an essential nutrient for the physiology of live organisms, but excessive copper can be harmful. Copper radioisotopes are used for measurement of copper fluxes in live organisms using a radioactivity assay of body fluids or whole-body positron emission tomography (PET). Hybrid positron emission tomography-computed tomography (PET/CT) is a versatile tool for real-time measurement of copper fluxes combining the high sensitivity and quantification capability of PET and the superior spatial resolution of CT for anatomic localization of radioactive tracer activity. Kinetic analysis of copper metabolism in the liver and extrahepatic tissues of Atp7b(-/-) knockout mice, a mouse model of Wilson's disease, demonstrated the feasibility of measuring copper fluxes in live organisms with PET/CT using copper-64 chloride ((64) CuCl2 ) as a radioactive tracer ((64) CuCl2 -PET/CT). (64) CuCl2 -PET/CT holds potential as a useful tool for the diagnosis of inherited and acquired human copper metabolism disorders and for monitoring the effects of copper-modulating therapy.
24611802##2014-2-24##Design of intrahepatocyte copper(I) chelators as drug candidates for Wilson's disease.##Wilson's disease is an autosomal recessive disease caused by mutations on the ATP7B gene found on chromosome 13. Since the corresponding ATPase is in charge of copper (Cu) distribution and excretion in the liver, its malfunctioning leads to Cu overload. This short review deals with treatments of this rare disease, which aim at decreasing Cu toxicity and are, therefore, based on chelation therapy. The drugs used since the 1950s are described first, then a novel approach developed in our laboratory is presented. Since the liver is the main organ of Cu distribution in the body, we targeted the pool of intracellular Cu in hepatocytes. This Cu pool is in the +1 oxidation state, and therefore soft sulfur ligands inspired from binding sites found in metallothioneins were developed. Their targeting to the hepatocytes by functionalization with ligands of the asialoglycoprotein receptor led to their cellular incorporation and intracellular Cu chelation.
24605914##2014-3-7##Current status of human hepatocyte transplantation and its potential for Wilson's disease.##Wilson's disease (WD) is a genetic disorder of liver copper excretion leading to its accumulation in various vital organs like the liver, brain, and kidneys. Drugs such as penicillamine, trientine, and zinc salts are the mainstay of treatment, with good outcomes; but nonresponders or a lack of compliance to the drug treatment can result in disease progression and acute liver failure (ALF). Current treatment for WD with ALF is an emergency liver transplantation and lifelong immunosuppression. Human hepatocyte transplantation (HTx) is increasingly used as treatment for liver-based metabolic defects. HTx may benefit WD patients with ALF, either as transient support until chelation treatment shows its effect or as a definitive cure through liver repopulation by healthy donor cells, as shown in animal models of WD. Although clinical trials of HTx have already proven safety and efficacy in different ALF etiologies, it remains to be demonstrated similarly in cases of WD.
24547944##2014-2-18##Treatment of Wilson's disease motor complications with deep brain stimulation.##A considerable proportion of patients with Wilson's disease (WD) experience neurologic symptoms that are functionally disabling. The most common neurologic problems in advanced WD include dystonia and tremor. Medically refractory idiopathic dystonia and essential tremor (ET) have been successfully treated with deep brain stimulation (DBS), functional surgical therapy targeting the globus pallidus pars interna (GPi), or the ventral intermediate (Vim) thalamic nucleus. Even though the pathophysiology of tremor is different in WD and ET, available experience supports DBS targeting the Vim for WD patients. Dystonia associated with WD is classified as secondary dystonia and GPi stimulation has yielded mixed results in these patients. The presence of structural changes in the basal ganglia may limit the therapeutic success of DBS for WD dystonia compared with idiopathic dystonia. In spite of these limitations, DBS in WD may be an effective approach to treat medically refractory residual neurologic symptoms in carefully selected patients.
24517326##2014-2-12##Pathological mitochondrial copper overload in livers of Wilson's disease patients and related animal models.##In Wilson's disease (WD) and related animal models, liver mitochondria are confronted with an increasing copper burden. Physiologically, the mitochondrial matrix may act as a dynamic copper buffer that efficiently distributes the metal to its copper-dependent enzymes. Mitochondria are the first responders in the event of an imbalanced copper homeostasis, as typical changes of their structure are among the earliest observable pathological features in WD. These changes are due to accumulating copper in the mitochondrial membranes and can be reversed by copper-chelating therapies. At the early stage, copper-dependent oxidative stress does not seem to occur. On the contrary, however, when copper is massively deposited in mitochondria, severe structural and respiratory impairments are observed upon disease progression. This provokes reactive oxygen species and consequently causes the mitochondrial membranes to disintegrate, which triggers hepatocyte death. Thus, in WD mitochondria are prime targets for copper, and the excessive copper burden causes their destruction, subsequently provoking tissue failure and death.
24517292##2014-2-12##Phenotype-genotype correlations in patients with Wilson's disease.##There is considerable phenotypic variation in Wilson's disease (WD). Some patients present with hepatic disease during the first decade of life and some with neurological degeneration in adolescence or adult life, with or without overt liver disease. Although the absence of neurologic disease in patients with liver disease in childhood or adolescence can be explained by the limited time exposure of the central nervous system to copper toxicity, it is surprising that late-onset neurologic WD can occur without any evidence of liver involvement. This huge variability in the clinical presentation of WD in general reflects our limited knowledge on the natural history of WD. Genetic association studies require the phenotype to be defined as accurately as possible.
24495036##2014-2-3##Morphological and functional imaging in neurological and non-neurological Wilson's patients.##Wilson's disease causes disturbances of the central nervous system, affecting it both directly through copper toxicity and indirectly subject to a copper-induced hepatopathy, resulting in morphological and physiological changes in brain structures that can be captured by means of magnetic resonance imaging (MRI), (123)I-β-CIT (2β-carbomethoxy-3β (4-iodophenyl)tropane)-SPECT (single photon emission computed tomography), (123)I-IBZM (benzamide)-SPECT and [(18)F]FDG -PET (fluorodeoxyglucose-positron emission tomography). MRI can reveal even slight morphological changes in non-neurological Wilson's patients. More marked findings in neurological Wilson's patients become evident in T1- and T2-weighted MRI. T1-weighted MRI predominantly detects atrophic changes, whereas T2-weighted MRI regularly records signal changes in the putamen. With the aid of these three nuclear-medicine examinations, nigrostriatal and metabolic disturbances are identified in neurological Wilson's patients only. Sufficient decoppering therapy prevents progression and even tends to improve symptoms. A correlation between any of the imaging findings in patients with the genetic phenotype and the incidence of the most common mutation H1069Q (homozygote or compound heterozygote) or other mutations could not be substantiated.
24718822##2014-4-11##Wilson disease in the South chinese han population.##
25076894##2014-6-19##Estrogen intake and copper depositions: implications for Alzheimer's disease?##We present a patient with chronic postmenopausal estrogen intake with presence of Kayser-Fleischer ring in the cornea and Alzheimer's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues, including the central nervous system. Sonography was compatible with copper accumulation in the basal ganglia, but the patient showed no clinical signs of Wilson's disease. Magnetic resonance imaging and positron emission tomography revealed a typical pattern for Alzheimer's disease. We propose increased copper levels as a direct effect of estrogen intake due to an augmented ATP7A-mRNA in the intestine. Moreover, we discuss the impact of elevated free serum copper on accompanying Alzheimer's disease, knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation. This might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and Alzheimer's disease.
25120295##2014-8-15##Wilson's disease - A rare cause of renal tubular acidosis with metabolic bone disease.##We report a 16-year-old boy who presented with weakness of lower limbs. He was diagnosed to have Wilson's disease, renal tubular acidosis and osteoporosis. Screening of siblings showed that his younger sister was also affected by the disease.
23494839##2012-9-19##Plasma exchange for hemolytic crisis and acute liver failure in Wilson disease.##Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism which primarily involves the liver and the central nervous system. Rarely, WD can present as acute liver failure (ALF) and this disease is universally fatal in the absence of liver transplantation. The authors report a young girl with WD ALF, who showed signs of recovery after prompt initiation of plasma exchange (PE) and chelation therapy. Though liver transplantation could not be done in this child and the child died 8 d after stopping PE, this case highlights that PE can be a successful medical treatment in WD ALF and should be considered as a therapeutic measure to stabilize a patient by decreasing serum copper, reducing hemolysis, and helping to prevent renal tubular injury from copper and copper complexes until liver transplantation is possible.
24220252##2013-11-14##Seven-tesla magnetic resonance imaging in Wilson disease using quantitative susceptibility mapping for measurement of copper accumulation.##
24668339##2013-12-14##MR image mimicking the "eye of the tiger" sign in Wilson's disease.##
24440710##2013-7-11##Metabolism and functions of copper in brain.##Copper is an important trace element that is required for essential enzymes. However, due to its redox activity, copper can also lead to the generation of toxic reactive oxygen species. Therefore, cellular uptake, storage as well as export of copper have to be tightly regulated in order to guarantee sufficient copper supply for the synthesis of copper-containing enzymes but also to prevent copper-induced oxidative stress. In brain, copper is of importance for normal development. In addition, both copper deficiency as well as excess of copper can seriously affect brain functions. Therefore, this organ possesses ample mechanisms to regulate its copper metabolism. In brain, astrocytes are considered as important regulators of copper homeostasis. Impairments of homeostatic mechanisms in brain copper metabolism have been associated with neurodegeneration in human disorders such as Menkes disease, Wilson's disease and Alzheimer's disease. This review article will summarize the biological functions of copper in the brain and will describe the current knowledge on the mechanisms involved in copper transport, storage and export of brain cells. The role of copper in diseases that have been connected with disturbances in brain copper homeostasis will also be discussed.
24786290##2014-2-24##Current status in the therapy of liver diseases.##Hepatic diseases, like viral hepatitis, autoimmune hepatitis, hereditary hemochromatosis, non-alcoholic fatty liver disease (NAFLD) and Wilson's disease, play an important role in the development of liver cirrhosis and, hence, hepatocellular carcinoma. In this review, the current treatment options and the molecular mechanisms of action of the drugs are summarized. Unfortunately, the treatment options for most of these hepatic diseases are limited. Since hepatitis B (HBV) and C (HCV) infections are the most common causes of liver cirrhosis and hepatocellular carcinoma, they are the focus of the development of new drugs. The current treatment of choice for HBV/HCV infection is an interferon-based combination therapy with oral antiviral drugs, like nucleos(t)ide analogues, which is associated with improving the therapeutic success and also preventing the development of resistances. Currently, two new protease inhibitors for HCV treatment are expected (deleobuvir, faldaprevir) and together with the promising drug, daclatasvir (NS5A-inhibitor, currently in clinical trials), adequate therapy is to be expected in due course (circumventing the requirement of interferon with its side-effects), while in contrast, efficient HBV therapeutics are still lacking. In this respect, entry inhibitors, like Myrcludex B, the lead substance of the first entry inhibitor for HBV/HDV (hepatitis D) infection, provide immense potential. The pharmacokinetics and the mechanism of action of Myrcludex B are described in detail.
24775716##2013-11-6##Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review.##
24706876##2014-3-24##Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B.##Wilson disease (WD) is a monogenic autosomal-recessive disorder of copper accumulation that leads to liver failure and/or neurological deficits. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. To date, most WD mutations have been shown to disrupt ATP7B activity and/or stability. Using a multidisciplinary approach, including clinical analysis of patients, cell-based assays, and computational studies, we characterized a patient mutation, ATP7B(S653Y), which is stable, does not disrupt Cu(I) transport, yet renders the protein unable to exit the TGN. Bulky or charged substitutions at position 653 mimic the phenotype of the patient mutation. Molecular modeling and dynamic simulation suggest that the S653Y mutation induces local distortions within the transmembrane (TM) domain 1 and alter TM1 interaction with TM2. S653Y abolishes the trafficking-stimulating effects of a secondary mutation in the N-terminal apical targeting domain. This result indicates a role for TM1/TM2 in regulating conformations of cytosolic domains involved in ATP7B trafficking. Taken together, our experiments revealed an unexpected role for TM1/TM2 in copper-regulated trafficking of ATP7B and defined a unique class of WD mutants that are transport-competent but trafficking-defective. Understanding the precise consequences of WD-causing mutations will facilitate the development of advanced mutation-specific therapies.
24708151##2013-5-31##A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system.##
25024581##2013-11-11##Undulating tongue in Wilson's disease.##We report an unusual occurrence of involuntary movement involving the tongue in a patient with confirmed Wilson's disease (WD). She manifested with slow, hypophonic speech and dysphagia of 4 months duration, associated with pseudobulbar affect, apathy, drooling and dystonia of upper extremities of 1 month duration. Our patient had an uncommon tongue movement which was arrhythmic. There was no feature to suggest tremor, chorea or dystonia. It might be described as athetoid as there was a writhing quality, but of lesser amplitude. Thus, the phenomenology was uncommon in clinical practice and the surface of the tongue was seen to "ripple" like a liquid surface agitated by an object or breeze. Isolated lingual dyskinesias are rare in WD. It is important to evaluate them for WD, a potentially treatable disorder.
24246766##2013-10-7##Long-term outcome for Wilson disease: 85% good.##
24076416##2013-7-10##Long-term outcomes of patients with Wilson disease in a large Austrian cohort.##
24447648##2013-8-12##D-penicillamine versus zinc sulfate as first-line therapy for Wilson's disease.##
24534570##2013-9-7##Elemental analysis of sunflower cataract in Wilson's disease: a study using scanning transmission electron microscopy and energy dispersive spectroscopy.##Signature ophthalmic characteristics of Wilson's disease (WD) are regarded as diagnostically important manifestations of the disease. Previous studies have proved the common occurrence of copper accumulation in the liver of patients with WD. However, in the case of sunflower cataracts, one of the rare diagnostic signs of WD, no study has demonstrated copper accumulation in the lens capsules of sunflower cataracts in WD patients. To investigate the nanostructure and elemental composition of sunflower cataracts in WD, transmission electron microscopy (TEM) was done on the capsulorhexised anterior lens capsule of sunflower cataracts in WD in order to evaluate anatomical variation and elemental changes. We utilized energy dispersive X-ray spectroscopy (EDS) to investigate the elemental composition of the lens capsule using both point and mapping spectroscopy. Quantitative analysis was performed for relative comparison of the elements. TEM showed the presence of granular deposits of varying size (20-350 nm), appearing mainly in the posterior one third of the anterior capsule. The deposits appeared in linear patterns with scattered dots. There were no electron-dense particles in the epithelial cell layer of the lens. Copper and sulfur peaks were consistently revealed in electron-dense granular deposits. In contrast, copper and sulfur peaks were absent in other tissues, including granule-free lens capsules and epithelial tissue. Most copper was exclusively located in clusters of electron-dense particles, and the copper distribution overlapped with sulfur on mapping spectroscopy. Quantitative analysis presented inconsistent ratios of copper to sulfur in each electron-dense granule. The mean ratio of copper to sulfur was about 3.25 (with a range of 2.39-3.78). This is the first elemental analysis of single electron particles in sunflower cataracts using EDS in the ophthalmic area. Sunflower cataracts with WD are assumed to be the result of accumulation of heterogeneous compounds composed of several materials, including copper, sulfur, and/or copper-binding proteins. Linear patterns of copper and sulfur deposition were detected in various sizes and composition ratios with these elements in cases of WD.
24002824##2013-4-12##Never forget aceruloplasminemia in case of highly suggestive Wilson's disease score.##
24577547##2014-3-1##Acute hemolytic anemia as an initial presentation of Wilson disease in children.##
24375554##2013-5-28##Relative exchangeable copper: a promising tool for family screening in Wilson disease.##
24796105##2014-5-7##[Liver diseases].##Hepatic encephalopathy is frequently accompanied by reversible cognitive impairment, while chronic acquired hepatocerebral degeneration is a rare irreversible neurological disorder in patients with liver cirrhosis, characterized by parkinsonism and cognitive decline. Patients with Wilson disease can also present cognitive deficits. Recently, it was reported that non-alcoholic fatty liver disease (NAFLD) might be a risk factor for cognitive impairment. There may be the links among obesity, type 2 diabetes mellitus, NAFLD, insulin resistance and cognitive impairment. Reduced liver biosynthesis of docosahexaenoic acid (DHA) might also contribute to cognitive decline in Alzheimer's disease. The associations between chronic liver diseases and cognitive impairment need further investigation.
24963514##2014-6-26##Major depression caused by Wilson's disease.##
24855798##2014-5-27##[Wilson Disease].##
24711028##2014-4-9##[Whole blood allele-specific PCR, a simple method to detect four ATP7B gene mutations in Wilson disease].##
24637872##2014-3-19##Liver transplantation for liver malignancies in Wilson's disease: two novel cases.##
24661374##2013-12-15##Zinc monotherapy is effective in Wilson's disease patients with mild liver disease diagnosed in childhood: a retrospective study.##
24476933##2013-8-5##A novel ATP7B gene mutation in a liver failure patient with normal ceruloplasmin and low serum alkaline phosphatase.##Wilson's disease (WD) is a rare disorder of copper metabolism resulting in accumulation of copper in liver and other organs. We present a liver failure patient, who was misdiagnosed for two years, with normal ceruloplasmin and low serum alkaline phosphatase. Molecular testing revealed a novel p.Ala982Thr mutation within ATP7B gene. The pathology of liver sample showed a large amount of copper deposition in the hepatocytes and confirmed the diagnosis of WD. Our data highlighted the importance of molecular testing in the early diagnosis of atypical WD.
24598370##2014-3-7##Liver cirrhosis in patients newly diagnosed with neurological phenotype of Wilson's disease.##
24797980##2013-4-3##Serum fetuin A concentration is elevated in children with non-alcoholic fatty liver disease.##
24580393##2014-3-4##Copper removal strategies for Wilson's disease crisis in the ICU.##Wilson's disease is a rare, inherited, autosomal recessive disorder of copper metabolism which leads to an accumulation of copper in body tissues. If a patient develops a Wilson's crisis, mortality can approach 100%. The treatment of such patients is mostly organ support but a possible treatment goal is to try to rapidly remove copper from their system. We performed a literature search on methods for de-coppering strategies for patients in intensive care with known Wilson's disease. We found 11 case reports where therapeutic plasma exchange was used and six case reports where various forms of albumin dialysis were used as techniques for rapidly reducing serum copper levels. To date, the case reports are encouraging that therapeutic plasma exchange and albumin dialysis can either delay or prevent the need for liver transplantation in patients with fulminant hepatic failure due to Wilson's disease. However, these case reports are mainly in the paediatric or young adult population, thus further studies in adults are warranted.
24552867##2014-2-21##Drug induced liver injury: accuracy of diagnosis in published reports.##The diagnosis of drug induced liver injury (DILI) is based primarily on the exclusion of alternative causes. To assess the frequency of alternative causes in initially suspected DILI cases, we searched the Medline database with the following terms: drug hepatotoxicity, drug induced liver injury, and hepatotoxic drugs. For each term, we used the first 100 publications. We reviewed references, selected those reports relevant to our study, and retrieved finally 15 publications related to DILI and alternative causes. A total of 2,906 cases of initially assumed DILI were analyzed in these 15 publications, with diagnoses missed in 14% of the cases due to overt alternative causes. In another 11%, the diagnosis of DILI could not be established because of confounding variables. Alternative diagnoses included hepatitis B, C, and E, CMV, EBV, ischemic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, Gilbert's syndrome, fatty liver, non alcoholic steatohepatitis, alcoholic liver diseases, cardiac and thyroid causes, rhabdomyolysis, polymyositis, postictal state, tumors, lymphomas, chlamydial and HIV infections. Causality assessment methods applied in these 15 publications were the CIOMS (Council for International Organizations of Medical Sciences) scale alone (n = 5) or combined with the Maria and Victorino (MV) scale (n = 1), the DILIN (Drug-Induced Liver Injury Network) method (n = 4), or the Naranjo scale (n = 1); the qualitative CIOMS method alone (n = 3) or combined with the MV scale (n = 1). In conclusion, alternative diagnoses are common in primarily suspected DILI cases and should be excluded early in future cases, requiring a thorough clinical and causality assessment.
24676446##2013-10-15##Resolution of MRI findings of copper deficiency myeloneuropathy in a patient with Wilson's disease.##
24534048##2014-2-19##Gabapentin can improve dystonia in confirmed Wilson disease.##
23601675##2013-3-24##Secondary glaucoma with copper deposition in trabecular meshwork in Wilson disease.##
24332168##2013-7-11##Microstructure assessment of the thalamus in Wilson's disease using diffusion tensor imaging.##
24635804##2014-3-19##Cutaneous disorders in liver transplant recipients.##
24901148##2014-6-6##Thirty-five consecutive pediatric living donor liver transplantation: experiences and lessons learned from a single center.##
24783132##2013-8-07##An Early Sign of Wilson's Disease: Dysarthria.##
24211743##2013-7-19##Long term results of liver transplantation for Wilson's disease: experience in France.##
24390157##2013-10-11##Parkinsonian syndrome and ataxia as a presenting finding of acquired hepatocerebral degeneration.##The term "acquired hepatocerebral degeneration" (AHD) was coined to describe clinical entity distinct from genetically defined Wilson's disease. AHD is chronic neurological disorder, characterized by extrapyramidal and neuropsychiatric symptoms accompanied with advanced liver disease with portosystemic shunts. In majority of AHD cases, extrapyramidal symptoms appear in the presence of known liver disease. Here we present a patient with subacute onset of bilateral, asymmetric, hypokinetic-rigid syndrome and ataxia as initial presentation of liver cirrhosis. Manganese toxicity have major role in AHD pathogenesis. Failure of liver detoxification and presence of portosystemic shunting enables neurotoxic substance of manganese to avoid hepatic metabolism and to enter and accumulate in central nervous system. Predilection brain regions for manganese deposits are globus pallidum (GP) and substantia nigra (SN). Characteristic MRI findings of bilateral, symmetrical hyperintensities of GP and SN on T1-weighted sequences supported the diagnosis of AHD in our patient. In addition, increased T2 signal in dendate nuclei seen in our patient is rare radiological finding. So far, no consensus guidelines regarding medical treatment of AHD exist. We initiated low-dose levodopa treatment, but failed to provide beneficial effect. In conclusion, AHD is distinct clinical entity that should be included in differential diagnosis of both typical and atypical parkinsonian syndromes. Furthermore, our case highlights the importance of performing MRI in patients with atypical parkinsonism.
24337968##2013-6-3##Redox regulation of apurinic/apyrimidinic endonuclease 1 activity in Long-Evans Cinnamon rats during spontaneous hepatitis.##The Long-Evans Cinnamon (LEC) rat is an animal model for Wilson's disease. This animal is genetically predisposed to copper accumulation in the liver, increased oxidative stress, accumulation of DNA damage, and the spontaneous development of hepatocellular carcinoma. Thus, this animal model is useful for studying the relationship of endogenous DNA damage to spontaneous carcinogenesis. In this study, we have investigated the apurinic/apyrimidinic endonuclease 1 (APE1)-mediated excision repair of endogenous DNA damage, apurinic/apyrimidinic (AP)-sites, which is highly mutagenic and implicated in human cancer. We found that the activity was reduced in the liver extracts from the acute hepatitis period of LEC rats as compared with extracts from the age-matched Long-Evans Agouti rats. The acute hepatitis period had also a heightened oxidative stress condition as assessed by an increase in oxidized glutathione level and loss of enzyme activity of glyceraldehyde 3-phosphate dehydrogenase, a key redox-sensitive protein in cells. Interestingly, the activity reduction was not due to changes in protein expression but apparently by reversible protein oxidation as the addition of reducing agents to extracts of the liver from acute hepatitis period reactivated APE1 activity and thus, confirmed the oxidation-mediated loss of APE1 activity under increased oxidative stress. These findings show for the first time in an animal model that the repair mechanism of AP-sites is impaired by increased oxidative stress in acute hepatitis via redox regulation which contributed to the increased accumulation of mutagenic AP-sites in liver DNA.
24823724##2014-5-15##Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease.##
24900138##2013-3-27##Automated Analysis of (123)I-beta-CIT SPECT Images with Statistical Probabilistic Anatomical Mapping.##
24262340##2013-7-21##Punched holes in globus pallidi: a novel neuroimaging finding in Wilson disease.##
24477071##2013-4-2##Deep-gray nuclei susceptibility-weighted imaging filtered phase shift in patients with Wilson's disease.##
24575168##2013-9-23##Association between inherited monogenic liver disorders and chronic hepatitis C.##
24555712##2013-3-5##Evidence for synergistic effects of PRNP and ATP7B mutations in severe neuropsychiatric deterioration.##
24518638##2013-4-08##Hepatitis E virus infection results in acute graft failure after liver transplantation: a case report.##Hepatitis E virus (HEV) infection in most individuals is known as a self-limiting, acute, icteric hepatitis, but evidence shows HEV is responsible for choric hepatitis and rapid progressed liver cirrhosis in immuno-compromised patients. We present the case of a patient whose diagnosis of acute graft failure was due to a HEV infection 7 years after his first liver transplantation because of Wilson's disease. The process showed severe jaundice with fatigue, poor appetite and continually rising serum aminopherase. The blood serum was found positive for the anti-HEV IgG antibody but negative for anti-HEV IgM or other infections. Cholangiole cholestasis was detected in graft biopsy. Triple hepato-protective drugs (Transmetil, Polyene Phosphatidylcholine, and Compound Ammonium Glycyrrhetate S) alongside five times Artificial Liver Support System (ALSS) did not improve the patient's condition, but the total bilirubin level rose to more than 900umol/L. So re-transplantation was performed. Blood testing shows normal liver enzymes and bilirubin with persisting anti-HEV IgG antibody positive at the 3-month follow-up.
24517502##2013-8-30##Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease.##
24499483##2014-2-7##A neuropsychological comparison of siblings with neurological versus hepatic symptoms of Wilson's Disease.##
24368744##2013-10-11##Treatment with D-penicillamine or zinc sulphate affects copper metabolism and improves but not normalizes antioxidant capacity parameters in Wilson disease.##Copper accumulation in tissues due to a biallelic pathogenic mutation of the gene: ATP7B results in a clinical phenotype known as Wilson disease (WD). Aberrations in copper homeostasis can create favourable conditions for superoxide-yielding redox cycling and oxidative tissue damage. Drugs used in WD treatment aim to remove accumulated copper and normalise the free copper concentration in the blood. In the current study the effect of decoppering treatment on copper metabolism and systemic antioxidant capacity parameters was analyzed. Treatment naïve WD patients (TNWD) (n = 33), those treated with anti-copper drugs (TWD) (n = 99), and healthy controls (n = 99) were studied. Both TNWD and TWD patients characterised with decreased copper metabolism parameters, as well as decreased total antioxidant potential (AOP), glutathione (GSH) level, activity of catalase, glutathione peroxidase (GPx), and S-transferase glutathione, compared to controls. TWD patients had significantly lower copper metabolism parameters, higher total AOP and higher levels of GSH than TWD individuals; however, no difference was observed between these two patient groups with respect to the rest of the antioxidant capacity parameters. Patients who had undergone treatment with D-penicillamine or zinc sulphate did not differ with respect to copper metabolism or antioxidant capacity parameters, with the exception of GPx that was lower in D-penicillamine treated individuals. These data suggest that anti-copper treatment affects copper metabolism as well as improves, but does not normalize, natural antioxidant capacity in patients with WD. We propose to undertake studies aimed to evaluate the usefulness of antioxidants as well as selenium as a supplemental therapy in WD.
24253677##2013-10-7##In silico investigation of the ATP7B gene: insights from functional prediction of non-synonymous substitution to protein structure.##ATP7B is a copper-transporting ATPase that plays a key role in the regulation of copper homeostasis. Mutations in the ATP7B gene are causative for Wilson's disease, and recent reports have suggested that genetic variants are associated with susceptibility to Alzheimer's disease. Unfortunately, it is difficult to profile experimentally novel genetic variants in the ATP7B gene, because the human protein X-ray structure is not yet entirely understood. In order to investigate ATP7B non-synonymous substitutions, we used an in silico amino acid sequence-based approach. Specifically, we analyzed 337 ATP7B non-synonymous substitutions, which included Wilson's disease-causing mutations (DVs) and non Wilson's disease-causing variants (NDVs), with an algorithm that estimated a combined probability (cPdel) of an amino acidic change to be deleterious for the protein function. This approach appeared to reliably indentify the probability of DVs and NDVs to be deleterious and to profile still unknown gene variants. Specifically, after analyzing ATP7B protein domains with the cPdel method, we found results in line with the predicted-modeled domains and some new suggestions. In conclusion, a functional survey of amino acid changes in the ATP7B protein is provided herein, and we suggest that this bioinformatic method can furnish information about novel ATP7B mutations. Furthermore, the same approach can be applied to other uncharacterized proteins.
24470583##2014-1-29##Bilateral hypertrophic olivary nucleus degeneration on magnetic resonance imaging in children with Leigh and Leigh-like syndrome.##
24653660##2013-6-15##Genetic variants in diseases of the extrapyramidal system.##Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagno-sis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson's or Huntington's. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich's disease, ataxia with ocu-lomotorapraxia, Huntington's disease, dystonia type 1, Wilson's disease, and some cases of Parkinson's disease.
24220304##2013-11-12##Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease.##Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD. Female C3H control and tx-j mice were fed control (choline 8 mmol/Kg of diet) or choline-supplemented (choline 36 mmol/Kg of diet) diets for 2 weeks throughout mating and pregnancy to gestation day 17. A second group of C3H females, half of which were used to cross foster tx-j pups, received the same diet treatments that extended during lactation to 21 d postpartum. Compared with C3H, fetal tx-j livers had significantly lower copper concentrations and significantly lower transcript levels of Cyclin D1 and genes related to methionine and lipid metabolism. Maternal choline supplementation prevented the transcriptional deficits in fetal tx-j liver for multiple genes related to cell growth and metabolism. Global DNA methylation was increased by 17% in tx-j fetal livers after maternal choline treatment (P<0.05). Maternal dietary choline rescued the lower body weight of 21 d tx-j mice. Our results suggest that WD pathogenesis is modified by maternal in utero factors, including dietary choline.
24313946##2013-7-16##Compliant treatment with anti-copper agents prevents clinically overt Wilson's disease in pre-symptomatic patients.##
23962630##2012-7-19##Pathogenic compound heterozygous ATP7B mutations with hypoceruloplasminaemia without clinical features of Wilson's disease.##The authors report a 44-year-old man with a history of attention deficit and hyperactivity disorder, obsessive compulsive behaviour, vocal tics, depression, and anxiety, in whom a compound heterozygous ATP7B mutation was found, associated with hypoceruloplasminemia, but without clinical or pathological manifestation of Wilson's disease (WD). Genetic testing revealed a compound heterozygous ATP7B mutation already described in WD, p.Met645Arg (C1934TG/c.51+4A→T). Hypoceruloplasminaemia was detected but no clinical manifestations (hepatic or central nervous system) of WD were present. The authors conclude that patients can carry a heterozygous mutation of the ATP7B gene that is associated with hypoceruloplasminaemia and display no overt clinical hepatic and/or central nervous system manifestations of WD.
24033813##2013-7-26##Factors that predict mortality in children with Wilson disease associated acute liver failure and comparison of Wilson disease specific prognostic indices.##
24458219##2014-1-25##Effect of molecular adsorbents recirculating system treatment in children with acute liver failure caused by Wilson disease.##
25130000##2014-8-19##Biochemical staging of the chronic hepatic lesions of Wilson disease.##
24107488##2013-12-6##Comprehensive analysis on clinical features of Wilson's disease: an experience over 28 years with 133 cases.##
24067922##2013-6-6##Potent and long-lasting inhibition of human P2X2 receptors by copper.##P2X receptors are ion channels gated by ATP. In rodents these channels are modulated by zinc and copper. Zinc is co-released with neurotransmitter at some synapses and can modulate neuronal activity, but the role of copper in the brain is unclear. Rat P2X2 receptors show potentiation by 2-100 μM zinc or copper in the presence of a submaximal concentration of ATP but are inhibited by zinc or copper at concentrations above 100 μM. In contrast, human P2X2 (hP2X2) receptors show no potentiation and are strongly inhibited by zinc over the range of 2-100 μM. The effect of copper on hP2X2 is of interest because there are human brain disorders in which copper concentration is altered. We found that hP2X2 receptors are potently inhibited by copper (IC50 = 40 nM). ATP responsiveness recovered extremely slowly after copper washout, with full recovery requiring over 1 h. ATP binding facilitated copper binding but not unbinding from this inhibitory site. A mutant receptor in which the first six extracellular cysteines were deleted, C(1-6)S, showed normal copper inhibition, however reducing agents dramatically accelerated recovery from copper inhibition in wild type hP2X2 and the C(1-6)S mutant, indicating that the final two disulfide bonds are required to maintain the high affinity copper binding site. Three histidine residues required for normal zinc inhibition were also required for normal copper inhibition. Humans with untreated Wilson's disease have excess amounts of copper in the brain. The high copper sensitivity of hP2X2 receptors suggests that they are non-functional in these patients.
24283623##2013-10-24##Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry.##LDLT is indicated for a variety of metabolic disorders, primarily in Asian countries due to the absolute scarcity of deceased donor LT. We analyzed data for all pediatric LDLTs performed between November 1989 and December 2010, during which 2224 pediatric patients underwent LDLT in Japan. Of these patients, 194 (8.7%) underwent LDLT for metabolic disorders. Wilson's disease (n = 59; 30.4%) was the most common indication in the patients with metabolic disorders, followed by OTCD (n = 40; 20.6%), MMA (n = 20; 10.3%), and GSD (n = 15; 7.7%). The one-, five-, 10-, and 15-yr patient and graft survival rates were 91.2%, 87.9%, 87.0%, and 79.3%, and 91.2%, 87.9%, 86.1%, and 74.4%, respectively. Wilson's disease and urea cycle deficiency were associated with better patient survival. The use of heterozygous donors demonstrated no negative impact on either the donors or recipients. With regard to X-linked OTCD, symptomatic heterozygote maternal donors should not be considered potential donor candidates. Improving the understanding of the long-term suitability of this treatment modality will require the registration and ongoing evaluation of all patients with inherited metabolic disease considered for LT.
24918128##2014-6-12##Acute liver failure in Turkey: a systematic review.##
24375922##2013-9-2##Translocation of platinum anticancer drugs by human copper ATPases ATP7A and ATP7B.##Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance. Down-regulation of CTR1 and up-regulation of the Cu-ATPases, ATP7A and ATP7B, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on the COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, and adsorbed on a solid supported membrane. The experimental results indicate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation in a fashion similar to that of Cu. We then used NMR spectroscopy and ESI-MS to determine the binding mode of these drugs to the first N-terminal metal-binding domain of ATP7A (Mnk1).
24450973##2013-12-9##Pathogenesis and management of Wilson disease.##
24404914##2013-10-18##Detection of D-penicillamine in skin lesions in a case of dermal elastosis after a previous long-term treatment for Wilson's disease.##
24744820##2013-12-12##Chorea, Hyperglycemia, Basal Ganglia Syndrome (C-H-BG) in an uncontrolled diabetic patient with normal glucose levels on presentation.##
25250203##2014-7-10##Diagnosis of abnormal biliary copper excretion by positron emission tomography with targeting of (64)Copper-asialofetuin complex in LEC rat model of Wilson's disease.##Identification by molecular imaging of key processes in handling of transition state metals, such as copper (Cu), will be of considerable clinical value. For instance, the ability to diagnose Wilson's disease with molecular imaging by identifying copper excretion in an ATP7B-dependent manner will be very significant. To develop highly effective diagnostic approaches, we hypothesized that targeting of radiocopper via the asialoglycoprotein receptor will be appropriate for positron emission tomography, and examined this approach in a rat model of Wilson's disease. After complexing (64)Cu to asialofetuin we studied handling of this complex compared with (64)Cu in healthy LEA rats and diseased homozygous LEC rats lacking ATP7B and exhibiting hepatic copper toxicosis. We analyzed radiotracer clearance from blood, organ uptake, and biliary excretion, including sixty minute dynamic positron emission tomography recordings. In LEA rats, (64)Cu-asialofetuin was better cleared from blood followed by liver uptake and greater biliary excretion than (64)Cu. In LEC rats, (64)Cu-asialofetuin activity cleared even more rapidly from blood followed by greater uptake in liver, but neither (64)Cu-asialofetuin nor (64)Cu appeared in bile. Image analysis demonstrated rapid visualization of liver after (64)Cu-asialofetuin administration followed by decreased liver activity in LEA rats while liver activity progressively increased in LEC rats. Image analysis resolved this difference in hepatic activity within one hour. We concluded that (64)Cu-asialofetuin complex was successfully targeted to the liver and radiocopper was then excreted into bile in an ATP7B-dependent manner. Therefore, hepatic targeting of radiocopper will be appropriate for improving molecular diagnosis and for developing drug/cell/gene therapies in Wilson's disease.
24403508##2014-1-10##Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells.##
24895535##2014-3-11##Treatment of nongout joint deposition diseases: an update.##This update develops the actual therapeutic options in the management of the joint involvement of calcium pyrophosphate deposition disease (CPPD), basic calcium phosphate (BCP) deposition disease, hemochromatosis (HH), ochronosis, oxalosis, and Wilson's disease. Conventional pharmaceutical treatment provides benefits for most diseases. Anti-interleukine-1 (IL-1) treatment could provide similar results in CPPD than in gout flares. There is only limited evidence about the efficacy of preventive long-term colchicine intake, methotrexate, and hydroxychloroquine in chronic CPPD. Needle aspiration and lavage have satisfactory short and midterm results in BCP. Extracorporeal shockwave therapy has also proved its efficacy for high-doses regimes. Phlebotomy does not seem to have shown real efficacy on joint involvement in HH so far. Iron chelators' effects have not been assessed on joint involvement either, while IL-1 blockade may prove useful. NSAIDs have limited efficacy on joint involvement of oxalosis, while colchicine and steroids have not been assessed either. The use of nitisinone for ochronotic arthropathy is still much debated, but it could provide beneficial effects on joint involvement. The effects of copper chelators have not been assessed either in the joint involvement of Wilson's disease. NSAIDs should be avoided because of the liver affection they may worsen.
24895611##2013-12-23##The copper radioisotopes: a systematic review with special interest to 64Cu.##Copper (Cu) is an important trace element in humans; it plays a role as a cofactor for numerous enzymes and other proteins crucial for respiration, iron transport, metabolism, cell growth, and hemostasis. Natural copper comprises two stable isotopes, (63)Cu and (65)Cu, and 5 principal radioisotopes for molecular imaging applications ((60)Cu, (61)Cu, (62)Cu, and (64)Cu) and in vivo targeted radiation therapy ((64)Cu and (67)Cu). The two potential ways to produce Cu radioisotopes concern the use of the cyclotron or the reactor. A noncopper target is used to produce noncarrier-added Cu thanks to a chemical separation from the target material using ion exchange chromatography achieving a high amount of radioactivity with the lowest possible amount of nonradioactive isotopes. In recent years, Cu isotopes have been linked to antibodies, proteins, peptides, and nanoparticles for preclinical and clinical research; pathological conditions that influence Cu metabolism such as Menkes syndrome, Wilson disease, inflammation, tumor growth, metastasis, angiogenesis, and drug resistance have been studied. We aim to discuss all Cu radioisotopes application focusing on (64)Cu and in particular its form (64)CuCl2 that seems to be the most promising for its half-life, radiation emissions, and stability with chelators, allowing several applications in oncological and nononcological fields.
25276143##2014-7-15##Fulminant Wilson's Disease Managed with Plasmapheresis as a Bridge to Liver Transplant.##New-onset jaundice can be a manifestation of multiple pathologic processes including hemolysis, parenchymal liver disease, and cholestasis; the differential diagnosis is broad and requires a systematic approach. We report a case of a patient who presented with jaundice after starting minocycline for the treatment of acne vulgaris and rapidly developed fulminant liver failure found to be due to Wilson's disease. She also manifested severe Coomb's negative hemolytic anemia and renal failure secondary to hepatorenal syndrome. As a bridge to liver transplant, she was successfully treated with plasmapheresis to decrease serum copper in addition to hemodialysis for acidosis and hyperkalemia. She was able to receive a liver and made a full recovery. The case highlights the use of plasmapheresis as an adjunctive treatment modality in cases of fulminant liver failure due to Wilson's disease.
24697127##2014-4-5##Fulminant hepatic failure with virtually undetectable serum alkaline phosphatase.##Wilson's disease presenting as fulminant hepatic failure is a rare presentation that carries a high morbidity and mortality. We report a young patient who developed fulminant hepatic failure as the initial manifestation of Wilson's disease. Virtually undetectable serum alkaline phosphatase provided the first clue to the diagnosis. Our patient underwent a successful liver transplantation which is the only effective treatment in patients with Wilsonian fulminant hepatic failure. In this report, we discuss laboratory clues to the diagnosis of this form of Wilson's disease. Clinicians should have a high suspicion of Wilson's disease as any delay in diagnosis can be catastrophic.
24808725##2014-2-16##Reappraisal of the etiology of extracorpuscular non-autoimmune acquired hemolytic anemia in 2657 hospitalized patients with non-neoplastic disease.##
24317333##2013-12-10##Measurement of real-time tissue elastography in a phantom model and comparison with transient elastography in pediatric patients with liver diseases.##
24356057##2013-6-25##Worsening of Wilson disease following penicillamine therapy.##
24904274##2014-4-03##Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders.##Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na(+)/K(+)-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
24639652##2014-1-24##Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism.##Iron, copper, zinc, and eight other minerals are classified as essential trace elements because they present in minute in vivo quantities and are essential for life. Because either excess or insufficient levels of trace elements can be detrimental to life (causing human diseases such as iron-deficiency anemia, hemochromatosis, Menkes syndrome and Wilson's disease), the endogenous levels of trace minerals must be tightly regulated. Many studies have demonstrated the existence of systems that maintain trace element homeostasis, and these systems are highly conserved in multiple species ranging from yeast to mice. As a model for studying trace mineral metabolism, the zebrafish is indispensable to researchers. Several large-scale mutagenesis screens have been performed in zebrafish, and these screens led to the identification of a series of metal transporters and the generation of several mutagenesis lines, providing an in-depth functional analysis at the system level. Moreover, because of their developmental advantages, zebrafish have also been used in mineral metabolism-related chemical screens and toxicology studies. Here, we systematically review the major findings of trace element homeostasis studies using the zebrafish model, with a focus on iron, zinc, copper, selenium, manganese, and iodine. We also provide a homology analysis of trace mineral transporters in fish, mice and humans. Finally, we discuss the evidence that zebrafish is an ideal experimental tool for uncovering novel mechanisms of trace mineral metabolism and for improving approaches to treat mineral imbalance-related diseases.
25014046##2014-7-12##Liver cirrhosis in patients newly diagnosed with neurological phenotype of Wilson's disease.##Wilson's disease (WD) can manifest itself in different clinical forms, the neurological and hepatic ones being the most common. It is suggested that neurological signs and psychiatric symptoms develop secondary to liver involvement. The aim of this study was to characterize the liver disease in patients newly diagnosed with the neurological form of WD. Treatment-naive patients diagnosed with WD were classified into three phenotypic groups: hepatic, neurological and pre-symptomatic. Liver involvement was ascertained through surrogate markers: abdominal ultrasound and laboratory parameters. In addition, study participants were screened for esophageal varices. Of 53 consecutively diagnosed WD patients, 23 individuals (43.4%) had a predominantly neurological presentation. In this group, cirrhosis was diagnosed in 11 (47.8%) subjects. Esophageal varices were present in all of them. In every patient with neurological WD, there was at least one sign of hepatic disease on ultrasound examination, indicating universal presence of liver involvement. The prevalence of surrogate signs of cirrhosis was similar in patients with the neurological and in those with the hepatic phenotype.
24120023##2013-6-24##Psychiatric aspects of Wilson disease: a review.##
24365357##2013-12-25##Disorders of heavy metals.##Heavy metals and trace elements play an important role in relation to the physiology and pathology of the nervous system. Neurologic diseases related to disorders of metabolism of copper and iron are reviewed. Copper disorders are divided into two classes: ATP7A- or ATP7B-related inherited copper transport disorders (Menkes disease, occipital horn syndrome, ATP7A-related distal motor neuropathy, and Wilson disease) and acquired diseases associated with copper deficiency or copper excess. Iron brain disorders are divided into genetic neurodegeneration with brain iron accumulation (NBIA, neuroferritinopathy, and aceruloplasminemia), genetic systemic iron accumulation with neurologic features (hemochromatosis), and acquired diseases associated with iron excess (superficial siderosis) or iron deficiency (restless leg syndrome). The main features of cadmium, lead, aluminum, mercury, and manganese toxicity are summarized.
24365342##2013-12-25##Neurologic manifestations of malabsorption syndromes.##Although malabsorption is generally considered to be a gastrointestinal problem, the effects of malabsorption extend far beyond the gastrointestinal tract and can include neurologic dysfunction. Malabsorption may occur by a variety of mechanisms, both genetic and acquired, that interfere with the absorption of basic nutrients, vitamins, minerals, and trace elements. Disorders that interfere with fat absorption can lead to neurologic dysfunction as a consequence of associated impairment of fat-soluble vitamin absorption. Thus, individuals with genetic vitamin E deficiency and the familial hypocholesterolemias may develop symptoms of peripheral neuropathy, cerebellar ataxia, and other neurologic signs and symptoms. Disease processes that damage the enteric mucosa and produce malabsorption can trigger neurologic dysfunction both by immune-related processes, as in celiac disease, and by impairing absorption of essential vitamins and other nutrients, as in tropical sprue. Deficiencies of water-soluble vitamins, such as thiamine and niacin, can also develop in the setting of malabsorption and lead to neurologic dysfunction. Neurologists are aware of the neurologic damage that copper excess can cause in Wilson's disease, but copper deficiency due to malabsorption can also produce neurologic dysfunction in the form of myelopathy. It is vitally important for neurologists to be aware of the potential for malabsorptive processes to produce neurologic dysfunction, because effective treatment for such disorders is often available.
24734161##2013-10-19##Family screening for a novel ATP7B gene mutation, c.2335T>G, in the South of Iran.##
23774950##2013-2-21##Concordance rates of Wilson's disease phenotype among siblings.##Wilson's disease (WD) is an autosomal recessive disorder characterized by the functional disruption of adenosine triphosphatase 7B (ATP7B), which results in positive copper balance. Although the primary manifestations of the disease are hepatic or neurological in scope, the factors that cause a very diverse picture of WD are not well researched. We compared the first clinical presentation, ages of onset and diagnosis, copper metabolism parameters, and ceruloplasmin levels between index cases (ICs) and their siblings. We examined 73 ICs and 95 siblings from 73 families, including a total of 168 patients with biochemical and genetically confirmed WD diagnoses. We observed an 86% concordance rate of primary clinical symptoms among ICs with hepatic symptoms and their siblings. There was 66% concordance among ICs with neurological symptoms and their siblings. No differences regarding age at onset of symptoms or copper metabolism parameters at diagnosis were identified between hepatic ICs and their siblings. The age at symptom onset did not differ between neurological ICs and their siblings, although ICs presented lower ceruloplasmin and serum copper levels. These results demonstrate a high intra-familial concordance of the clinical and biochemical presentation of WD, suggesting that similar factors shared within the same families strongly influence the disease presentation.
24515687##2014-2-12##Control of mania with chelation-only in a case of Wilson's disease.##
24188895##2012-8-7##Assessment of trace elements in human brain using inductively coupled plasma mass spectrometry.##Recent brain research reveals a major role of trace elements in various diseases such as multiple sclerosis, Alzheimer's and Wilson's disease. The majority of published tissue concentrations dates back decades, and was assessed with various methods. Little is known about hemispherical differences, the correlation of trace elements or age-dependent changes in the human brain. Thus, the aim of this study was to examine trace element concentrations in different human brain regions after whole brain formalin fixation. 549 samples of 13 brain regions were investigated in 11 deceased subjects without known history of brain pathology. Regional wet-to-dry mass ratios and concentrations of iron, copper, magnesium, manganese, calcium and zinc were determined using inductively coupled plasma mass spectrometry. Cortical gray matter revealed higher water content (wet-to-dry mass ratios 5.84-6.40) than white matter regions (wet-to-dry mass ratios 2.95-3.05). Element concentrations displayed specific regional differences. Good linear correlation of concentrations between elements was found for iron/copper as well as for manganese/magnesium (Spearman's rank correlation coefficient 0.74 and 0.65, respectively). Significant inter-hemispherical differences were found for copper in occipital white matter, for magnesium and calcium in putamen and for iron and copper in temporal white matter. An age dependent increase was seen in cortical gray matter for calcium, for magnesium in all regions except in cortical gray matter, for copper in substantia nigra and for zinc in occipital cortex. The presented trace element concentrations can serve as a fundamental basis for further brain research. Wet-to-dry mass ratios allow a comparison with reference data from other studies.
24120082##2013-4-22##Polymorphisms of metal transporter genes DMT1 and ATP7A in Wilson's disease.##Wilson's disease (WND) is an inherited disorder of copper metabolism. Divalent metal transporter1 (DMT1) and ATP7A play important roles in metal transport in humans. The frequency of two single nucleotide polymorphisms of the DMT1 gene: DMT1 IVS4 C>A, DMT1 11245 T>C and two of the ATP7A gene: rs1062472 T>C, ATP7A rs 2227291 G>C have been evaluated in a population of 108 Wilson's disease patients and 108 sex- and age-matched healthy volunteers. The DMT1 IVS4 C(+) allele occurred more frequently in WND than in the healthy controls. The allele frequencies of other studied polymorphisms in WND group were in line with frequencies obtained for healthy volunteers. Neither of the polymorphisms had an impact on the age at onset or clinical phenotype of WND.
24266916##2013-10-28##Metal storage disorders: Wilson disease and hemochromatosis.##Hereditary hemochromatosis and Wilson disease are autosomal recessive storage disorders of iron and copper overload, respectively. These metals are involved in multiple redox reactions, and their abnormal accumulation can cause significant injury in the liver and other organs. Over the last few decades clinicians have developed a much better understanding of these metals and their mechanism of action. Moreover, sophisticated molecular genetic testing techniques that make diagnostic testing less invasive are now available. This article updates and discusses the pathogenesis, diagnosis, and management of these metal storage disorders.
24829700##2013-9-22##Causes of Persistently Elevated Alanine Aminotransferase Levels in Patients who Presented to Two Referral Hospitals in Mashhad, Iran during 2011.##BACKGROUND Worldwide, chronic liver disease is a major cause of morbidity and mortality. Causes of elevated serum alanine aminotransferase (ALT) levels vary depending on the population under study. The aim of this study is to evaluate the frequency and causes of persistently elevated ALT levels in patients of the Gastroenterology (GI) Clinics in Ghaem and Emam Reza Hospitals in Mashhad, Iran. METHODS A total of 100 consecutive patients with persistently elevated ALT levels that referred to the GI Clinics at Ghaem and Emam Reza Hospitals in 2011 were studied. Elevated levels were defined as ALT ≥40 U/L at least twice within six months. A comprehensive history that included previous surgeries, transfusion, alcohol consumption and medications was obtained. Patients underwent physical examinations, laboratory analyses and ultrasonography studies. When necessary, liver biopsies were performed. RESULTS Patients' mean age was 44.4 ± 11.83 years. Females comprised 62% of cases. Patients presented with the following conditions: non-alcoholic fatty liver disease (NAFLD, 55%), hepatitis B (17%), autoimmune hepatitis (13%), hepatitis C (4%), autoimmune hepatitis and hepatitis C (2%), overlapping autoimmune disease (2%), Wilson disease (1%), celiac disease (1%), alcoholiche patitis (1%), primary biliary cirrhosis (PBC, 1%), primary sclerosing cholangitis (PSC, 1%), and cryptogenic (2%). CONCLUSION NAFLD was the most common cause of persistently elevated serum ALT levels in this study.
24038543##2013-1-29##Prominent extensor truncal dystonia in Egyptian patients with Wilson's disease.##
24584398##2014-3-4##Neurologic manifestations, diagnosis and management of Wilson's disease in children - an update.##Wilson's disease (WD) is a genetic disorder of copper (Cu) metabolism. It is a progressive hepatolenticular degenerative disease due to toxic accumulation of copper in the various tissues particularly in the liver, brain and eyes. The neurologic manifestations of Wilson's disease are extremely varied like simple behavioral change such as irritability, depression, deterioration of school performance to severe form of neurologic presentations like dystonia, dysarthria, tremor and gait disturbance. Early diagnosis is possible by history of progressive neurologic dysfunction, clinical examination of Kayser Flescher rings (K-F rings) in eyes, along with some important investigations like low serum ceruloplasmin, high 24 hours urinary excretion of copper, presence of basal ganglia lesion in neuro imaging of the brain. Though hepatic copper estimation done by liver biopsy is the gold standard, is not available in Bangladesh. Most of the neurodegenerative diseases have no specific treatment and worse outcome. But it has a specific treatment with life long medication that reduces copper absorption or removes the excess copper from the body. Children on therapy must be monitored regularly for response, side effects and compliance. The aim of this article is to gather update information of neurologic manifestations of Wilson's disease and proper management as well to prevent the major neurological complications and better out come.
24343273##2013-12-18##Interference of CuO nanoparticles with metal homeostasis in hepatocytes under sub-toxic conditions.##Copper oxide nanoparticles (CuO-NP) were studied for their toxicity and mechanism of action on hepatocytes (HepG2), in relation to Cu homeostasis disruption. Indeed, hepatocytes, in the liver, are responsible for the whole body Cu balance and should be a major line of defence in the case of exposure to CuO-NP. We investigated the early responses to sub-toxic doses of CuO-NP and compared them to equivalent doses of Cu added as salt to see if there is a specific nano-effect related to Cu homeostasis in hepatocytes. The expression of the genes encoding the Cu-ATPase ATP7B, metallothionein 1X, heme oxygenase 1, heat shock protein 70, superoxide dismutase 1, glutamate cysteine ligase modifier subunit, metal responsive element-binding transcription factor 1 and zinc transporter 1 was analyzed by qRT-PCR. These genes are known to be involved in response to Cu, Zn and/or oxidative stresses. Except for MTF1, ATP7B and SOD1, we clearly observed an up regulation of these genes expression in CuO-NP treated cells, as compared to CuCl2. In addition, ATP7B trafficking from the Golgi network to the bile canaliculus membrane was observed in WIF-B9 cells, showing a need for Cu detoxification. This shows an increase in the intracellular Cu concentration, probably due to Cu release from endosomal CuO-NP solubilisation. Our data show that CuO-NP enter hepatic cells, most probably by endocytosis, bypassing the cellular defence mechanism against Cu, thus acting as a Trojan horse. Altogether, this study suggests that sub-toxic CuO-NP treatments induce successively a Cu overload, a Cu-Zn exchange on metallothioneins and MTF1 regulation on both Cu and Zn homeostasis.
24317491##2013-5-23##Copper-transporting P-type ATPases use a unique ion-release pathway.##Heavy metals in cells are typically regulated by PIB-type ATPases. The first structure of the class, a Cu(+)-ATPase from Legionella pneumophila (LpCopA), outlined a copper transport pathway across the membrane, which was inferred to be occluded. Here we show by molecular dynamics simulations that extracellular water solvated the transmembrane (TM) domain, results indicative of a Cu(+)-release pathway. Furthermore, a new LpCopA crystal structure determined at 2.8-Å resolution, trapped in the preceding E2P state, delineated the same passage, and site-directed-mutagenesis activity assays support a functional role for the conduit. The structural similarities between the TM domains of the two conformations suggest that Cu(+)-ATPases couple dephosphorylation and ion extrusion differently than do the well-characterized PII-type ATPases. The ion pathway explains why certain Menkes' and Wilson's disease mutations impair protein function and points to a site for inhibitors targeting pathogens.
24981187##2014-3-6##Symptomatic copper deficiency in three Wilson's disease patients treated with zinc sulphate.##Wilson's disease (WD) is caused by excess of copper that leads to accumulation of copper mainly in the liver, brain and needs life-long decoppering therapy. However, overtreatment with anti-copper agents may lead to copper deficiency which may cause neurological and hematological symptoms. Copper is an important cofactor for many enzymes. This report describes three WD patients with diagnosed copper deficiency during zinc sulphate (ZS) treatment. After 5-16 years of therapy all patients developed leucopenia. Spinal cord injury was manifested in two of the patients. One of them also presented myopathy. In conclusion, copper deficiency may occur in different time after treatment onset, therefore regular copper metabolism and hematological monitoring is necessary.
24342654##2013-11-10##Copper toxicity induced hepatocerebral and neurodegenerative diseases: an urgent need for prognostic biomarkers.##Copper (Cu) has been the subject of intensive research over several decades as numerous evidence robustly support the involvement of excess Cu induced neurotoxicity in hepatocerebral (Wilson's disease) and neurodegenerative disorders (especially Alzheimer's disease and Parkinson's disease); notwithstanding, the ideal Cu neurotoxicity biomarker/s for early prognosis remains elusive. Non-ceruloplasmin bound Cu is a biological marker of Wilson's disease and recent studies have shown that its levels are also increased in Alzheimer's disease. Copper chaperone for superoxide dismutase seems to be the other most promising biomarker of Cu toxicity (subject to its validation). Serum/plasma Cu, urine Cu and ceruloplasmin concentrations, most widely used laboratory indicators to diagnose Wilson's disease, are not specific for Cu excess milieu as these are also influenced by age, sex, inflammation and hormonal status. High inter-individual variability, nonexistence of standardized assays and non-specificity limit the use of other cuproenzymes as biomarkers of Cu neurotoxicity. The majority of Cu neurotoxicity biomarker research has focused in plasma/serum where other factors including inflammation, oxidative stress, dietary and environmental factors influence the Cu condition being studied. Proteomics study of cerebrospinal fluid, due to its high specificity and sensitivity represents an alternative approach to study early peripheral Cu neurotoxicity biomarker/s in experimental animals. In addition, network biology, transcriptomics in conjunction with novel in vivo Cu imaging techniques allow us to explore other potential candidates and propose new targets to be studied for chronic Cu neurotoxicity biomarker/s, and for possible therapeutic interventions.
24107714##2013-2-5##Study of corneal copper deposits in Wilson's disease by in vivo confocal microscopy.##
24932333##2013-1-13##[Nodular hepatic tuberculosis: unusual complication during Wilson's disease].##
24262164##2013-11-23##Movement disorders in childhood.##The aim of this article is to review movement disorders in children. They are common but have etiology and phenomenology different than in adults. Tics are the most common phenomena although in most instances they are mild and have a favorable long-term prognosis. Dystonia is the second most common phenomena but when present it is usually genetic or idiopathic and causes meaningful disability. Sydenham's chorea is the most common cause of chorea in children worldwide. Systemic lupus erythematosus is a much rarer cause of chorea but it is always to be ruled out given the lack of a specific diagnostic marker for Sydenham's chorea. Tremor, usually caused by drugs or essential tremor, is regarded as rather uncommon in children. Arguably, most pediatric patients with tremor do not seek medical attention because of the lack of disability. Stereotypies are relatively uncommon but their recognition is clinically relevant since they are usually associated with severe conditions such as autism and Rett syndrome. Parkinsonism is quite rare in children and either results from encephalitis or is a side effect of medications. Wilson's disease must be ruled out in all children with movement disorders.
24094725##2013-6-25##Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation.##Wilson disease (WD) is caused by defects in ATP7B gene due to impairment of normal function of the copper transporting P-type ATPase. This study describes a comprehensive genetic analysis of 199 Indian WD patients including mutations detected in our previous studies, undertakes functional assessment of the nucleotide variants in ATP7B promoter and correlates genotype with disease phenotype. The patient cohort harbors a total of 10 common and 48 rare mutations in the coding region of ATP7B including 21 novel changes. The common mutations represent 74% of characterized coding mutant alleles with p.C271X (63/260) and p.G1101R (7/31) being the most prevalent in eastern and western Indian patients, respectively. The mutation spectrum between east and west is mostly different with only three mutations (p.G1061E, p.N1270S and p.A1049A-fs) being shared between both the groups. Eight novel and 10 reported variants have been detected in the promoter and non-coding regions (5' and 3'UTRs) of ATP7B. Promoter reporter assay demonstrated that 3 novel variants and 5 reported polymorphisms alter the gene expression to a considerable extent; hence might play important role in ATP7B gene regulation. We devised the neurological involvement score to capture the spectrum of neurological involvement in WD patients. By utilizing the age at onset, neurological involvement score and ATP7B mutation background, we generated a genotype-phenotype matrix that could be effectively used to depict the phenotypic spectra of WD affected individuals and serve as a platform to identify prospective "outliers" to be investigated for their remarkable phenotypic divergence.
24949936##2014-2-12##Selective impairment of attentional networks of alerting in Wilson's disease.##Wilson's disease (WD) is typically affected by attention, which is one of the cognitive domains. The Attention Network Test (ANT) was developed to measure the functioning of the following three individual attentional networks: orienting, alerting, and executive control. The ANT has been used in a variety of neuropsychiatric conditions; however, it has not been used in WD. The aim of this study was to investigate the attentional function of WD patients, and 35 patients with early and moderate neurological WD, as well as 35 gender-, age-, and education-matched healthy controls performed the ANT. Remarkable differences between the patients and healthy controls were observed in the alerting network (p = 0.007) in contrast the differences in the orienting (p = 0.729) and executive control (p = 0.888) networks of visual attention. The mean reaction time in the ANT was significantly longer in the WD patients than in the controls (p<0.001, 0.001). In the WD patients, there was an effect specifically on the alerting domain of the attention network, whereas the orienting and executive control domains were not affected.
24897373##2014-3-8##Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity.##Wilson's disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson's disease ever reported of 1 ∶ 1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18 ± 1 years) showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson's disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson's disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.
24892424##2014-2-28##The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line.##Mutations in the copper (Cu) transporter gene ATP7B, the primary cause of Wilson disease (WD), result in high liver Cu and death of hepatocytes. Cu chelators and zinc salts are the two most important drugs used in the treatment of WD patients; however, the molecular mechanisms of the drugs with regard to ATP7B expression have not been determined. A targeted knockout of ATP7B (KO) was established in the most widely used human hepatoma cell line, HepG2 for molecular studies of the pathogenesis and treatment of the disease. KO cells showed similar growth, Cu uptake, release, and gene expression as compared to parental cells. However, in the presence of Cu, morphological changes, oxidative stress, apoptosis, and loss of viability were observed. Induction of metallothionein (MT1X) after Cu exposure was significantly reduced in KO cells. Following zinc treatment, MT1X expression was strongly induced and a high percentage of KO cells could be rescued from Cu induced toxicity. D-penicillamine treatment had a minor effect on the viability of KO cells whereas the parental cell line showed a pronounced improvement. Combined treatment displayed a highly synergistic effect in KO cells. The data suggest that zinc has a previously unrecognized effect on the viability of hepatocytes that lack ATP7B due to a high induction of MT1X expression that compensates low gene expression after Cu exposure. A combination therapy that simultaneously targets at MT1X induction and Cu chelation improves the overall survival of hepatocytes for most efficient therapy of patients having WD.
24475083##2013-8-10##Zinc mono-therapy in pre-symptomatic Chinese children with Wilson disease: a single center, retrospective study.##
24798599##2014-5-7##Wilson's disease.##(Full text is available at http://www.manu.edu.mk/prilozi). Wilson's disease (WD) is a disorder of copper transport resulting from the defective function of a copper transporting P-type ATPase, ATP7B. The WD incidence is approximately 1/50-10,000 live births worldwide. Clinical manifestations of WD may be of any kind, but usually the symptoms of presentation are hepatic or neuropsychiatric, with a vast range of disturbances for both groups of symptoms. In children, however, clinical symptoms may be absent, making the diagnosis of the disease more difficult than in adults. Hepatic manifestations may range from asymptomatic minor biochemical disturbances, to acute, but mostly chronic, hepatitis, cirrhosis or severe fulminant hepatic failure. The spectrum of neurological manifestations is wide, including tremor, hypersalivation, Dysarthria, coordination defects, dystonia, ataxia. The spectrum of psychiatric manifestations is considerable and may include different disturbances such as altered working performance, anxiety, depression and antisocial behaviour. Kayser-Fleischer rings (KF) are present in 95% of patients with neurological symptoms and somewhat over half of those without neurological symptoms. In children presenting with liver disease, KF rings are usually absent. To obtain a more reliable diagnosis of WD, the Leipzig scoring system was proposed by an international consensus of experts. Wilson's disease copper overload is treated with chelating agents such as penicillamine, trientine and tetrathiomolybdate. Zinc is used mostly for mantainance therapy or the treatment of asymptomatic WD patients. Key words: Wilson diseases, copper, cirrhosis, children.
24378118##2013-9-18##Fetal hypoplastic left heart syndrome and maternal liver transplantation for Wilson's disease: a case report.##
23877843##2013-7-23##Role of p38 Mapk in development of acute hepatic injury in Long-Evans Cinnamon (LEC) rats, an animal model of human Wilson's disease.##The Long-Evans Cinnamon (LEC) rat, an animal model of human Wilson's disease, spontaneously develops fulminant hepatitis associated with severe jaundice at about 4 months of age. In this study, we examined the changes in gene expression during progression of acute hepatic injury. When levels of gene expression in the liver of LEC rats at 13 weeks of age were compared to those in rats at 4 weeks of age using oligonucleotide arrays, 1,620 genes out of 7,700 genes analyzed showed more than 2-fold differences. Expression levels of 11 of 29 genes related to stress-activating protein kinase (SAPK) changed by more than 2-fold in the liver of LEC rats, but none of the SAPK-related genes showed changes in expression levels in the liver of control rats. Activity of p38 mapk in the liver of LEC rats at 13 weeks of age was about 8.1-fold higher than that in rats at 4 weeks of age. When LEC rats were administered SB203580, a p38 mapk-specific inhibitor, by s.c. injection twice a week from 10 to 13 weeks of age, activities of p38 mapk in the liver, activities of AST and ALT and concentrations of bilirubin in sera of rats administered SB203580 significantly decreased compared to those in rats not administered. These results showed that the increase in activities of p38 mapk was related to the occurrence of acute hepatic injury in LEC rats.
23541064##2013-5-3##Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-κB pathway in a transgenic mouse model of Alzheimer's disease.##
24697006##2014-4-5##Wilson's disease in pregnancy.##Wilson's disease is a rare autosomal recessive disorder of copper metabolism. It causes cirrhosis of the liver, consequently followed by disorder of the menstrual cycle and infertility. Successful decopperizing may lead to restoration of the ovulatory cycle and enable pregnancy. Increased copper levels may cause preeclampsia, intrauterine growth restriction and neurologic damages in the fetus. Pregnant women with decompensated liver cirrhosis face more complications, including bleeding from esophageal varices, liver failure, encephalopathy, and rupture of the splenic artery. We present a case of Wilson's disease in a patient who had spontaneously conceived three times. The first pregnancy ended with delivery of a healthy baby at term. In second pregnancy, medically induced abortion was performed in the 12th week because of deterioration of the underlying disease, liver cirrhosis with portal hypertension. In the same year, the patient underwent liver transplantation. Two years after the transplantation, the patient spontaneously conceived and delivered vaginally a healthy child.
24207084##2013-3-13##Gastrointestinal and liver disease in pregnancy.##This chapter on the gastrointestinal and hepatic systems in pregnancy focusses on those conditions that are frequent and troublesome (gastro-oesophageal reflux and constipation), distressing (hyperemesis gravidarum) or potentially fatal (obstetric cholestasis, acute fatty liver of pregnancy and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome). It also highlights the clinical challenge obstetricians may face in managing rare conditions such as the Budd-Chiari syndrome, liver transplantation, primary biliary cirrhosis and Wilson disease. The clinical presentation of liver and gastrointestinal dysfunction in pregnancy is not specific, and certain 'abnormalities' may represent physiological changes of pregnancy. Diagnosis and management are often difficult because of atypical symptoms, a reluctance to use invasive investigations and concerns about the teratogenicity of the medications. The best available evidence to manage these conditions is discussed in the chapter.
23963605##2013-3-12##Intestinal expression of metal transporters in Wilson's disease.##In Wilson's disease (WND), biallelic ATP7B gene mutation is responsible for pathological copper accumulation in the liver, brain and other organs. It has been proposed that copper transporter 1 (CTR1) and the divalent metal transporter 1 (DMT1) translocate copper across the human intestinal epithelium, while Cu-ATPases: ATP7A and ATP7B serve as copper efflux pumps. In this study, we investigated the expression of CTR1, DMT1 and ATP7A in the intestines of both WND patients and healthy controls to examine whether any adaptive mechanisms to systemic copper overload function in the enterocytes. Duodenal biopsy samples were taken from 108 patients with Wilson's disease and from 90 controls. CTR1, DMT1, ATP7A and ATP7B expression was assessed by polymerase chain reaction and Western blot. Duodenal CTR1 mRNA and protein expression was decreased in WND patients in comparison to control subjects, while ATP7A mRNA and protein production was increased. The variable expression of copper transporters may serve as a defense mechanism against systemic copper overload resulting from functional impairment of ATP7B.
23849977##2013-1-21##A pilot study of autologous CD34-depleted bone marrow mononuclear cell transplantation via the hepatic artery in five patients with liver failure.##
24369002##2013-4-26##Multiple osteochondritis dissecans of knee joint in a patient with Wilson disease, focusing on magnetic resonance findings.##A 17-year-old man was admitted with a complaint of knee pain. He was diagnosed with Wilson disease by ophthalmologic and laboratory studies during hospitalization. Initial plain radiography of both knees showed multiple osteochondritis dissecans (OCD) on the medial and lateral femoral condyles of both knees. Subsequent magnetic resonance imaging showed multiple OCDs, which were symmetric on both knees. Subchondral cysts on the medial condyle and trochlear dysplasia were additionally evident on both femurs. We report this case with a focus on the imaging findings.
24176139##2013-9-11##Brain cholesterol homeostasis in Wilson disease.##Wilson disease (WD) is an autosomal recessive inherited disorder of copper (Cu) metabolism, resulting in pathological accumulation of Cu in many organs and tissues, predominantly in the liver and brain. There clearly is a close and complex relationship between Cu and the cholesterol's metabolic pathway; therefore any theory about the cholesterol metabolism in the brain of patients with WD must take it into account. The hypothesis presented in this paper is that the imbalance in cerebral copper homeostasis caused by WD may plays a key role in the derangement of the cholesterol homeostasis in the brain, and thus promoting the observed WD related neurological disorders.
24511518##2013-11-29##Abnormality on liver function test.##Children with abnormal liver function can often be seen in outpatient clinics or inpatients wards. Most of them have respiratory disease, or gastroenteritis by virus infection, accompanying fever. Occasionally, hepatitis by the viruses causing systemic infection may occur, and screening tests are required. In patients with jaundice, the tests for differential diagnosis and appropriate treatment are important. In the case of a child with hepatitis B virus infection vertically from a hepatitis B surface antigen positive mother, the importance of the recognition of immune clearance can't be overstressed, for the decision of time to begin treatment. Early diagnosis changes the fate of a child with Wilson disease. So, screening test for the disease should not be omitted. Non-alcoholic fatty liver disease, which is mainly discovered in obese children, is a new strong candidate triggering abnormal liver function. Muscular dystrophy is a representative disease mimicking liver dysfunction. Although muscular dystrophy is a progressive disorder, and early diagnosis can't change the fate of patients, it will be better to avoid parent's blame for delayed diagnosis.
24239345##2013-10-15##[Foreword. Wilson's disease].##
24125461##2013-2-28##Samuel Alexander Kinnier Wilson. Wilson's disease, Queen Square and neurology.##This historical article describes the life and work of the British physician Samuel Alexander Kinnier Wilson (1878-1937), who was one of the world's greatest neurologists of the first half of the 20th century. Early in his career, Wilson spent one year in Paris in 1903 where he learned from Pierre-Marie at Bicêtre Hospital. He subsequently retained uninterrupted links with French neurology. He also visited in Leipzig the German anatomist Paul Flechsig. In 1904, Wilson returned to London, where he worked for the rest of his life at the National Hospital for the Paralysed and Epileptic (later the National Hospital for Nervous Diseases, and today the National Hospital for Neurology and Neurosurgery) in Queen Square, and also at Kings' College Hospital. He wrote on 'the old motor system and the new', on disorders of motility and muscle tone, on the epilepsies, on aphasia, apraxia, tics, and pathologic laughing and crying, and most importantly on Wilson's disease. The other objective of our paper is to commemorate the centenary of Wilson's most important work published in 1912 in Brain, and also in Revue Neurologique, on an illness newly recognized and characterized by him entitled "Progressive lenticular degeneration, a familial nervous disease associated with liver cirrhosis". He analyzed 12 clinical cases, four of whom he followed himself, but also four cases previously published by others and a further two that he considered in retrospect had the same disease as he was describing. The pathological profile combined necrotic damage in the lenticular nuclei of the brain and hepatic cirrhosis. This major original work is summarized and discussed in the present paper. Wilson not only delineated what was later called hepato-lenticular degeneration and Wilson's disease, but also introduced for the first time the terms extrapyramidal syndrome and extrapyramidal system, stressing the role of the basal ganglia in motility. The present historical work emphasizes the special contributions made by Wilson to the study of movement disorders, including akinesia and bradykinesia in Parkinson's disease, and their relation to basal ganglia pathology.
24120329##2013-3-12##Cognitive profile in Wilson's disease: a case series of 31 patients.##
24119853##2013-3-28##Wilson's disease, 100 years later….##Texts published, in 1912, 100 years ago, by Sir K. Wilson on his eponymous disease in Brain, The Lancet and La Revue Neurologique highlight the relevance of his descriptions in the light of the current knowledge. Wilson's invocation of an "unknown toxin" appears today as a prophetic intuition as the presence of excess copper in the liver was mentioned for the first time a year later whereas the role of copper in this disease was not described until 1929. Progress has been made to better understand the physiology of Wilson's disease (WD). The ATP7B gene implicated in WD is located on chromosome 13 and more than 500 mutations and 100 polymorphisms have been to date identified. The phenotypic expression is highly variable, even within a family. This can partly be explained by environmental factors as nutrition. Modulator genes are also involved in the phenotypic expression of the disease. Most of symptoms observed in WD have already been described in detail by Wilson in 1912, but subsequent progress was made over the following 100 years, helping the physician diagnose WD. Hepatic and neurological symptoms are the most frequent expressions of the disease. Other extrahepatic features include renal manifestations, osteoarticular disorders, myocardial abnormalities, endocrine disturbances, realizing a multisystemic disease. The diagnosis of the disease is based on a combination of clinical symptoms, biological, radiological and genetic data and new tools (Brain MRI, relative exchangeable copper…) allow reducing delay to diagnosis. Therapeutic findings have also changed the disease prognosis. Treatment is based on the use of copper chelators to promote copper excretion from the body (D-penicillamine and Triethylenetetramine) and zinc salts to reduce copper absorption. Tetratiomolybdate appears to be a promising treatment. While significant progress has been made during this century, many physiological aspects of this disease remain unknown and require further research to find answers in the next 100 years.
24164422##2013-10-28##Uneven distribution of hepatic copper concentration and diagnostic value of double-sample biopsy in Wilson's disease.##BACKGROUND AND AIMS. Determination of hepatic copper (Cu) concentration is important in Wilson's disease (WD) diagnosis. The aim of this study was to evaluate uneven distribution of liver Cu concentration and the utility of double-sample biopsy in WD diagnosis. METHODS. Thirty-five WD patients (20 male; mean age 41 ± 9 years) were enrolled in the study and double-liver samples for biopsy were obtained. A further 30 WD patients, in whom Cu determination was performed using single-liver samples, were also enrolled as controls. RESULTS. A marked difference in hepatic Cu concentration was observed between the two sample groups (p < 0.0001). This difference is statistically significant for all levels of liver fibrosis (p < 0.001) and for the comparison of hepatic and neurological phenotypes (p < 0.01). The sensitivity of the Cu concentrations obtained from the double-sample biopsies for the conventional cut-off value of 250 mg/g dry weight of tissue was 85.7% compared to 80% in the single-sample biopsies. By lowering the cut-off value from 250 to 50 µg/g of dry weight of tissue, the sensitivity of Cu content to diagnose WD increased to 97% for double-sample liver biopsy compared to 93% for single-sample liver biopsy. CONCLUSIONS. Liver Cu content was unevenly distributed in the WD subjects, irrespective of fibrosis levels and disease phenotypes; hence WD can be misdiagnosed using single-sample liver Cu measurement. Double-sample biopsy sensitivity is greater than that obtained with single-sample biopsy and should therefore be considered to evaluate liver Cu concentration at initial diagnosis in all patients.
24303094##2013-6-17##Diagnostic challenges of Wilson's disease presenting as acute pancreatitis, cholangitis, and jaundice.##Wilson's disease is a rare disorder of copper transport in hepatic cells, and may present as cholestatic liver disease; pancreatitis and cholangitis are rarely associated with Wilsons's disease. Moreover, cases of Wilson's disease presenting as pigmented gallstone pancreatitis have not been reported in the literature. In the present report, we describe a case of a 37-year-old man who was admitted with jaundice and abdominal pain. The patient was diagnosed with acute pancreatitis, cholangitis, and obstructive jaundice caused by pigmented gallstones that were detected during retrograde cholangiopancreatography. However, because of his long-term jaundice and the presence of pigmented gallstones, the patient underwent further evaluation for Wilson's disease, which was subsequently confirmed. This patient's unique presentation exemplifies the overlap in the clinical and laboratory parameters of Wilson's disease and cholestasis, and the difficulties associated with their differentiation. It suggests that Wilson's disease should be considered in patients with pancreatitis, cholangitis, and severe protracted jaundice caused by pigmented gallstones.
24282352##2013-6-10##Liver diseases in pregnancy: diseases not unique to pregnancy.##Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver. Liver disease can cause significant morbidity and mortality in both pregnant women and their infants. Few challenges arise in reaching an accurate diagnosis in light of such physiological changes. Laboratory test results should be carefully interpreted and the knowledge of what normal changes to expect is prudent to avoid clinical misjudgment. Other challenges entail the methods of treatment and their safety for both the mother and the baby. This review summarizes liver diseases that are not unique to pregnancy. We focus on viral hepatitis and its mode of transmission, diagnosis, effect on the pregnancy, the mother, the infant, treatment, and breast-feeding. Autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, Budd Chiari and portal vein thrombosis in pregnancy are also discussed. Pregnancy is rare in patients with cirrhosis because of the metabolic and hormonal changes associated with cirrhosis. Variceal bleeding can happen in up to 38% of cirrhotic pregnant women. Management of portal hypertension during pregnancy is discussed. Pregnancy increases the pathogenicity leading to an increase in the rate of gallstones. We discuss some of the interventions for gallstones in pregnancy if symptoms arise. Finally, we provide an overview of some of the options in managing hepatic adenomas and hepatocellular carcinoma during pregnancy.
24118554##2013-9-5##Outcome and development of symptoms after orthotopic liver transplantation for Wilson disease.##
24119323##2013-7-16##Zinc monotherapy and a low-copper diet are beneficial in patients with Wilson disease after liver transplantation.##
23921268##2013-8-8##MRI of diffuse liver disease: the common and uncommon etiologies.##Diffuse liver disease, including all causes of chronic liver disease, affects tens of millions of people worldwide. There is a growing need for diagnostic evaluation as treatments become more readily available, particularly for viral liver disease. Magnetic resonance imaging (MRI) provides unique capabilities for noninvasive characterization of liver tissue that rival or surpass the diagnostic utility of liver biopsies. There has been incremental improvement in the use of standardized MRI sequences, acquired before and after administration of contrast for the evaluation of diffuse liver disease, and this includes study of the liver parenchyma and blood supply. More recent developments have led to methods for quantifying important liver metabolites, including fat and iron, and liver fibrosis, which is the hallmark for chronic liver disease. In this study, we review the MRI techniques and diagnostic features associated with common and uncommon etiologies of diffuse liver diseases, including processes that lead to abnormal perfusion (e.g. Budd-Chiari syndrome, congestive hepatomegaly), deposition diseases (e.g. fatty liver, hemochromatosis, Wilson's disease), and abnormalities that are related to inflammation and fibrosis (e.g. primary sclerosing cholangitis, sarcoidosis).
23486543##2012-9-26##The homozygosity index (HI) approach reveals high allele frequency for Wilson disease in the Sardinian population.##Wilson disease (WD) is an autosomal recessive disorder resulting in pathological progressive copper accumulation in liver and other tissues. The worldwide prevalence (P) is about 30/million, while in Sardinia it is in the order of 1/10,000. However, all of these estimates are likely to suffer from an underdiagnosis bias. Indeed, a recent molecular neonatal screening in Sardinia reported a WD prevalence of 1:2707. In this study, we used a new approach that makes it possible to estimate the allelic frequency (q) of an autosomal recessive disorder if one knows the proportion between homozygous and compound heterozygous patients (the homozygosity index or HI) and the inbreeding coefficient (F) in a sample of affected individuals. We applied the method to a set of 178 Sardinian individuals (3 of whom born to consanguineous parents), each with a clinical and molecular diagnosis of WD. Taking into account the geographical provenance of the parents of every patient within Sardinia (to make F computation more precise), we obtained a q=0.0191 (F=7.8 × 10(-4), HI=0.476) and a corresponding prevalence P=1:2732. This result confirms that the prevalence of WD is largely underestimated in Sardinia. On the other hand, the general reliability and applicability of the HI approach to other autosomal recessive disorders is confirmed, especially if one is interested in the genetic epidemiology of populations with high frequency of consanguineous marriages.
24374999##2013-12-31##Does brain degeneration in Wilson disease involve not only copper but also iron accumulation?##
24036231##2013-4-18##A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases.##The past decade has witnessed an explosion of evidence suggesting that many neurodegenerative diseases can be detected years, if not decades, earlier than previously thought. To date, these scientific advances have not provoked any parallel translational or clinical improvements. There is an urgency to capitalize on this momentum so earlier detection of disease can be more readily translated into improved health-related quality of life for families at risk for, or suffering with, neurodegenerative diseases. In this review, we discuss health-related quality of life (HRQOL) measurement in neurodegenerative diseases and the importance of these "patient reported outcomes" for all clinical research. Next, we address HRQOL following early identification or predictive genetic testing in some neurodegenerative diseases: Huntington disease, Alzheimer's disease, Parkinson's disease, Dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, prion diseases, hereditary ataxias, Dentatorubral-pallidoluysian atrophy and Wilson's disease. After a brief report of available direct-to-consumer genetic tests, we address the juxtaposition of earlier disease identification with assumed reluctance toward predictive genetic testing. Forty-one studies examining health-related outcomes following predictive genetic testing for neurodegenerative disease suggested that (a) extreme or catastrophic outcomes are rare; (b) consequences commonly include transiently increased anxiety and/or depression; (c) most participants report no regret; (d) many persons report extensive benefits to receiving genetic information; and (e) stigmatization and discrimination for genetic diseases are poorly understood and policy and laws are needed. Caution is appropriate for earlier identification of neurodegenerative diseases but findings suggest further progress is safe, feasible and likely to advance clinical care.
23842488##2013-7-9##The acute haemolytic syndrome in Wilson's disease--a review of 22 patients.##An analysis of 321 case notes of patients with Wilson's disease seen between 1955 and 2000 and one case seen in 1949 has revealed that 22 patients presented with a haemolytic crisis. This study was not a specific research project but a retrospective analysis of 321 patients with Wilson's disease seen between 1949 and 2000. All investigations were carried out in the best interests of diagnosis and management of patients referred to my clinic. The delay in diagnosis in 18 cases resulted in progression to severe hepatic disease in 14 cases and to neurological disease in 4 cases. One patient had no symptoms at the time her sister's illness was diagnosed as Wilson's disease. In a second patient, with liver disease, the diagnosis was also made when a sister was found to have Wilson's disease. There was a female to male ratio of 15:7. The average age of onset was 12.6 years and the incidence 6.9%. Delay in diagnosis resulted in nine deaths. Three patients, late in the series, were admitted in the acute phase, two female and one male; of these two responded to chelation therapy, the third required liver transplantation. Haemolysis appeared to be extravascular, and possible mechanisms of the haemolysis are discussed.
24146181##2012-2-13##Isolated persistent elevation of alanine transaminase for early diagnosis of pre-symptomatic Wilson's disease in Chinese children.##
24483109##2014-2-4##[Research on the correlation between Chinese medical syndrome types and objective indices of Wilson's disease].##
23675861##2013-5-29##Small pH and salt variations radically alter the thermal stability of metal-binding domains in the copper transporter, Wilson disease protein.##Although strictly regulated, pH and solute concentrations in cells may exhibit temporal and spatial fluctuations. Here we study the effect of such changes on the stability, structure, and dynamics in vitro and in silico of a two-domain construct (WD56) of the fifth and sixth metal-binding domains of the copper transport protein, ATP7B (Wilson disease protein). We find that the thermal stability of WD56 is increased by 40 °C when increasing the pH from 5.0 to 7.5. In contrast, addition of salt at pH 7.2 decreases WD56 stability by up to 30 °C. In agreement with domain-domain coupling, fractional copper loading increases the stability of both domains. HSQC chemical shift changes demonstrate that, upon lowering the pH from 7.2 to 6, both His in WD6 as well as the second Cys of the copper site in each domain become protonated. MD simulations reveal increased domain-domain fluctuations at pH 6 and in the presence of high salt concentration, as compared to at pH 7 and low salt concentration. Thus, the surface charge distribution at high pH contributes favorably to overall WD56 stability. By introducing more positive charges by lowering the pH, or by diminishing charge-charge interactions by salt, fluctuations among the domains are increased and thereby overall stability is reduced. Copper transfer activity also depends on pH: delivery of copper from chaperone Atox1 to WD56 is more efficient at pH 7.2 than at pH 6 by a factor of 30. It appears that WD56 is an example where the free energy landscapes for folding and function are linked via structural stability.
24145882##2013-10-23##Extensive striatal, cortical, and white matter brain MRI abnormalities in Wilson disease.##
24139602##2012-11-28##Wilson's disease in pregnancy: case series and review of literature.##
23973307##2013-6-16##Alterations of cortical excitability and central motor conduction time in Wilson's disease.##Wilson's disease (WD) leads to widespread structural alterations of central nervous system and our objectives were to determine the cortical excitability changes in WD by using transcranial magnetic stimulation (TMS). Thirteen patients with WD, diagnosed by the presence of Kayser-Fleischer ring and biochemical tests, were studied. TMS was performed using a figure-of-eight coil attached to Magstim 200 stimulator. Motor evoked potentials (MEP) were recorded from right first dorsal interosseous at rest. Resting motor threshold (RMT) was determined using standard techniques and central motor conduction time (CMCT) by 'F' wave method. Comparison was made with control data of our laboratory. Dysarthria was the presenting symptom in 5 patients (38.5%) and chorea, tremors, dystonia and abnormal gait in 2 patients each (15.4%). RMT was recordable in 10 patients and not recordable in 3. Compared to controls, patients in whom RMT was recordable, had significantly higher mean RMT (80.9 ± 14.8 vs. 41.1 ± 7, p<0.0001) and CMCT (6.7 ± 0.5 ms vs. 4.8 ± 0.6 ms; p<0.0001). In 2 of the 3 patients with non-recordable RMT, MEP could be obtained with active contraction. CMCT in these 2 patients was also prolonged. Patients with WD have reduced cortical excitability and prolonged CMCT which may be due to the intracortical presynaptic motor dysfunction.
23953876##2012-12-24##The overuse of serum ceruloplasmin measurement.##
24142730##2013-5-3##Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease.##The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy.
24070537##2013-9-28##50 Years Ago in The Journal of Pediatrics: hepatolenticular degeneration: observations on a case treated with D-penicillamine.##
23903872##2013-8-2##What can flies tell us about copper homeostasis?##Copper (Cu) is an essential redox active metal that is potentially toxic in excess. Multicellular organisms acquire Cu from the diet and must regulate uptake, storage, distribution and export of Cu at both the cellular and organismal levels. Systemic Cu deficiency can be fatal, as seen in Menkes disease patients. Conversely Cu toxicity occurs in patients with Wilson disease. Cu dyshomeostasis has also been implicated in neurodegenerative disorders such as Alzheimer's disease. Over the last decade, the fly Drosophila melanogaster has become an important model organism for the elucidation of eukaryotic Cu regulatory mechanisms. Gene discovery approaches with Drosophila have identified novel genes with conserved protein functions relevant to Cu homeostasis in humans. This review focuses on our current understanding of Cu uptake, distribution and export in Drosophila and the implications for mammals.
23636000##2013-5-02##Perioperative management of Wilson disease for therapeutic abortion: a report.##
23877404##2013-3-27##Neurochemical and behavioral characteristics of toxic milk mice: an animal model of Wilson's disease.##Toxic milk mice have an inherited defect of copper metabolism. Hepatic phenotype of the toxic milk mice is similar to clinical findings in humans suffering from Wilson's disease (WND). In the present study, neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of WND. Mice aged 2 and 12 months were used in the experiment. The mice were tested according to rotarod and footprint protocols. Monoamine content in brain structures was measured by high performance liquid chromatography. In order to detect neuronal loss, expression of enzymes specific for dopaminergic [tyrosine hydroxylase (TH)], noradrenergic (dopamine beta-hydroxylase) and serotoninergic [tryptophan hydroxylase (TPH)] neurons was analyzed by Western blot. The 12-month-old toxic milk mice demonstrated impaired locomotor performance in behavioral tests. Motor deficits were accompanied by increased copper and serotonin content in different brain regions and slight decrease in dopamine concentration in the striatum. The expression of TH, dopamine beta-hydroxylase and TPH in the various brain structures did not differ between toxic milk mice and control animals. Despite differences in brain pathology between humans and rodents, further exploration of neuronal injury in toxic milk mice is warranted to broaden the understanding of neuropathology in WND.
23999958##2013-9-2##Spasmodic muscle cramps and weakness as presenting symptoms in Wilson disease.##Wilson disease (WD) is an autosomal-recessive disorder of hepatic copper metabolism that has tremendous variability in its presentation. Phenotypic diversity of the disease can lead to delayed diagnosis. We describe a case of WD in a 10-year-old boy presenting with 3 months of increasingly intense, spasmodic lower extremity muscle cramps. Physical examination revealed tenderness on calf palpation and dark flat lesions over his ankles, knees, and elbows. Initial testing revealed creatine kinase of 302 IU/L (normal 24-248 IU/L), hemoglobin of 8.9 g/dL (11.5-15.5 g/dL), aspartate aminotransferase of 114 IU/L (16-52 IU/L), alanine aminotransferase of 54 IU/L (2-30 IU/L), and myoglobinuria. Extensive evaluation of his myopathy, including MRI and muscle biopsy, was negative. Additional laboratory tests revealed a prothrombin time of 21.3 seconds (11.8-15.5 seconds), total bilirubin of 1.4 mg/dL (<1 mg/dL), direct bilirubin of 0.5 mg/dL (<0.3 mg/dL), albumin of 2.1 g/dL (3.1-4.6 g/dL), a reticulocyte percentage of 4.5% (0.5%-2.5%), a negative Coombs direct antibody test, ceruloplasmin of 3 mg/dL (21-51 mg/dL), and 24-h urine copper of 393 μg/24 h (15-60 μg/24 h). Liver biopsy showed patchy advanced fibrosis, mild inflammation, positive staining for copper, and a tissue copper concentration of 768 µg/g (10-35 μg/g). Brain MRI revealed symmetric intrinsic T1 shortening within bilateral basal ganglia. Trientene therapy was initiated for WD. Symptoms and laboratory abnormalities resolved and remain normal at 21 months' follow-up. Musculoskeletal involvement in WD is uncommon and typically defined as bone demineralization, arthropathy, or hypokalemic muscle weakness. In patients with unexplained musculoskeletal symptoms and hepatic abnormalities, a diagnosis of WD should be considered and appropriate evaluation initiated.
24505222##2013-8-08##Intracranial lesions with high signal intensity on T1-weighted MR images - review of pathologies.##In the article we present pathological intracranial substances and lesions, which produce high signal intensity on T1-weighted MR images. Six groups of substances are discussed: 1. Gadolinium - based contrast agents, 2.hemoglobin degradation products (intra- and extra-cellular methemoglobin), 3. lipid-containing lesions (lipoma, dermoid cyst, implanted fatty materials, laminar cortical necrosis), 4. substances with high concentration of proteins (colloid cyst, craniopharyngioma, Rathke's cleft cyst, ectopic posterior pituitary gland), 5. melanin (metastatic melanoma), 6. lesions containing mineral substances such as: calcium (calcifications, Fahr's disease), copper (Wilson's disease) and manganese (hepatic encephalopathy, manganese intoxication in intravenous drug abusers). Appropriate interpretation of signal intensity as well as analysis of location of lesions and clinical symptoms enables planning of further diagnostics and, in many cases, establishing the final diagnosis based on MR examination.
24081601##2013-10-2##Hepatocellular carcinoma in a young man with resting and postural tremors.##A 25-year-old man who was normally fit and well, presented with a 2-year history of progressively worsening tremor. His tremor was generalised, affecting head, neck and all four limbs. One of the patient's brothers had suffered from similar problems, but never sought medical attention. Examination revealed a generalised tremor, of greater amplitude on the patient's left side, which increased in its amplitude upon exertion. Slit-lamp examination revealed bilateral Kayser-Fleischer rings and serum caeruloplasmin was found to be low, while 24 h urinary copper excretion was elevated. A diagnosis of Wilson's disease was made and an abdominal ultrasound was performed, revealing evidence of portal hypertension and a hyperechoic hepatic nodule, later confirmed to be hepatocellular carcinoma. The patient underwent partial hepatic resection and was started on D-penicillamine.
24067156##2012-9-21##Unusual epileptic deterioration and extensive white matter lesion during treatment in Wilson's disease.##
23843626##2013-7-10##The cytosolic chaperone α-crystallin B rescues folding and compartmentalization of misfolded multispan transmembrane proteins.##The α-crystallin B chain (CRYAB or HspB5) is a cytosolic chaperone belonging to the small heat shock protein family, which is known to help in the folding of cytosolic proteins. Here we show that CRYAB binds the mutant form of at least two multispan transmembrane proteins (TMPs), exerting an anti-aggregation activity. It rescues the folding of mutant Frizzled4, which is responsible for a rare autosomal dominant form of familial exudative vitreoretinopathy (Fz4-FEVR), and the mutant ATP7B Cu transporter (ATP7B-H1069Q) associated with a common form of Wilson's disease. In the case of Fz4-FEVR, CRYAB prevents the formation of inter-chain disulfide bridges between the lumenal ectodomains of the aggregated mutant chains, which enables correct folding and promotes appropriate compartmentalization on the plasma membrane. ATP7B-H1069Q, with help from CRYAB, folds into the proper conformation, moves to the Golgi complex, and responds to copper overload in the same manner as wild-type ATP7B. These findings strongly suggest that CRYAB plays a pivotal role, previously undetected, in the folding of multispan TMPs and, from the cytosol, is able to orchestrate folding events that take place in the lumen of the ER. Our results contribute to the explanation of the complex scenario behind multispan TMP folding; additionally, they serve to expose interesting avenues for novel therapeutic approaches.
24023303##2013-9-12##Utility of ATP7B in prediction of response to platinum-based chemotherapy in urothelial bladder cancer.##
23846821##2013-6-28##Golgi in copper homeostasis: a view from the membrane trafficking field.##Copper is essential for a variety of important biological processes as a cofactor and regulator of many enzymes. Incorporation of copper into the secreted and plasma membrane-targeted cuproenzymes takes place in Golgi, a compartment central for normal copper homeostasis. The Golgi complex harbors copper-transporting ATPases, ATP7A and ATP7B that transfer copper from the cytosol into Golgi lumen for incorporation into copper-dependent enzymes. The Golgi complex also sends these ATPases to appropriate post-Golgi destinations to ensure correct Cu fluxes in the body and to avoid potentially toxic copper accumulation. Mutations in ATP7A or ATP7B or in the proteins that regulate their trafficking affect their exit from Golgi or subsequent retrieval to this organelle. This, in turn, disrupts the homeostatic Cu balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease). Research over the last decade has yielded significant insights into the enzymatic properties and cell biology of the copper ATPases. However, the mechanisms through which the Golgi regulates trafficking of ATP7A/7B and, therefore, maintains Cu homeostasis remain unclear. This review summarizes current data on the role of the Golgi in Cu metabolism and outlines questions and challenges that should be addressed to understand ATP7A and ATP7B trafficking mechanisms in health and disease.
24083160##2013-10-2##Metabolic pancreatitis: Etiopathogenesis and management.##Acute pancreatitis is a medical emergency. Alcohol and gallstones are the most common etiologies accounting for 60%-75% cases. Other important causes include postendoscopic retrograde cholangiopancreatography procedure, abdominal trauma, drug toxicity, various infections, autoimmune, ischemia, and hereditary causes. In about 15% of cases the cause remains unknown (idiopathic pancreatitis). Metabolic conditions giving rise to pancreatitis are less common, accounting for 5%-10% cases. The causes include hypertriglyceridemia, hypercalcemia, diabetes mellitus, porphyria, and Wilson's disease. The episodes of pancreatitis tend to be more severe. In cases of metabolic pancreatitis, over and above the standard routine management of pancreatitis, careful management of the underlying metabolic abnormalities is of paramount importance. If not treated properly, it leads to recurrent life-threatening bouts of acute pancreatitis. We hereby review the pathogenesis and management of various causes of metabolic pancreatitis.
23578885##2012-11-14##Monogenic diseases that can be cured by liver transplantation.##While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management and LT results in both paediatric and adult populations of selected liver-based monogenic diseases, which represent examples of different transplantation strategies, driven by the understanding of the expression of the underlying genetic defect.
23338780##2012-2-1##Various copper and iron overload patterns in the livers of patients with Wilson disease and idiopathic copper toxicosis.##Wilson disease (WD) is a major type of primary copper toxicosis associated with hypoceruloplasminemia, while idiopathic copper toxicosis (ICT) is a minor type characterized by normoceruloplasminemia. Because ceruloplasmin is the major circulating ferroxidase, iron metabolism may be affected in patients with WD. Biopsied liver specimens obtained from patients with primary copper toxicosis were fixed with glutaraldehyde solution and embedded in epoxy resin. Ultrathin sections that had or had not been stained with uranyl acetate solution were examined under an electron microscope equipped with an energy dispersive X-ray analyzer. A 7-year-old boy with WD was free from any metal overloading at the pre-treatment stage. Pre-treatment liver specimens of another 16 patients showed a variety of copper and iron overload patterns, from isolated copper to evenly distributed combined overloading. A 19-year-old female patient was free from any metal overloading after 7 years of treatment. Post-treatment overloading in another 6 patients ranged between evenly distributed combined patterns and isolated iron patterns. All patients had hypoceruloplasminemia throughout treatment periods. A patient with normoceruloplasminemic ICT continued to display isolated copper overloading after 2.5 years of treatment. In conclusion, these observations support the hypothesis that iron accumulates in patients with hypoceruloplasminemia.
23636656##2013-1-7##Diffusion tensor imaging (DTI) and its clinical correlates in drug naïve Wilson's disease.##The purpose is to evaluate white matter (WM) abnormalities in Wilson's disease (WD) using the technique of diffusion tensor imaging (DTI). The prospective case-control study comprised of 15 drug-naïve patients with WD and 15 controls. The phenotype of subjects was evaluated. The DTI/conventional MRI was acquired (3T MRI): Fractional anisotropy (FA) and mean diffusivity (MD) values were extracted from regions of interest placed in pons, midbrain, bilateral frontal and occipital cerebral white matter, bilateral internal capsules (IC), middle cerebellar peduncles (MCP) and corpus callosum (CC). Six patients showed lobar WM signal changes on T(2)-Weighted (T2W)/Fluid attenuation inversion recovery (FLAIR) images while remaining had normal appearing WM. MD was significantly increased in the lobar WM, bilateral IC and midbrain of WD patients. FA was decreased in the frontal and occipital WM, bilateral IC, midbrain and pons. Normal-appearing white matter on FLAIR images showed significantly increased MD and decreased FA values in both frontal and occipital lobar WM and IC compared with those in controls. Correlation of clinical scores and DTI metrics revealed positive correlation between neurological symptom score (NSS) and MD of anterior limb of right internal capsule, Chu stage and MD of frontal and occipital WM. Negative correlation was observed between the Modified Schwab and England Activities of Daily Living (MSEADL) score and MD of bilateral frontal and occipital WM and IC. This is the probably the first study to reveal widespread alterations in WM by DTI metrics in drug naïve WD. DTI analysis revealed lobar WM abnormalities which is less frequently noted on conventional MRI and suggests widespread WM abnormalities in WD. It may be valuable in assessing the true extent of involvement and therefore the severity of the illness.
23519890##2012-12-29##Influence of BDNF polymorphisms on Wilson's disease susceptibility and clinical course.##Susceptibility to Wilson's disease (WD) and its clinical manifestations are thought to be affected by genetic factors, including polymorphisms. The role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases is now widely discussed. The aim of the present study was to evaluate the frequency of the BDNF Val66Met (G-196A) and C-270T polymorphisms in WD patients and in healthy controls, and to determine the role of these polymorphisms in the clinical characteristics of WD. We found that the BDNF Val/Val (-196 G/G) and -270 C/T genotypes occurred more frequently in WD patients than in healthy controls (66 % versus 45.5 %, p = 0.0001, and 14 % versus 6 %, p = 0.018, respectively). Similarly, symptomatic patients carried the BDNF Val/Val genotype more often than presymptomatic patients (75 % versus 53 %, p = 0.0097). No association was detected between any of the determined polymorphisms and the dominant form of the disease or the age of onset for WD.
24166573##2013-10-30##Acute focal dystonia induced by a tricyclic antidepressant in a patient with Wilson disease: a case report.##The authors present the case of a 19-year-old patient with Wilson disease (WD) who developed symptoms of acute focal dystonia of the left hand (a 'starfish' hand presentation) shortly after treatment with the tricyclic antidepressant clomipramine. The diagnosis of WD was made 8 months earlier based on abnormal copper metabolism parameters and was confirmed by genetic testing. Initially, the patient presented with akathisia, sialorrhea, oromandibular dystonia (occasionally grimacing) and slight dysarthria. The patient's symptoms diminished after treatment with d-penicillamine was initiated. No further deterioration was observed after copper-chelating therapy was started. The authors diagnosed acute focal dystonia induced by clomipramine. Botulinum toxin and intensive rehabilitation was initiated; complete regression of hand dystonia was observed. Based on the case, the authors suggest that care should be exercised with regard to starting medications that could potentially impact the extrapyramidal system in WD patients.
23760784##2013-4-3##ATP7B variants as modulators of copper dyshomeostasis in Alzheimer's disease.##To understand the role of the key copper-regulating gene, ATP7B, in copper dyshomeostasis associated with Alzheimer's disease (AD), we analyzed the serum levels of copper, ceruloplasmin and 'free' (i.e., non-ceruloplasmin bound) copper in 399 patients with AD and 303 elderly healthy controls. We also performed analyses of informative variants of ATP7B. AD patients had higher levels of copper and free copper than controls. Individuals with free copper levels higher than 1.6 μmol/L (the upper value of the normal reference range) were more frequent among cases (p < 0.001). Among these individuals, those who were carriers of the ATP7B variants accounted for a large proportion of the free copper levels, specifically in the AD group (p < 0.01). Our results suggest the existence of a 'copper dysfunction' phenotype of sporadic AD which has a genetic basis. They also suggest that free copper is a risk factor for this disorder, modulating additional pathways leading to the disease cascade.
23142125##2012-8-11##[Parkinsonian disorders: from clinical manifestations to diagnostic classification].##Parkinsonism may include atypical clinical manifestations, which are warning signs for the clinicians and motivate further investigations to identify an etiology other than idiopathic Parkinson's disease. The dismemberment of pathological entities, the advances of morphological and functional imaging of the brain, and new insights into molecular biology have successively led to more precise clinical phenotype and mechanisms. Except for etiologies with specific treatment, such as Wilson's disease or Parkinsonism secondary to a lesion of basal ganglia, or the discontinuation of a culprit drug, the treatment of Parkinsonian syndrome is mainly based on a multidisciplinary approach, involving occupational therapist, physiotherapist, speech therapist, psychologist and social worker. L-Dopa may be tried but it is less effective in atypical Parkinsonian syndrome than in Parkinson's disease. Formal diagnosis, only achievable post-mortem, is not available during the lifetime of the patient. Although some additional tests provide undeniable assistance, the clinical approach remains an essential and critical step to avoid costly and unnecessary investigations.
23966348##2013-8-23##Acute onset anarthria without hepatic manifestation: a rare presentation of Wilson disease.##Wilson disease (WD) is one of the few inherited but treatable disorder mainly affecting the liver and brain resulting in severe disability or death if left untreated. Hence, it is important to keep a high index of suspicion for diagnosing this clinical entity in appropriate clinical settings. The clinical presentation can be quite variable and they may present solely with neurological features sans hepatic symptoms. Such neurological manifestations usually follow subacute to chronic course. Acute onset anarthria as the heralding and predominant presenting feature has been rarely reported in the literature. We reported a case of a 12-year-old girl who presented with acute onset anarthria and dystonia of 1-month duration. On further evaluation, a diagnosis of WD was made. The patient showed partial improvement after she was started on copper chelating agents and anticholinergics.
23751120##2013-6-12##Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification.##Human copper transporters ATP7B (Wilson's disease protein) and ATP7A (Menkes' disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N-terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A.
23946400##2013-8-16##Copper block of extrasynaptic GABAA receptors in the mature cerebellum and striatum.##Inhibition of GABAA receptors by Cu(2+) has been appreciated for some time, but differences between synaptic and extrasynaptic GABAA receptors have not been explored. We show that Cu(2+) potently blocks steady-state GABA currents mediated by extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) with an IC50 of 65 nM. This compares with an IC50 of 85 μM for synaptic γ subunit-containing GABAARs (γ-GABAARs). To test the significance of this subunit selectivity, we examined the blocking action of Cu(2+) on neurons of the mouse cerebellum and striatum, brain regions that are known to express both types of receptor. Cu(2+) was shown to significantly reduce tonic inhibition mediated by extrasynaptic δ-GABAARs with little action on phasic inhibition mediated by conventional synaptic γ-GABAARs. We speculate on the implications of these observations for conditions, such as Wilson's disease, that can involve raised Cu(2+) levels in the brain.
23933866##2013-8-13##Classic neuroimaging, the bird's eye view in Wilson's disease.##
23982005##2013-1-04##Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene.##
23982004##2013-7-12##Wilson's disease.##
23542331##2013-2-13##Efficacy and safety of oral chelators in treatment of patients with Wilson disease.##
23787769##2013-6-22##Metals and movement disorders.##
23307056##2012-12-10##Wilson disease, genotype and infertility: is there a correlation?##
23759337##2013-4-2##Do children with Wilson's disease have distinct craniofacial morphology? A cephalometric study.##
23803742##2013-6-28##The role of metal binding and phosphorylation domains in the regulation of cisplatin-induced trafficking of ATP7B.##The copper (Cu) exporter ATP7B mediates cellular resistance to cisplatin (cDDP) by increasing drug efflux. ATP7B binds and sequesters cDDP in into secretory vesicles. Upon cDDP exposure ATP7B traffics from the trans-Golgi network (TGN) to the periphery of the cell in a manner that requires the cysteine residues in its metal binding domains (MBD). To elucidate the role of the various domains of ATP7B in its cDDP-induced trafficking we expressed a series of mCherry-tagged variants of ATP7B in HEK293T cells and analyzed their subcellular localization in basal media and after a 1 h exposure to 30 μM cDDP. The wild type ATP7B and a variant in which the cysteines in the CXXC motifs of MBD 1-5 were converted to serines trafficked out of the trans-Golgi (TGN) when exposed to cDDP. Conversion of the cysteines in all 6 of the CXXC motifs to serines, or in only the sixth MBD, rendered ATP7B incapable of trafficking on exposure to cDDP. Truncation of MBD1-5 or MBD1-6 resulted in the loss of TGN localization. Addition of the first 63 amino acids of ATP7B to these variants restored TGN localization to a great extent and enabled the MBD1-5 variant to undergo cDDP-induced trafficking. A variant of ATP7B in which the aspartate 1027 residue in the phosphorylation domain was converted to glutamine localized to the TGN but was incapable of cDDP-induced trafficking. These results demonstrate that the CXXC motif in the sixth MBD and the catalytic activity of ATP7B are required for cDDP-induced trafficking as they are for Cu-induced redistribution of ATP7B; this provides further evidence that cDDP mimics Cu with respect to the molecular mechanisms by they control the subcellular distribution of ATP7B.
23554137##2013-1-16##Bilateral pallidal stimulation for Wilson's disease.##
23623710##2012-9-24##[Unexplained, subclinical chronically elevated transaminases].##Unexplained, subclinical chronically elevated transaminases is mainly a marker of non-alcoholic fatty liver disease, metabolic syndrome, alcoholism and diabetes, which are very common situations but viral hepatitis and iatrogenic origin must also be considered. Before looking for hepatic or genetic rare diseases, it is worth considering hypertransaminasemia as a clue for muscular disease, particularly in paediatric settings, and creatine phosphokinase is a specific marker. Then, patient history, examination and appropriate biologic requests can permit the identification of less frequent disorders where isolated hypertransaminasemia is possibly the unique marker of the disease for a long while: hemochromatosis, celiac disease, autoimmune hepatitis, Wilson's disease, α1-anti-trypsine deficiency, thyroid dysfunctions, Addison's disease. Liver biopsy should be performed only in patients with aspartate aminotransferases upper the normal range or alanine aminotransferases higher than twice the normal range after 6 months delay with dietetic corrections.
23583003##2012-8-17##Urinary excretion of copper, zinc and iron with and without D-penicillamine administration in relation to hepatic copper concentration in dogs.##Hereditary copper-associated hepatitis in dogs resembles Wilson's disease, a copper storage disease in humans. Values for urinary copper excretion are well established in the diagnostic protocol of Wilson's disease, whereas in dogs these have not been evaluated. The objectives of this study were to characterize both basal and D-penicillamine induced urinary copper, zinc and iron excretion in dogs in relation to hepatic copper concentration. Beagles, Beagle-Bedlington terrier cross-breeds homozygous for the COMMD1 gene mutation that causes copper toxicosis, and Labrador retrievers with normal or increased hepatic copper concentrations were investigated. The hepatic copper phenotype was determined by histological evaluation of liver biopsies and measurement of the hepatic copper concentration by instrumental neutron activation analysis. Urinary excretion of copper, iron and zinc was measured via inductively coupled plasma optical emission spectrometry under basal conditions and after oral administration of a single dose (20mg/kg bodyweight) of the chelator D-penicillamine. There was a rapid increase in urinary excretion of copper and zinc, but not iron after D-penicillamine administration. This increase was not different between dogs with high or normal hepatic copper concentrations. D-penicillamine-induced urinary copper excretion and the copper/creatinine ratio did not correlate with hepatic copper concentrations in the dogs studied, although basal urinary copper/zinc ratios did correlate with hepatic copper concentrations in Labrador retrievers. The latter parameter may be useful in diagnostic and follow-up protocols for copper-associated hepatitis in Labrador retrievers.
23885147##2012-10-15##Gastrointestinal side effects in children with Wilson's disease treated with zinc sulphate.##
23843956##2013-3-1##Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease.##Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu(2+) transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.
23551039##2012-12-5##Wilson disease mutation pattern with genotype-phenotype correlations from Western India: confirmation of p.C271* as a common Indian mutation and identification of 14 novel mutations.##Wilson disease (WD) is an autosomal recessive disorder resulting from mutations in the ATP7B gene, with over 600 mutations described. Identification of mutations has made genetic diagnosis of WD feasible in many countries. The heterogeneity of ATP7B mutants is, however, yet to be identified in the Indian population. We analyzed the mutational pattern of WD in a large region of Western India. We studied patients (n = 52) for ATP7B gene mutations in a cohort of families with WD and also in first-degree relatives (n = 126). All 21 exon-intron boundaries of the WD gene were amplified and directly sequenced. We identified 36 different disease-causing mutations (31 exonic and five intronic splice site variants). Fourteen novel mutations were identified. Exons 2, 8, 13, 14, and 18 accounted for the majority of mutations (86.4%). A previously recognized mutation, p.C271*, and the novel mutation p.E122fs, were the most common mutations with allelic frequencies of 20.2% and 10.6%, respectively. Frequent homozygous mutations (58.9%) and disease severity assessments allowed analysis of genotype-phenotype correlations. Our study significantly adds to the emerging data from other parts of India suggesting that p.C271* may be the most frequent mutation across India, and may harbor a moderate to severely disabling phenotype with limited variability.
24101851##2013-10-9##"Sleep in Wilson's disease: Questionnaire based study" - Comments on the article.##
23645415##2012-2-29##Visualizing hepatic copper release in Long-Evans cinnamon rats using single-photon emission computed tomography.##The potential utility of an imaging agent for the detection of hepatic copper was investigated in a Wilson's disease animal model. Solid-phase peptide synthesis was used to construct an imaging agent which consisted of a copper-binding moiety, taken from the prion protein, and a gamma ray-emitting indium radiolabel. Long-Evans Cinnamon (LEC) rats were used for the Wilson's disease animal model. Our evaluation methodology consisted of administering the indium-labeled agent to both LEC and genetically healthy Long-Evans (LE) cohorts via a tail vein injection and following the pharmacokinetics with single-photon emission computed tomography (SPECT) over the course of an hour. The animals were then sacrificed and their livers necropsied. An additional control agent, lacking the copper-binding moiety, was used to gauge whether any change in the hepatic uptake might be caused by other physiological differences between the two animal models. LEC rats injected with the indium-labeled agent had roughly double the amount of hepatic radioactivity as compared to the healthy control animals. The control agent, without the copper-binding moiety, displayed a hepatic signal similar to that of the control LE animals. Additional intraperitoneal spiking with CuSO4 in C57BL/6 mice also found that the pharmacokinetics of the indium-labeled, prion-based imaging agent is profoundly altered by exposure to in vivo pools of extracellular copper. The described SPECT application with this compound represented a significant improvement over a previous MRI application using the same base peptide sequence.
23786753##2013-6-22##A viewpoint about the treatment of Wilson's disease.##
23786721##2013-6-22##Treating neurological Wilson's disease; the expert opinion is not good enough.##
23958100##2013-8-1##Living donor liver transplantation with dual grafts -- a case report.##
23898395##2012-3-16##A Case of Colonic Adenocarcinoma in a Patient with Wilson's Disease.##Wilson's disease (WD) is an autosomal recessive inherited disorder of copper metabolism that results in the accumulation of copper in the body and primarily in the liver, brain, and cornea. Copper is a toxic metal and might be associated with cancer induction. Most malignancies associated with WD are hepatocellular carcinoma and cholangiocarcinoma. Other intra-abdominal malignancies have been only rarely reported. To our knowledge, this is the first report to suggest that patients with WD may be vulnerable to a malignant change in the colonic mucosa during long-term copper chelating therapy. We report a case of colonic adenocarcinoma in a patient with WD and review the related literature.
23401182##2012-9-25##The effect of zinc and the role of p53 in copper-induced cellular stress responses.##Metals can directly or indirectly cause an increase in reactive oxygen species (ROS) accumulation in cells, and this may result in programmed cell death. A number of previous studies have shown that zinc (Zn) modulates mitogenic activity via several signalling pathways, such as AKT, mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF -κB), AP-1 and p53. The exact role that Zn plays in the regulation of apoptosis remains ambiguous. Intracellular free Zn modulates p53 activity and stability, and excess Zn alters the p53 protein structure and down-regulates p53's binding to DNA. Copper (Cu) accumulation causes apoptosis that seems to be mediated by DNA damage and subsequent p53 activation. Cu can also displace Zn from its normal binding site on p53, resulting in abnormal protein folding and disruption of p53 function. In spite of the induction of the tumour suppressor p53, hepatic Cu accumulation significantly increases the risk of cancerous neoplasm both in humans and rats, suggesting that p53 function may be impaired in these cells. It is generally understood that imbalances in Cu and Zn levels may lead to a higher prevalence of p53 mutations. An increased number of p53 mutations have been found in liver samples from Wilson's disease (WD) patients. High levels of the p53 mutation most probably contribute to the pathogenesis of cancer in individuals with WD, but the cause and effect are not clear. The protein p53 also plays a crucial role in the transcriptional regulation of metallothionein, which indicates a novel regulatory role for p53. This review discusses the central role of p53 and the redox-inert metal Zn in the cellular stress responses induced by the redox active biometal Cu.
24772766##2014-4-30##Wilson's disease unmasked by antitubercular therapy induced liver injury.##
24772751##2014-4-30##Chorea.##Chorea is an involuntary movement disorder characterised by flowing and rhythmic in nature. Hyperkinetic movement disorders such as myoclonus may be mistaken for chorea. Pathogenes of chorea is complex and results from dysfunction of network between motor nucleus of thalamus and subcortical nuclei including globus pallidus interna. There are genetic and non genetic causes of chorea. Huntington's disease is most common genetic cause of chorea. Clinical manifestations of Huntington's disease are mainly neurological and psychiatric. Recently non neurological clinical manifestations of this disease have been described. Genetic test for Huntington's disease is available which may be done for diagnosis and detection of family members at risk of developing disease. Other genetic causes of chorea are neuroacanthocytosis and Wilson's disease. Treatment of genetic causes of chore is usually symptomatic with exception of Wilson's disease. Sydenham's chorea is a neurological manifestation of acute rheumatic fever and most important cause of chorea seen in paediatric population. Treatment includes penicillin prophylaxis and drugs such as sodium valproate and carbamazepine. Diagnosis of chorea is mainly clinical. Family history is very important in diagnosis of genetic causes of chorea. In other patients a detailed work up is required before a final diagnosis is made. Hematological and blood chemistry investigations are helpful in diagnosis of some of the patients. Neuro imaging may also be useful mainly in Huntington's disease patients. Metabolic disorders and drugs are very important causes of non genetic chorea. Early diagnosis is important because majority of the patients respond to the treatment.
23998100##2013-2-27##Wilson's Disease with Neurological Presentation, without Hepatic Involvement in Two Siblings.##Wilson's Disease (WD) is a rare, autosomal, recessive, inborn error of the copper metabolism, which is caused by a mutation in the copper-transporting gene, ATP7B. The presentation is usually neurologic or hepatic, which is seen in 40% of the patients. The diagnosis depends primarily on the clinical features, the biochemical parameters and the presence of the Kayser - Fleischer ring. Here, we are reporting two siblings who were affected by Wilson's disease, with only neurological manifestations, without any hepatic involvement.
23823966##2012-5-14##Wilson's disease: Experience at a tertiary care hospital.##Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism. Data regarding WD is not available from Pakistan. A cross-sectional study was conducted at The Aga Khan University Hospital, Karachi, and all patients admitted with primary and secondary diagnosis of Wilson's disease were added. A total of 47 patients were seen; 68% (n = 32) were male. The mean age was 26.6 ± 9.97 years. Most of the patients presented with hepatic, (n = 22, 46.8%), neurological, (n = 17, 36.2%) and psychiatric (n = 8, 17%) symptoms. Mean ceruloplasmin level was 0.17 ± 0.13 g/dl; it was < 0.25 g/dl in 39 (86.6%) patients. Serum copper (Cu) was reduced in 32 (68.1%) patients and 24-hr-urinary Cu was raised in 22 (47.6%) patients. Slit lamp examination for Kayser-Fleischer (KF) rings was done on 15 (31.9%) patients and 9 (60%) of them had KF rings. Mean serum aspartate transaminase (AST) / alanine transaminases (ALT) ratio was 1.92 and median alkaline phosphatase / total bilirubin ratio was 79.30 (IQR 35.05; 166.50).
23712800##2013-2-18##Recovery after copper-deficiency myeloneuropathy in Wilson's disease.##
23986430##2013-8-30##Effect of liver transplantation on brain magnetic resonance imaging pathology in Wilson disease: a case report.##The authors present a case report of a 28-year-old patient with hepatic, but no neurological, signs of Wilson disease, with pathological changes in both the globi pallidi and caudate found with routine brain magnetic resonance imaging (MRI). The patient was recommended for liver transplantation by hepatologists, and during the two years of observation after liver transplantation, MRI brain abnormalities due to Wilson disease completely regressed. On the basis of this case, the authors present an argument for the prognostic significance of brain MRI in Wilson disease as well as current recommendations concerning liver transplantation in Wilson disease.
23805355##2013-2-21##Non-viral factors contributing to hepatocellular carcinoma.##Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide, accounting for over half a million deaths per year. The geographic pattern of HCC incidence is parallel to exposure to viral etiologic factors. Its incidence is increasing, ranging between 3% and 9% annually depending on the geographical location, and variability in the incidence rates correspond closely to the prevalence and pattern of the primary etiologic factors. Chronic infections with hepatitis B viruses or hepatitis C viruses have both been recognized as human liver carcinogens with a combined attributable fraction of at least 75% of all HCC cases. Multiple non-viral factors have been implicated in the development of HCC. Increased body mass index and diabetes with subsequent development of non-alcoholic steatohepatitis represent significant risk factors for HCC. Other non-viral causes of HCC include iron overload syndromes, alcohol use, tobacco, oral contraceptive, aflatoxin, pesticides exposure and betel quid chewing, a prevalent habit in the developing world. Wilson disease, α-1 antitrypsin deficiency, Porphyrias, autoimmune hepatitis, Schistosoma japonicum associated with positive hepatitis B surface antigen, and thorotrast-ray are also contributing hepatocellualar carcinoma. In addition, primary biliary cirrhosis, congestive liver disease and family history of liver cancer increase the risk of HCC incident. In conclusion, clarification of relevant non-viral causes of HCC will help to focus clinicians on those risk factors that are modifiable. The multilevel preventative approach will hopefully lead to a reduction in incidence of non-viral HCC, and a decrease in the patient morbidity and mortality as well as the societal economic burden associated with HCC.
23844331##2013-5-13##Copper phenotype in Alzheimer's disease: dissecting the pathway.##Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. Unfortunately, none of these seems to clarify the complexity of the pathogenesis. In fact, diverse and independent pathogenetic pathways can be disrupted at the same time, and each contributes to disease etiology. In recent years, researchers have begun studying biometals more deeply. A number of studies have shown that metal dyshomeostasis may enhance AD onset and progression. Specifically, different authors have hypothesized that alterations in metal metabolism are associated with an increased in metal-related oxidative stress and beta-amyloid oligomer formation and precipitation. Studies conducted in vivo, in vitro, in living patients and in silico studies have demonstrated that local and systemic defects in copper metabolism are characteristic signs of AD. This strongly supports the hypothesis that copper pathways may be disrupted by the disease. More specifically, a copper phenotype can be proposed for AD, based on defects found in genes involved in copper metabolism. In this review, we describe copper dyshomeostasis in AD patients and attempt to explain the basis of the AD copper phenotype. Dissecting copper pathways, we highlight mechanisms which may be at the basis of the disease. We also discuss various associated translation outcomes.
23780767##2013-6-20##Acquired hepatocerebral degeneration.##Acquired (non-Wilsonian) hepatocerebral degeneration is a rare irreversible neurological syndrome that occurs in patients with chronic liver disease associated with multiple metabolic insults. Van Woerkom was the first to describe acquired hepatocerebral degeneration in 1914 followed by the landmark article by Victor et al in 1965. Multiple bouts of hepatic coma are the only known risk factors that trigger this devastating neurodegenerative disease with features suggesting toxic exposure to the brain. Clinically and pathologically the disorder is similar to Wilson's disease although subtle differences in immunostaining of glial fibrillar acidic protein have been documented. Acquired hepatocerebral degeneration occurs in 0.8-2% of patients with cirrhosis. As acquired hepatocerebral degeneration is relatively rare, we are reporting one such case from our hospital in a 50-year-old male patient who had long-standing portal systemic shunt and presented with progressive cognitive decline, bradykinesia, tremors and bilateral extrapyramidal signs.
23597670##2013-1-9##Brain metal accumulation in Wilson's disease.##
22826023##2012-4-28##Ataxia-telangiectasia or neurologic Wilson's disease: when strong family history becomes a diagnostic bias.##
23215772##2012-10-2##Cognitive impairment and magnetic resonance imaging correlations in Wilson's disease.##
23605177##2013-4-23##Penicillamine revisited: historic overview and review of the clinical uses and cutaneous adverse effects.##Penicillamine is a well-known heavy metal chelator, classically used in the treatment of Wilson disease, rheumatoid arthritis, and cystinuria. From a dermatologic standpoint, penicillamine was found to be useful in the treatment of systemic sclerosis. The successful therapeutic uses of penicillamine have been hindered by its numerous adverse effects, both cutaneous and extra-cutaneous. It is a unique drug since it provokes a diversity of dermatologic manifestations that include (1) acute hypersensitivity reactions, (2) dermopathies characterized by elastic fiber abnormalities including elastosis perforans serpiginosa and pseudo-pseudoxanthoma elasticum, (3) autoimmune disorders such as pemphigus and penicillamine-induced lupus erythematosus-like syndrome, and (4) miscellaneous dermatoses that result from undefined mechanisms. These cutaneous adverse effects may correlate with the dosage and duration of penicillamine therapy as well as the disease being treated.
23707004##2013-2-28##"Not so rare" Wilson disease.##
23567103##2012-11-1##Wilson disease in offspring of affected patients: report of four French families.##
23798012##2012-2-6##Newborn screening for lysosomal storage disorders and other neuronopathic conditions.##Newborn screening (NBS) is a public health program aimed at identifying treatable conditions in presymptomatic newborns to avoid premature mortality, morbidity, and disabilities. Currently, every newborn in the Unites States is screened for at least 29 conditions where evidence suggests that early detection is possible and beneficial. With new or improved treatment options and development of high-throughput screening tests, additional conditions have been proposed for inclusion into NBS programs. Among those are several conditions with a strong neuronopathic component. Some of these conditions have already been added to a few national and international screening programs, whereas others are undergoing pilot studies to determine the test performance metrics. Here, we review the current state of NBS for 13 lysosomal storage disorders, X-adrenoleukodystrophy, Wilson disease, and Friedreich ataxia.
23794426##2013-6-21##[Therapy for systemic metabolic disorders based on the detection of basic corneal landmarks in childhood].##Many systemic lysosomal storage disorders show basic corneal opacities already in childhood. The lysosome is a cell organelle, produced by Golgi's apparatus, that is surrounded by a membrane and contains hydrolytic enzymes that break down food molecules, especially proteins and other complex molecules. The ophthalmologist's precise diagnosis of corneal clouding at the slit-lamp may reveal the correct interpretation of the specific lysosomal storage disorder. It is very important to diagnose such diseases as soon as possible because today the development of systemic enzymatic therapies has broadened the therapeutic armamentarium for the current standard of care. The following corneal landmarks of systemic storage diseases and of the modern systemic therapy are presented: cornea verticillata in Fabry's disease, periodic infusion of alpha-galactosidase a; Kayser-Fleischer's ring in Wilson's disease, zinc, trienetin, low copper diet; multiple, punctiform crystals in cystinosis, cysteamine, Raptor RP 103(DR cysteamine) that reduces the cytotoxity in form of continous dissolving of cystine from lysosome, renal transplantation, haematopoietic stem cell transplantation; peripheral ring, but not true lipid arc, and moderate stromal haze in LCAT-deficiency, injection of recombinant enzyme or of encapsulated LCAT-secreting cells; diffuse stromal haze in mucopolysaccharidoses (MPS). Enzyme replacement therapy is currently indicated for MPS I, MPS II, and MPS VI, haematopoietic stem cell transplantation; painful, bilateral pseudo-dendritic opacities in tyrosinemia type II (eponym: Richner-Hanhart syndrome), low phenylalanine and tyrosine diet result in complete disappearance of corneal alterations with a consecutive painfree period. Strict diet during the whole life is necessary to prevent corneal recurrences and the occurrence of palmo-plantar keratoses. Such therapies can enable the patient to lead an otherwise normal life for decades.
23712499##2012-11-12##MRI and transcranial sonography findings in Wilson's disease.##
23692600##2013-3-15##Re-evaluation of the indications for liver transplantation in Wilson's disease based on the outcomes of patients referred to a transplant center.##The aim of this study was to re-evaluate the indications and timing of LT for WD. From 2000 to 2009, eight patients with WD who had been referred to our institution for LT were enrolled in this study. The mean patient age was 15.9 yr (range, 7-37 yr). Four patients could not receive LT, because there were no available donors. All four patients were treated with chelating agent medication. Three of them (two of two patients with fulminant WD and one of two with cirrhotic WD) who did not undergo LT are still alive and doing well with stable liver functional tests. Only one of the patients with cirrhotic WD who did not undergo LT died of hepatic failure. Even among the four patients who underwent LT, one with fulminant WD recovered from hepatic encephalopathy with apheresis therapy and chelating agent. He later required LT because of severe neutropenia from d-penicillamine. The other three patients who underwent LT recovered and have been doing well. Some of the patients with WD can recover and avoid LT with medical treatment. Even when WD has progressed liver cirrhosis and/or fulminant hepatic failure at the time of diagnosis, medical treatment should be tried before considering LT.
23623809##2012-8-21##[Could speech rate of Wilson's disease dysarthric patient be improved in dual task condition?].##
23619327##2013-4-22##Therapeutic plasma exchange in patients with neurological diseases: multicenter retrospective analysis.##Therapeutic plasma exchange (TPE), is a procedure, changing pathologic substances in the plasma of patients with replacement fluid. TPE has an increasing list of indications in recent years such as neurological, connective tissue, hematological, nephrological, endocrinological and metabolic disorders. We report our multicenter data about therapeutic plasma exchange in patients with neurological diseases. Six University Hospitals' aphaeresis units medical records about neurologic diseases were reviewed retrospectively. Hundred and fifteen patients and 771 TPE sessions from six aphaeresis units' were included to this study. Of the 115 patients, 53 (46%) were men and 62 (54%) were women. The median age was 50 (range: 5-85) years. Of these patients 58.3% were Guillain-Barre syndrome (GBS), 17.4% were acute disseminated encephalomyelitis (ADEM), 10.4% were chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 7% were multiple sclerosis, 6.1% were myasthenia gravis (MG) and 0.9% were Wilson disease (WD). The median number of TPE sessions per patient was 5 (range 1-72). Human albumin was used as a replacement fluid in 66% and fresh frozen plasma was used in 34% of cases. TPE was done through central venous catheters in 66%, and peripheral venous access in 34% of patients. Some complications were seen in patients (18.3%) during TPE sessions. These complications were, complications related to catheter placement procedure (8.7%), hypotension (3.5%), hypocalcaemia (3.5%) and allergic reactions (1.7%). The complication ratios were 2.7% in total 771 TPE procedures. TPE procedure was terminated in 6% of sessions depending on these complications. Overall responses to TPE were noted in 89.5% of patients. In conclusion; Therapeutic plasma exchange is an effective treatment option in several neurologic diseases.
23375251##2012-7-4##D-penicillamine treatment of copper-associated hepatitis in Labrador retrievers.##d-penicillamine is effectively used in the lifelong treatment of copper toxicosis in Bedlington terriers and Wilson's disease in humans. A complex form of copper-associated hepatitis has recently been characterized in the Labrador retriever. The aims of this study were to evaluate the effectiveness of d-penicillamine treatment for copper-associated hepatitis in this breed, to study the effects on hepatic copper, iron and zinc concentrations, and to evaluate parameters to predict optimal duration of treatment. Forty-three client owned Labrador retrievers that were diagnosed with increased hepatic copper were treated with d-penicillamine and underwent at least one follow-up examination including a liver biopsy for histopathological scoring of inflammatory lesions. Hepatic copper, iron and zinc concentrations were determined in the initial and follow-up biopsies by instrumental neutron activation analysis. The influence of initial hepatic copper concentration, sex, age, d-penicillamine formulation and the occurrence of side effects were investigated for their influence on hepatic copper concentration after a certain period of treatment by generalized mixed modelling. d-penicillamine proved to be effective in reducing hepatic copper concentration and associated inflammatory lesions. Parameters derived from the model can be used to estimate the necessary duration of d-penicillamine treatment for Labrador retrievers with increased hepatic copper concentration. Continuous, lifelong d-penicillamine treatment is not recommended in this breed, as there may be a risk for hepatic copper and zinc deficiency.
24120054##2013-10-15##[The importance of confirmative diagnosis of presymptomatic patients with Wilson's disease].##
23744310##2013-6-8##[Clinical and genetic study of Wilson's disease in affected twins and siblings].##
23717739##2013-2-17##Nonalcoholic steatohepatitis in nonalcoholic fatty liver disease patients of Bangladesh.##
23704419##2013-5-25##Central pontine myelinolysis associated with Wilson disease in a 7-year-old child.##Wilson disease is a rare heredodegenerative inborn error of copper metabolism with varied neuropsychiatric, hepatic and other manifestations. Here we report a case of Wilson disease with neurological manifestations in a 7-year-old girl with concurrent asymptomatic liver involvement and characteristic radiological findings of signal intensity alterations in bilateral striata and thalami along with changes in central pons too like central pontine myelinolysis (CPM), which is of rare occurrence.
23692912##2013-5-23##[CME laboratory tests. Non-cirrhotic portal hypertension with nearly lethal consequences. Wilson disease]].##
23922560##2012-8-23##Autoimmune Hepatitis or Wilson's Disease, a Clinical Dilemma.##
24025510##2013-9-13##[Clinicopathological features of Wilson disease: report of 29 cases].##
23202417##2012-12-3##Complex formation equilibria of Cu(II) and Zn(II) with triethylenetetramine and its mono- and di-acetyl metabolites.##Triethylenetetramine (TETA) dihydrochloride, or trientine, is a therapeutic molecule that has long been used as a copper-chelating agent for the second-line treatment of patients with Wilson's disease. More recently, it has also been employed as an experimental therapeutic molecule in diabetes where it improves cardiac structure in patients with diabetic cardiomyopathy and left-ventricular hypertrophy. TETA is metabolized by acetylation, which leads to the formation of two main metabolites in humans and other mammals, monoacetyl-TETA (MAT) and diacetyl-TETA (DAT). These metabolites have been identified in the plasma and urine of healthy and diabetic subjects treated with TETA, and could themselves play a role in TETA-mediated copper chelation and restoration of physiological copper regulation in diabetes. In this regard, a potentiometric and spectrophotometric study of Cu(II)-complex formation equilibria of TETA, MAT and DAT is presented here, to provide a comprehensive evaluation of the stoichiometries of the complexes formed and of their relative stability constants. A potentiometric study has also been conducted on the corresponding Zn(II) complexes, to evaluate any possible interference with TETA-mediated Cu(II) binding by this second physiological transition-metal ion, which is present in similar concentrations in human plasma and which also binds to TETA. An ESI-MS study of these systems has both confirmed the complex formation mechanisms established from the potentiometric and spectrophotometric results, and in addition provided direct information on the stoichiometry of the complexes formed in solution. These data when taken together show that the 1 : 1 complexes formed with Cu(II) and Zn(II) have different degrees of protonation. The stability of the Cu(II) and Zn(II) complexes with the three ligands, evaluated by the parameters pCu and pZn, decreases with the introduction of the acetyl groups. Nevertheless the stability of Cu(II) complexes with MAT is sufficiently high to enable its participation in copper scavenging from the patient. A speciation study of the behavior of TETA and MAT with Cu(II) in the presence of Zn(II) at peri-physiological plasma concentrations is also presented. While Zn(II) did not hinder copper binding, the possibility is raised that prolonged TETA treatment could possibly alter the homeostatic regulation of this essential metal ion. The lack of reliable literature stability constants concerning the Cu(II) and Zn(II) interaction with the major transport proteins in plasma is also briefly considered.
23518715##2013-3-21##A genetic study of Wilson's disease in the United Kingdom.##Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.
23607698##2012-12-17##EGFP tags affect cellular localization of ATP7B mutants.##
23570841##2012-10-15##[Common problems in the diagnosis and treatment of Wilson's disease].##The present article aims to provide answers to questions frequently asked by physicians attending patients with Wilson's disease (WD) or those with a suspected diagnosis of WD. The article is divided into 2 parts: a first part with answers to questions relating to the diagnosis of this entity and a second with answers to questions concerning treatment. A brief appendix is included with responses to questions not falling into either of these 2 categories.
23709134##2013-5-24##Coincidence of 2 severe chronic diseases: presymptomatic diagnosis of Wilson disease in a boy with severe haemophilia A.##
23519153##2013-3-21##The early molecular processes underlying the neurological manifestations of an animal model of Wilson's disease.##The Long-Evans Cinnamon (LEC) rat shows age-dependent hepatic manifestations that are similar to those of Wilson's disease (WD). The pathogenic process in the brain has, however, not been evaluated in detail due to the rarity of the neurological symptoms. However, copper accumulation is noted in LEC rat brain tissue from 24 weeks of age, which results in oxidative injuries. The current study investigated the gene expression profiles of LEC rat brains at 24 weeks of age in order to identify the important early molecular changes that underlie the development of neurological symptoms in WD. Biological ontology-based analysis revealed diverse altered expressions of the genes related to copper accumulation. Of particular interest, we found altered expression of genes connected to mitochondrial respiration (Sdhaf2 and Ndufb7), calcineurin-mediated cellular processes (Ppp3ca, Ppp3cb, and Camk2a), amyloid precursor protein (Anks1b and A2m) and alpha-synuclein (Snca). In addition to copper-related changes, compensatory upregulations of Cp and Hamp reflect iron-mediated neurotoxicity. Of note, reciprocal expression of Asmt and Bhmt is an important clue that altered S-adenosylhomocysteine metabolism underlies brain injury in WD, which is directly correlated to the decreased expression of S-adenosylhomocysteine hydrolase in hepatic tissue in LEC rats. In conclusion, our study indicates that diverse molecular changes, both variable and complex, underlie the development of neurological manifestations in WD. Copper-related injuries were found to be the principal pathogenic process, but Fe- or adenosylhomocysteine-related injuries were also implicated. Investigations using other animal models or accessible human samples will be required to confirm our observations.
23037949##2012-10-4##Lithium treatment of a bipolar patient with Wilson's disease: a case report.##We present the case of a male patient with a family history of both bipolar disorder (BD) and Wilson's disease (WD). Wilson's disease was diagnosed for this patient in 2008, at the age of 28 years, and shortly thereafter his bipolar illness began with depressive episodes. The patient has been treated with zinc sulphate for WD and with antidepressants for depression. In 2009, lithium was added, and in 2010 antidepressants were discontinued. During treatment with zinc sulphate, a gradual improvement of hepatic indices and a decrease of mandibulofacial dystonia was noted. In 2011, a hypomanic state occurred which subsided with an increase of the lithium dose. Since then, the patient has been mostly in a euthymic mood with subclinical hypomanic periods. We suggest that lithium may be a viable option for treating bipolar illness in patients with Wilson's disease.
23789284##2013-6-25##Mutational analysis of ATP7B gene and the genotype-phenotype correlation in patients with Wilson's disease in Serbia.##
23275100##2011-9-27##Identification of one novel and nine recurrent mutations of the ATP7B gene in 11 children with Wilson disease.##
23599247##2013-4-18##The "Double Panda" Sign in Leigh Disease.##
23576656##2013-4-12##Pathological fractures as an initial presentation of Wilson's disease.##Wilson's disease (WD) has varied phenotypic presentations. Here we report the case of a 16-year-old boy who presented with a history of multiple pathological fractures, severe joint deformities, hepatic dysfunction, cognitive decline and limb dystonia. On examination, the patient had pinched out facies, pallor and leukonychia totalis. Bilateral Kayser Fleischer (KF) ring was present. Musculoskeletal examination revealed pectus carinatum, bilateral genu valgus and gun-stock deformity of the left elbow joint. Splenomegaly and moderate ascites were present. Neurological examination revealed mild rigidity and intermittent episodes of dystonic posturing of all four limbs. On this basis a diagnosis of WD with dystonia with cirrhosis of liver with portal hypertension with renal tubular acidosis with renal rickets was thought likely. Investigations confirmed the diagnosis. The patient was started on treatment but he did not improve. He suffered aspiration pneumonia during his hospital stay and succumbed to the illness.
23599633##2012-7-22##Hepatocellular carcinoma in a non-cirrhotic patient with Wilson's disease.##We report the exceptional case of hepatocellular carcinoma in a non-cirrhotic patient, whose Wilson's disease was diagnosed at the unusual age of 58 years. The liver histology revealed macrovesicular steatosis with fibrosis, but no cirrhosis. The disease was treated with D-penicillamine for 3 years until acute discomfort in the right upper quadrant led to detection of multifocal hepatocellular carcinoma, which was successfully resected. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Hepatocellular carcinoma is rare in Wilson's disease, especially in the absence of cirrhosis. The literature's 28 published cases are reviewed and the contributory role of copper in the hepatocarcinogenic process is discussed.
23705561##2013-5-28##Subclinical diastolic dysfunction in children with Wilson's disease assessed by tissue Doppler echocardiography: a possible early predictor of cardiac involvement.##
23219664##2012-7-5##Wilson's disease in two consecutive generations: the detection of three mutated alleles in the ATP7B gene in two Sardinian families.##
23333878##2012-2-7##Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations.##Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene that encodes a P-type copper transporting ATPase. The aim of this study was to screen and detect mutations of the ATP7B gene in unrelated Turkish Wilson disease patients (n = 46) and control group (n = 52). Mutations were screened and detected by DNA sequencing. 30 out of 46 patients had mutations. 24 different Wilson disease related mutations were identified in those patients. The distribution of mutations in ATP7B gene was as follow: 17 missense, 3 nonsense, 1 silent, 3 frameshift (1 insertion, 2 deletion). None of them were not found in the control group. Five out of 24 mutations were found to be novel. Four of them were missense (c.2363C > T, c.3106G > A, c.3451C > T, c.3733C > A). The last one was deletion (c.3111delC). 10 single nucleotide polymorphisms (SNPs) given in the literature were found in both control and patients groups. Moreover one new polymorphism in exon 18 (c.3727G > A) not reported previously was discovered in both groups. It was striking that most of the mutations were found in exons 8, 12-14. This is the first study covering Turkish Wilson disease patients and control groups for mutation screening in all the coding regions of ATP7B gene by DNA sequencing method and adding five new mutations and one polymorphism into the HUGO Wilson disease mutation database.
23599735##2012-12-15##Long-term effects of a combination of D-penicillamine and zinc salts in the treatment of Wilson's disease in children.##The aim of this study was to investigate the effectiveness of a high-dose zinc sulfate and low-dose D-penicillamine combination in the treatment of pediatric Wilson's disease (WD). A retropective chart review of 65 patients with WD was conducted. These patients received D-penicillamine (8-10 mg/kg/day) and zinc sulfate as the primary treatment. The pediatric dose of elemental zinc is 68-85 mg/day until 6 years of age, 85-136 mg/day until 8 years of age, 136-170 mg/day until 10 years of age and then 170 mg/day, in 3 divided doses 1 h before meals. After clinical and biochemical improvement or stabilization, zinc sulfate alone was administered as the maintenance therapy. Under treatment, the majority of patients (89.2%) had a favourable outcome and 3 patients succumbed due to poor therapy compliance. No penicillamine-induced neurological deterioration was noted and side-effects were observed in <11% of patients over the entire follow-up period. Benefical results on the liver and neurological symptoms were reported following extremely long-term treatment with a combination of low-dose D-penicillamine and high-dose zinc sulfate. Therefore, this regimen is an effective and safe treatment for children with WD.
24049234##2013-9-20##Electro Convulsive Therapy in Psychiatric Manifestations in Wilson's Disease.##Wilson's disease occurs due to an inborn error of metabolism. Psychiatric symptoms are often the first manifestation of the disease and can obscure the diagnosis. There are five neuropsychiatric symptoms clusters established for Wilson's disease patients: Behavior and/or personality disorders, mood disorders, cognitive deficits, psychotic manifestations, and others. The frequency with which psychiatric manifestations appears in Wilson's disease remains vague. However, whenever they occur, they need to be correctly identified and treated. Though encouraging results have been obtained in controlling psychiatric manifestations of Wilson's with psychotropic medications, some sub-group of patients fail to respond to any therapy. We aim at finding options for controlling psychosis in these patients with electro convulsive therapy (ECT). A patient exhibiting rare neuropsychiatric manifestations of Wilson's and who is not responding to psychotropic medication was considered for ECT. Considerable control over psychiatric manifestations with ECT was observed and later treated with maintenance ECTs for relapse control.
23830383##2013-7-9##Genetic variability in copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with Alzheimer's disease in a Chinese population.##Previous experiments demonstrated that transgenic mice carrying both amyloid precursor protein and mutant ATP7B transgenes reduce amyloid plaques and diminish plasma Abeta levels. These experiments showed that a structural change of ATP7B may affect Alzheimer’s disease (AD) susceptibility. In this study three missense SNPs in ATP7B gene (rs1801243, rs1801244, and rs1801249) were chosen to test whether they were associated with AD. We tested this hypothesis using a case control design. The experimental data showed that there was a significant deviation from Hardy-Weinberg equilibrium (HWE) for SNP rs1801249 (c.3419 T greater than C, Val1140Ala) in the case group (p = 0.014) but not in the control group and that there was an association between SNP rs1801249 and AD under a recessive model (p = 0.003). The data also showed that the genotype frequency distribution of the ATP7B c.1366 G greater than C polymorphism (rs1801244, Val456Leu) differed significantly between the AD patients and the normal subjects (p = 0.012). In addition, the frequency of the TGC haplotype of SNPs rs1801243, rs1801244, and rs1801249 was significantly higher in the AD patients compared with the normal subjects (p = 8.49×10-7). These observations suggested that genetic variations in the copper transporter gene ATP7B might contribute to AD pathogenesis in the Taiwanese population.
23274038##2012-1-10##Trientine-induced neurological deterioration in a patient with Wilson's disease.##Trientine (triethylenetetramine dihydrochloride) is a copper-chelating agent used to treat patients with Wilson's disease (WD). It has been considered safe, rarely causing neurological deterioration during initial treatment. We describe a patient diagnosed with WD who became neurologically disabled after treatment with trientine. On a fluid attenuated inversion recovery sequence, brain MRI showed increased areas of high signal intensity compared with initial brain MRI. The patient's neurological signs partially resolved after cessation of trientine treatment. Our findings suggest that treatment with trientine is associated with a risk of neurological deterioration in patients with WD.
23543978##2013-4-2##Kayser-Fleischer rings of acute Wilson's disease.##Here we describe a case of a 22-year-old woman who presented with acute liver failure and Kayser-Fleischer rings suggesting the diagnosis of Wilson's disease.
23556051##2011-8-24##Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases.##Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by alteration of the adenosine triphosphatase 7B gene. It is rare to diagnose WD below the age of three years. Molecular genetic testing is one of the most important diagnostic methods and may confirm the diagnosis in equivocal cases. We report a case of a 9-mo old boy with WD who presented as chronic hepatitis. Genetic analysis showed compound heterozygotes of p.G1186S and c.4006delA.
23556045##2012-8-1##Liver transplantation in Wilson's disease: Single center experience from Saudi Arabia.##
23358449##2013-1-30##Noninvasive urine-derived cell lines derived from neurological genetic patients.##Many major inherited neurological disorders are characterized by early childhood onset, high lethality rate, and the absence of effective treatments. A poor understanding of the underlying mechanisms of such disorders is partly because of the scarcity of patient-specific samples. In this study, we cultured the urine sediments of such patients, aiming to explore the capacity of urine cell cultures to obtain specimens from patients suffering from rare inherited neurological diseases. We collected fresh urine from a variety of neurogenetic patients; cultured the specimens; generated different urine cell lines; and classified these cell lines through morphology, reverse transcription-PCR, and immunofluorescence. We then used these cell lines to detect the affected genes in spinal muscular atrophy and Duchenne muscular dystrophy. We successfully established cell lines from patients with spinal muscular atrophy, Duchenne muscular dystrophy, paroxysmal kinesigenic dyskinesia, and Wilson's disease. All established cell lines consisted of urinary tract epithelial cells and podocytes, and had the same gene defects as the blood specimens. Urine cell culture is thus a new, simple, and noninvasive avenue for getting patient-specific samples not only for genetic diagnosis, but also for storing the samples from patients with rare neurological inherited diseases.
23493534##2013-3-16##Discovery of human zinc deficiency: its impact on human health and disease.##The essentiality of zinc in humans was established in 1963. During the past 50 y, tremendous advances in both clinical and basic sciences of zinc metabolism in humans have been observed. The major factor contributing to zinc deficiency is high phytate-containing cereal protein intake in the developing world, and nearly 2 billion subjects may be zinc deficient. Conditioned deficiency of zinc has been observed in patients with malabsorption syndrome, liver disease, chronic renal disease, sickle cell disease, and other chronic illnesses. Major clinical problems resulting from zinc deficiency in humans include growth retardation; cell-mediated immune dysfunction, and cognitive impairment. In the Middle East, zinc-deficient dwarfs did not live beyond the age of 25 y, and they died because of intercurrent infections. In 1963, we knew of only 3 enzymes that required zinc for their activities, but now we know of >300 enzymes and >1000 transcription factors that are known to require zinc for their activities. Zinc is a second messenger of immune cells, and intracellular free zinc in these cells participate in signaling events. Zinc has been very successfully used as a therapeutic modality for the management of acute diarrhea in children, Wilson's disease, the common cold and for the prevention of blindness in patients with age-related dry type of macular degeneration and is very effective in decreasing the incidence of infection in the elderly. Zinc not only modulates cell-mediated immunity but is also an antioxidant and anti-inflammatory agent.
22610954##2010-12-16##Wilson's disease: update on integrated Chinese and Western medicine.##Wilson's disease (WD), or hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism caused by ATP7B gene mutation. As WD is an inherited disease of the nervous system that is not curable; early diagnosis with early and life-long treatment leads to better prognoses. Currently, the recommended treatment for WD is integrated Chinese and Western medicine. A number of studies indicate that treatment of integrative medicine can not only enforce the de-copper effect but also improve liver function, intelligence, and other factors. This article reviewed in detail the advantages of WD treated with Chinese and Western medicine together.
23141870##2012-8-24##Comment to "Non-invasive assessment of hepatic fibrosis in a series of patients with Wilson's disease".##
23776928##2013-6-19##Hypoparathyroidism in a case of Wilson's disease: Rare association of a rare disorder.##
23441660##2012-3-23##Tacrolimus-induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients.##Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5-3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus-induced TMA. We identified four patients with tacrolimus-induced TMA post-OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post-partum thrombotic thrombocytopenic purpura) and hepatitis C virus-related cirrhosis. All patients had tacrolimus post-OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post-TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes.
23781712##2013-6-21##[Copper intoxication decreases lifespan and induces neurologic alterations in Drosophila melanogaster].##Wilson disease is a hereditary disorder caused by mutations of the ATP7B gene, which leads to intoxication with copper as a result of an unbalance of copper homeostasis. The clinical manifestations resulting from this intoxication are related to the affectation of liver and the encephalon in most cases. Several animal models are currently available for the study of the malady. However, in such models no neurological symptoms are observed, which limits their use for the study of pathogenic effects of this disease on the central nervous system. The aim of the present study was to evaluate if copper feeding could induce a disease state in Drosophila melanogaster to model Wilson disease. The effect of the feeding of copper at the doses of 31 microM and 47 microM on the survival was initially evaluated. Next, behavioral experiments were conducted to determine whether the motor performance was altered by the 47 microM concentration. The results suggest that copper treatment decreases the viability of the flies. In addition, the decrease of viability was associated to an increase and decrease of spontaneous motor activity at early and late stages of the intoxication, respectively. Finally, the role of the dopaminergic neurotransmission system on the observed motor alterations was evaluated. The dopamine precursor L-dopa increased motor activity. In contrast, D2 receptor antagonist, Fluphenazine, was able to block both the increase and decrease of motor activity scores induced by copper. These results suggest that Drosophila melanogaster could be used as a model organism for the study of possible interventions with potential neuroprotective effects in Wilson disease.
23524455##2012-11-22##Relationship between ceruloplasmin and oxidative biomarkers including ferritin among healthy Japanese.##Serum ceruloplasmin (CP), a marker relevant to copper metabolism, is one of famous inflammation markers with a reduction in Wilson's disease, whereas serum ferritin is a marker relevant to iron metabolism. Recently, ferritin is pointed out to be related with oxidative stress. However, there is still no population research which showed the relation of CP and ferritin. Therefore, we investigated the relationship between CP and ferritin including oxidative stress biomarkers among healthy Japanese (n = 389). We measured serum CP, ferritin, Fe, high-sensitivity C-reactive protein (hs-CRP), and urinary oxidative stress biomarkers [H2O2, 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane] and so on. Subjects showed that age; 41.7 ± 10.0 (year), CP; 31.9 ± 6.8 (mg/dl), ferritin; 123.5 ± 121.0 (ng/ml), hs-CRP; 0.89 ± 2.53 (mg/l), 8-OHdG; 10.2 ± 4.4 [ng/mg creatinine (Cre)] and H2O2; 6.5 ± 10.9 (µM/g Cre), (All data mentioned above were expressed as mean ± SD). CP was significantly and positively correlated with hs-CRP and inversely correlated with ferritin, Fe and 8-OHdG. By a multiple logistic regression analysis, odds ratio of CP according to quartiles of hs-CRP was 4.86, and according to quartiles of 8-OHdG was 0.39 after adjusting for age and other confounding factors. In conclusion, our findings suggest that CP was an antioxidative biomarker which controls oxidative stress, whereas ferritin was a marker which may participate in the generation of oxidative stress.
23458042##2012-2-28##Etiology, clinical spectrum and outcome of metabolic liver diseases in children.##
23482821##2011-9-24##Bilateral hypertrophic olivary degeneration in Wilson disease.##Hypertrophic olivary degeneration resulting from lesions of the dento-rubro-olivary pathway, also called Guillain-Mollaret-triangle, has been described previously in a number of cases. Reports about bilateral hypertrophic olivary degeneration of the inferior olivary nuclei are very limited, and the magnetic resonance imaging findings of hypertrophic olivary degeneration in Wilson disease have not yet been described to the best of our knowledge. Herein, we present the first report of bilateral hypertrophic olivary degeneration diagnosed by magnetic resonance imaging in a patient suffering from Wilson disease.
23315358##2012-10-19##The effect of gender on brain MRI pathology in Wilson's disease.##Gender influence on the clinical manifestations of Wilson's Disease (WD) has been suggested; however, brain MRI pathology based on sexual dimorphism in WD has not yet been examined. The aim of this study was to analyse the effect of gender on brain MRI pathology according to the predominant form of WD. We retrospectively analysed the brain MR images of 204 newly diagnosed and untreated WD patients. The predominant form of the disease was neuropsychiatric (n = 105), hepatic (n = 67) or presymptomatic (n = 32). Overall, neuroimaging pathologies were found in 64.2 % WD patients. The clinical form analysis revealed significant gender-related differences. In the neuropsychiatric form, men presented with cerebellar atrophy and cortical brain atrophy more often than women (25/58 vs. 11/47; p < 0.05) and (23/58 vs. 12/47; p = 0.09), respectively. In contrast, women tended to present with globus pallidus lesions more often than men (25/47 vs. 20/58; p = 0.054). There were no gender differences observed in the hepatic form, but cortical brain atrophy presented more often in men than women (3/12 vs. 0/20; p < 0.05) in the presymptomatic form. According to our findings, there is a gender-dependent brain vulnerability to copper toxicity. We speculate that these differences are potentially related to an oestrogen protective effect and are due to differences in gender-related clinical forms.
23389864##2012-7-14##Neurological Wilson's disease lethal for the son, asymptomatic in the father.##
23650006##2013-5-8##[Wilson disease - factors affecting clinical presentation].##Wilson disease (WD) is a genetic disorder with copper metabolism disturbances leading to copper accumulation in many organs with their secondary damage. It is caused by mutation in the ATP7B gene on chromosome 13, which encodes ATP-ase 7B involved in copper transport. The age of neurologic symptom onset in WD is 20-30 years, but there is a wide spectrum of disease including: age at onset, clinical signs and treatment efficacy. More than 500 mutations of ATP7B have been described so far, but the WD genotype does not explain the disease variability. Several other factors are suspected to influence WD presentation, including polymorphisms in the genes encoding: apolipoprotein E, prion-related protein, methyltenetetrahydrofolate reductase, Murr1, antioxidant-1, X-linked inhibitor of apoptosis as well as iron metabolism disturbances, gender impact, inflammatory reactions and oxidative stress. The explanation of their significance can change the therapy of WD. The aim of our study was to review and assess the clinical significance of the factors affecting WD presentation.
23713242##2013-5-30##[Study on correlation between neuropsychological features and Chinese medical syndrome types in patients with Wilson's disease].##
23477073##2013-3-13##[Wilson's disease: programed wandering?].##
23079951##2012-7-9##Opportunities in multidimensional trace metal imaging: taking copper-associated disease research to the next level.##Copper plays an important role in numerous biological processes across all living systems predominantly because of its versatile redox behavior. Cellular copper homeostasis is tightly regulated and disturbances lead to severe disorders such as Wilson disease and Menkes disease. Age-related changes of copper metabolism have been implicated in other neurodegenerative disorders such as Alzheimer disease. The role of copper in these diseases has been a topic of mostly bioinorganic research efforts for more than a decade, metal-protein interactions have been characterized, and cellular copper pathways have been described. Despite these efforts, crucial aspects of how copper is associated with Alzheimer disease, for example, are still only poorly understood. To take metal-related disease research to the next level, emerging multidimensional imaging techniques are now revealing the copper metallome as the basis to better understand disease mechanisms. This review describes how recent advances in X-ray fluorescence microscopy and fluorescent copper probes have started to contribute to this field, specifically in Wilson disease and Alzheimer disease. It furthermore provides an overview of current developments and future applications in X-ray microscopic methods.
23287530##2012-2-01##Vitamin B6 metabolism influences the intracellular accumulation of cisplatin.##Vitamin B6 metabolism influences the adaptive response of non-small lung carcinoma (NSCLC) cells to distinct, potentially lethal perturbations in homeostasis, encompassing nutrient deprivation, hyperthermia, hypoxia, irradiation as well as the exposure to cytotoxic chemicals, including the DNA-damaging agent cisplatin (CDDP). Thus, the siRNA-mediated downregulation of pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6, protects NSCLC cells (as well as a large collection of human and murine malignant cells of distinct histological derivation) from the cytotoxic effects of CDDP. Accordingly, the administration of pyridoxine, one of the inactive precursors of vitamin B6, exacerbates cisplatin-induced cell death, in vitro and in vivo, but only when PDXK is expressed. Conversely, antioxidants such as non-oxidized glutathione (GSH) are known to protect cancer cells from CDDP toxicity. Pyridoxine increases the amount of CDDP-DNA adducts formed upon the exposure of NSCLC cells to CDDP and aggravates the consequent DNA damage response. On the contrary, in the presence of GSH, NSCLC cells exhibit near-to-undetectable levels of CDDP-DNA adducts and a small fraction of the cell population activates the DNA damage response. We therefore wondered whether vitamin B6 metabolism and GSH might interact with CDDP in a pharmacokinetic fashion. In this short communication, we demonstrate that GSH inhibits the intracellular accumulation of CDDP, while pyridoxine potentiates it in a PDXK-dependent fashion. Importantly, such pharmacokinetic effects do not involve plasma membrane transporters that mediate a prominent fraction of CDDP influx, i.e., solute carrier family 31, member 1 (SLC31A1, best known as copper transporter 1, CTR1) and efflux, i.e., ATPase, Cu ( 2+) transporting, β polypeptide (ATP7B).
22572525##2011-10-10##The relationship between copper and steatosis in Wilson's disease.##
23089210##2012-5-10##[Wilson's disease: clinical spectrum of liver disease].##Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism,characterized by copper accumulation in the liver and brain. This rare entity, which has a broad clinical spectrum, is often difficult to diagnose and should therefore always be suspected in patients with liver disease of unclear cause. We describe two types of manifestation of liver disease in two patients; the first developed fulminant hepatic failure requiring urgent liver transplantation and the second showed advanced chronic liver disease and received standard medical treatment. The objective of this clinical observation is to analyze the diagnosis of Wilson's disease in two patients with distinct onset, illustrating the broad clinical spectrum of the disease, and its treatment.
23159873##2012-6-14##A new ATP7B gene mutation with severe condition in two unrelated Iranian families with Wilson disease.##Wilson disease is associated with a defect in copper metabolism and caused by different mutations in ATP7B gene. The aim of this study was to determine mutation frequency of ATP7B exons 8 and 14 in Wilson disease patients from the south of Iran. The exons 8 and 14 of ATP7B gene were analyzed in 65 unrelated Wilson disease patients by Denaturing High Performance Liquid Chromatography, and samples with abnormal peak profile were selected for direct DNA sequencing. Seven out of 65 (10.8%) patients had mutations at exon 14, including c.3061-1G>A in four and c.3207C>A in three patients. In addition, four different mutations were identified at exon 8 of six patients (9.2%). Three of these mutations have been previously reported, including c.2304delC in two patients, c.2293G>A and 2304dupC each in one patient. Furthermore, a novel mutation, c.2335T>G (p.Trp779Gly), was identified in two unrelated patients. The patients with this novel mutation demonstrated severe neuropsychiatric condition. All together, 13 out of 65 (20%) patients had mutations within exons 8 and 14. We also identified a lower frequency of the most common mutations of exons 8 and 14 in the southern Iranian population.
22945834##2012-4-20##Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease.##
23143727##2012-11-8##Late occurrence of isolated obsessive-compulsive behavior in a boy with Wilson's Disease on treatment.##
22973866##2012-9-14##Do we need authorized orphan drugs when compounded medications are available?##
23392711##2012-11-20##Copper ions stimulate the proliferation of hepatic stellate cells via oxygen stress in vitro.##This study examined the effect of copper ions on the proliferation of hepatic stellate cells (HSCs) and the role of oxidative stress in this process in order to gain insight into the mechanism of hepatic fibrosis in Wilson's disease. LX-2 cells, a cell line of human HSCs, were cultured in vitro and treated with different agents including copper sulfate, N-acetyl cysteine (NAC) and buthionine sulfoximine (BSO) for different time. The proliferation of LX-2 cells was measured by non-radioactive cell proliferation assay. Real-time PCR and Western blotting were used to detect the mRNA and protein expression of platelet-derived growth factor receptor β subunit (PDGFβR), ELISA to determine the level of glutathione (GSH) and oxidized glutathione (GSSG), dichlorofluorescein assay to measure the level of reactive oxygen species (ROS), and lipid hydroperoxide assay to quantify the level of lipid peroxide (LPO). The results showed that copper sulfate over a certain concentration range could promote the proliferation of LX-2 cells in a time- and dose-dependent manner. The effect was most manifest when LX-2 cells were treated with copper sulfate at a concentration of 100 μmol/L for 24 h. Additionally, copper sulfate could dose-dependently increase the levels of ROS and LPO, and decrease the ratio of GSH/GSSG in LX-2 cells. The copper-induced increase in mRNA and protein expression of PDGFβR was significantly inhibited in LX-2 cells pre-treated with NAC, a precursor of GSH, and this phenomenon could be reversed by the intervention of BSO, an inhibitor of NAC. It was concluded that copper ions may directly stimulate the proliferation of HSCs via oxidative stress. Anti-oxidative stress therapies may help suppress the copper-induced activation and proliferation of HSCs.
23235335##2012-12-13##Mutational analysis of ATP7B in north Chinese patients with Wilson disease.##Wilson disease (WD) is an autosomal recessive inherited disease caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in 114 individuals of Chinese Han population living in north China who were diagnosed as WD. Totally, we identified 36 mutations and 11 single-nucleotide polymorphisms (SNPs), of which 14 mutations have never been reported previously and 5 were firstly described in Chinese. Among these, p.R778L (21.5%), p.A874V (7.5%) and p.P992L (6.1%) were the most frequent mutations. A genotype of p.L770L+p.R778L+p.P992L was the most frequent triple mutations and two pairs of mutations, p.L770L/p.R778L and p.A874V/p.I929V, were closely related. In addition, a database was established to summarize all ATP7B mutations, including those reported previously and those identified in this study. Popular algorithms were used to predict the functional effects of these mutations, and finally, by comparative genomics approaches, we predicted a group of mutation hot spots for ATP7B. Our study will broaden our knowledge about ATP7B mutations in WD patients in north China, and be helpful for clinical genetic testing.
23936979##2013-8-14##Comparison of long-term outcome of patients with Wilson's disease presenting with acute liver failure versus acute-on-chronic liver failure.##
23833859##2013-7-10##Infraclavicular brachial plexus block in Wilson's disease.##Wilson's disease (WD) is characterized by progressive copper accumulation with hepatic and neurological impairment. Anesthesia and surgical practices may exacerbate WD and liver damage, and even cause life-threatening liver failure. Due to this existing liver damage, anesthetic management is important in WD cases in terms of drug choice, dose, and technique used. This study reports an emergency surgical procedure for trauma in a 24-year-old WD patient suffering the disease for 18 years. The operation was planned under infraclavicular brachial plexus block because of a right supracondiller/proximal humerus fracture. The selected type of anesthetic technique and agents in WD is specific. The pharmacokinetic changes in these cases are difficult to predict and require attention to drug choice and dose.
22950421##2012-9-7##Linkage disequilibrium and haplotype analysis of the ATP7B gene in Alzheimer's disease.##Copper dyshomeostasis leading to a labile Cu(2+) not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.
23452766##2013-3-5##[Have centers of rare neurological diseases modified practices and the care of Wilson's disease?].##Wilson's disease is a particularly rare disease. It is a multisystemic affection related to a genetic abnormality of copper metabolism. Drug treatment is particularly effective if administered at an early stage of the disease and continued throughout life. The French Wilson's disease center, certified for only the one disorder, is easily identifiable by everyone, professionals and patients, which has allowed a rapid increase in the number of patients followed by the center, and considerably reduced the delay between first symptoms and diagnosis. Of its numerous ongoing research projects, it is important to mention the development of a new diagnostic test that would allow the speedy introduction of treatment of both the symptomatic forms and presymptomatic familial forms. Collaborations among professionals permit multidisciplinary care and improve the follow-up of patients in terms of all their medical and social aspects. In addition, the organization of the French Wilson's disease network serves as an exemplar for the implementation of Wilson's disease networks in other European countries and the development of collaborations between Wilson's disease patients'associations across Europe. At present, the center is also working to improve the care of patients presenting with other inherited or acquired pathologies related to copper and other heavy metals.
23200399##2012-6-25##A novel HPLC-electrochemical detection approach for the determination of D-penicillamine in skin specimens.##D-penicillamine is a thiol drug mainly used for Wilson's disease, rheumatoid arthritis and cystinuria. Adverse effects during normal use of the drug are frequent and may include skin lesions. To evaluate its toxic effects in clinical cases an original method based on high performance liquid chromatography coupled to amperometric detection in a specific biological matrix such as skin has been developed. The chromatographic analysis of D-penicillamine was carried out on a C18 column using a mixture of acid phosphate buffer and methanol as the mobile phase. Satisfactory sensitivity was obtained by oxidizing the molecule at +0.95 V with respect to an Ag/AgCl reference electrode. A chemical reduction of D-penicillamine-protein disulphide bonds using dithioerythritol combined with microwaves was necessary for the determination of the total amount of D-penicillamine in skin specimens. A further solid-phase extraction procedure on C18 cartridges was implemented for the sample clean-up. The whole analytical procedure was validated: high extraction yield (>91.0%) and satisfactory precision (RSD<6.8%) values were obtained. It was successfully applied to skin samples from a patient who was previously under a long-term, high-dose treatment with the drug and presented serious D-penicillamine-related dermatoses. Thus, the method seems to be suitable for the analysis of D-penicillamine in skin tissues.
24349711##2013-5-4##Wandering spleen with gastric volvulus and intestinal non-rotation in an adult male patient.##We report an extremely rare case of wandering spleen (WS) complicated with gastric volvulus and intestinal non-rotation in a male adult. A 22-year-old man who had been previously treated for Wilson disease was admitted with severe abdominal pain. Radiological findings showed WS in the midline of the pelvic area. The stomach was mesenteroaxially twisted and intestinal non-rotation was observed. Radiology results did not show any evidence of splenic or gastrointestinal (GI) infarction. Elective emergency laparoscopy confirmed WS and intestinal non-rotation; however, gastric volvulus was not observed. It was suspected that the stomach had untwisted when gastric and laparoscopic tubes were inserted. Surgery is strongly recommended for WS because of the high risk of serious complications; however, some asymptomatic adult patients are still treated conservatively, such as the patient in this study. The present case is reported with reference to the literature.
23270902##2012-12-29##Revisiting the topic of histochemically detectable copper in various liver diseases with special focus on venous outflow impairment.##We surveyed histochemically detectable copper in various liver diseases with emphasis on chronic biliary disease (CBD) and venous outflow impairment. Using rhodanine, we graded copper accumulation in 298 liver specimens: venous outflow impairment (n = 64), CBD (n = 123), Wilson disease (WD) (n = 12), chronic hepatitis C (n = 32), steatohepatitis (n = 28), sarcoidosis (n = 15), cholestatic hepatitis (n = 12), and acute large bile duct obstruction (n = 12). Copper was detected in 39% of specimens; all had chronic liver disease. Copper increased with increasing fibrosis. CBD accumulated copper more frequently than other chronic diseases (except WD), both in early (61% vs 3%) and late (94% vs 59%) stages and in larger amounts. Rhodanine was positive in 73% of livers with CBD, 20% with sarcoidosis, 9% with chronic hepatitis C, and 7% with steatohepatitis. Copper was detected in 14% of chronic venous outflow impairment specimens; with 1 exception, stainable copper was absent in early stages but detected in 38% of cirrhotic livers. In conclusion, rhodanine helps differentiate CBD from other conditions, including venous outflow impairment; in the absence of advanced fibrosis, rhodanine positivity strongly favors CBD. In contrast, rhodanine positivity is nonspecific in cirrhosis, but the absence of copper in that setting excludes CBD.
22877894##2012-4-29##An unusual cause of headache and hypertension.##Children with both headache and hypertension present a relatively rare condition with a broad range of differential diagnoses in pediatric emergency medicine. Some possible diagnoses are potentially life-threatening conditions and merit aggressive evaluation management. We report a case of a 14-year-old girl who presented with headache and hypertension. She responded poorly to medical treatment and subsequently developed anxiety and difficulties with concentration. Three months later, she visited our ophthalmology department because of blurred vision. Ophthalmic evaluation revealed bilateral Kayser-Fleischer rings. Finally, she was diagnosed with Wilson disease. This case emphasizes that children with headache and hypertension merit aggressive evaluation and management.
23689110##2013-5-03##Update on zinc deficiency and excess in clinical pediatric practice.##The critical importance of adequate zinc status to human health, including normal growth and development, is indisputable. The high prevalence of zinc deficiency on a global basis and its importance to public health have been well documented through large-scale randomized controlled zinc supplementation trials. Similar evidence in the clinical setting, however, is much less widely available due to the nonspecific features of zinc deficiency and to the lack of sensitive biomarkers to detect zinc deficiency, especially that of a mild degree of severity. The current understanding of zinc homeostasis indicates that the primary determinants of zinc absorption are the amount of zinc ingested and dietary phytate, the latter having a major effect on zinc bioavailability. In normal as well as in many pathologic conditions, the gastrointestinal tract is the major site of zinc losses resulting from secretion of endogenous zinc into the lumen and subsequent excretion in the feces. The amount excreted is dependent on host status, the amount reabsorbed, and sometimes the presence of pathophysiologic conditions, including diarrhea and steatorrhea. Assessment in the clinical setting dictates that the clinician obtain a careful medical and diet history, recognize clinical presentations in which zinc adequacy may be compromised, and link this risk with nonspecific but plausible manifestations of deficiency. Examples discussed in this article include primary zinc deficiency due to dietary inadequacy (older breastfed infants or toddlers without zinc-rich complementary foods); genetically based deficiency (acrodermatitis enteropathica, acquired zinc deficiency of lactogenic origin), and acquired secondary deficiency in low birth weight and prematurity, gastrointestinal and hepatic disease, and cystic fibrosis. Evidence for efficacy of zinc therapy with pharmacologic doses for two conditions, Wilson's disease and viral upper respiratory infections, is also discussed.
24222913##2013-7-2##An update on laboratory diagnosis of liver inherited diseases.##Liver inherited diseases are a group of genetically determined clinical entities that appear with an early chronic liver involvement. They include Wilson's disease (hepatolenticular degeneration), hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. In addition, cystic fibrosis, although it is not specifically a liver disease, may cause a severe liver involvement in a significant percentage of cases. For all these pathologies, the disease gene is known, and molecular analysis may contribute to the unequivocal diagnosis. This approach could avoid the patient invasive procedures and limit complications associated with a delay in diagnosis. We review liver inherited diseases on the basis of the genetic defect, focusing on the contribution of molecular analysis in the multistep diagnostic workup.
24024049##2013-6-1##Autoimmune hepatitis: diagnostic dilemma in the setting of suspected iron overload.##Autoimmune hepatitis (AIH) is an inflammatory condition of the liver that has a multitude of clinical presentations from chronic hepatitis to acute fulminant hepatitis. AIH diagnosis is typically suspected after ruling out other causes of hepatitis (such as vial hepatitis, hemochromatosis, Wilson's disease, and primary biliary cirrhosis) through serological tests and by findings of high titers of certain autoantibodies (ANA and anti-SMA for type 1 AIH and anti-LKM-1 for type 2 AIH). AIH like most inflammatory conditions is associated with increased ferritin levels (acute-phase reactant) but typically near-normal transferrin saturation. The presence of excessive ferritin level in absence of high-transferrin saturation helps differentiate secondary iron overload from hemochromatosis where transferrin saturation is typically high. We herein describe a case of AIH that presented with high ferritin levels and transferrin saturation suggesting a diagnosis of hemochromatosis and needed arduous work-up to arrive at accurate diagnosis of AIH.
23024204##2012-9-28##Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase.##Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1.
23011036##2012-9-27##Histologic evolution and long-term outcome of Wilson's disease: results of a single-center experience.##
23986700##2013-5-06##Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis.##Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.
23531702##2013-1-25##Biometals in rare neurodegenerative disorders of childhood.##Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.
23622398##2013-4-30##Inborn errors of copper metabolism.##Two copper-transporting ATPases are essential for mammalian copper homeostasis: ATP7A, which mediates copper uptake in the gastrointestinal tract and copper delivery to the brain, and ATP7B, which mediates copper excretion by the liver into bile. Mutations in ATP7A may cause three distinct X-linked conditions in infants, children, or adolescents: Menkes disease, occipital horn syndrome (OHS), and a newly identified allelic variant restricted to motor neurons called X-linked distal hereditary motor neuropathy. These three disorders show variable neurological findings and ages of onset. Menkes disease presents in the first several months of life with failure to thrive, developmental delay, and seizures. OHS features more subtle developmental delays, dysautonomia, and connective tissue abnormalities beginning in early childhood. ATP7A-related distal motor neuropathy presents even later, often not until adolescence or early adulthood, and involves a neurological phenotype that resembles Charcot-Marie-Tooth disease, type 2. These disorders may be treatable through copper replacement or ATP7A gene therapy. In contrast, mutations in ATP7B cause a single known phenotype, Wilson disease, an autosomal recessive trait that results from copper overload rather than deficiency. Dysarthria, dystonia, tremor, gait abnormalities, and psychiatric problems may be presenting symptoms, at ages from 10 to 40 years. Excellent treatment options exist for Wilson disease, based on copper chelation. In the past 2 years (2012-2013), three new autosomal recessive copper metabolism conditions have been recognized: 1) Huppke-Brendel syndrome caused by mutations in an acetyl CoA transporter needed for acetylation of one or more copper proteins, 2) CCS deficiency caused by mutations in the copper chaperone to SODI, and 3) MEDNIK syndrome, which revealed that mutations in the σ1A subunit of adaptor protein complex 1 (AP-1) have detrimental effects on trafficking of ATP7A and ATP7B.
24003324##2012-9-29##Multiplex ARMS PCR to Detect 8 Common Mutations of ATP7B Gene in Patients With Wilson Disease.##
23221602##2012-12-11##Is ATP7B a predictive marker in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy?##
24209444##2013-11-12##Update on Wilson disease.##Wilson disease (WD) is an inherited disorder of chronic copper toxicosis characterized by excessive copper deposition in the body, primarily in the liver and the brain. It is a progressive disease and fatal if untreated. Excessive copper accumulation results from the inability of liver to excrete copper in bile. Copper is an essential trace metal and has a crucial role in many metabolic processes. Almost all of the body copper is protein bound. In WD, the slow but relentless copper accumulation overwhelms the copper chaperones (copper-binding proteins), resulting in high levels of free copper and copper-induced tissue injury. Liver is the central organ for copper metabolism, and copper is initially accumulated in the liver but over time spills to other tissues. WD has protean clinical manifestations mainly attributable to liver, brain, and osseomuscular impairment. Diagnosis of WD is challenging and based on combination of clinical features and laboratory tests. Identification of various high-frequency mutations identified in different population studies across the world has revived interest in developing DNA chips for rapid genetic diagnosis of WD. All symptomatic and all presymptomatic patients require lifelong decoppering with careful clinical tracking. Decoppering ensures that presymptomatic individuals remain symptom free. With judicious decoppering, given time, even patients with severe neurological disability improve and can return to normal life and resume school or work at par with their peers. Treatment regimens and tracking patients using the WD-specific Global Assessment Scale for WD (GAS for WD) are discussed.
23728578##2013-6-4##Midbrain panda sign in a patient with Wilson's disease.##
23948886##2013-8-17##Intronic rs2147363 variant in ATP7B transcription factor-binding site associated with Alzheimer's disease.##Copper homeostasis abnormalities have been shown to be associated with Alzheimer's disease (AD), possibly by accelerating amyloid-β toxicity and plaque formation. The ATP7B gene plays a key role in controlling body copper balance. Our previous studies showed an association between ATP7B variants and AD risk. Among these variants, an intronic single nucleotide polymorphism, rs2147363, was associated with AD risk. In order to understand this intronic association, we screened a population of 286 AD patients and 283 healthy controls, and verified the presence of other functional coding variants in linkage disequilibrium (LD). Then we searched for a regulatory function region close to rs2147363. An LD analysis revealed the presence of an LD between rs2147363 and a Wilson's disease-causing variant, rs7334118. However, this mutation did not explain the observed genetic association. Conversely, in silico analyses of rs2147363 functionality highlighted that this variant is located in a binding site of a transcription factor, and is, consequently, associated with regulatory function. These data suggest that the genetic variation in cis-regulatory elements located in non-coding regions can have a role in determining ATP7B functionality and account for some of the AD missing hereditability.
23621355##2013-4-27##Decision-making impairments in patients with Wilson's disease.##Wilson's disease (WD) causes deposition of copper, mainly in the basal ganglia. One consequence of deposition seems to be impairment of executive functions, which could cause problems in decision making. In 30 WD patients and 30 healthy controls (HCs), we examined decision making under risk in the Game of Dice Task, and we assessed working memory and executive functions. WD patients exhibited a greater preference for disadvantageous choices than did HCs. Reduced decision-making performance was closely correlated to lower executive functions. Decision-making deficits of WD might be associated with frontostriatal loops, which are involved in executive functions and feedback processing.
23546359##2013-4-3##Generalized hyperpigmentation in Wilson's disease: An unusual association.##Wilson's disease, an autosomal recessive disorder of copper metabolism, most commonly presents either with hepatic or neurological features. But, it may sometimes have certain atypical presentations posing diagnostic difficulties. We report here a case of Wilson's disease presenting with generalized hyperpigmentation of skin who also developed neurological manifestations subsequently. We aim to highlight the importance of keeping Wilson's disease as one of the differentials in patients who present with hyperpigmentation and neurological symptoms compatible with copper deposits in the central nervous system and proceed for investigations accordingly.
22922372##2012-8-28##Transient elastography is a useful noninvasive tool for the evaluation of fibrosis in paediatric chronic liver disease.##
23430806##2012-9-26##An exceptional family with three consecutive generations affected by Wilson disease.##Wilson disease (WD) is a disorder of copper transport that can cause hepatic and neuropsychiatric symptoms. Because of its broad spectrum of clinical manifestations that can present in almost any decade of life, a high degree of clinical suspicion is needed for diagnosis. We present an exceptional family with three consecutive generations affected by WD. Autosomal recessive disorders are not typically present in consecutive generations, but this can occur, particularly when carrier frequencies are as high as in WD. This point is of critical importance in counseling families affected by WD. This case also highlights the importance of genetic testing in confirming the diagnosis of WD, particularly when there is a positive family history. To our knowledge, this is the first report of WD in three consecutive generations.
23430523##2012-2-20##Association of dopamine receptor gene polymorphisms with the clinical course of Wilson disease.##
23076575##2012-10-19##Localization of copper and copper transporters in the human brain.##Disturbances in brain copper result in rare and severe neurological disorders and may play a role in the pathogenesis and progression of multiple neurodegenerative diseases. Our current understanding of mammalian brain copper transport is based on model systems outside the central nervous system and no data are available regarding copper transport systems in the human brain. To address this deficit, we quantified regional copper concentrations and examined the distribution and cellular localization of the copper transport proteins Copper transporter 1, Atox1, ATP7A, and ATP7B in multiple regions of the human brain using inductively coupled plasma-mass spectrometry, Western blot and immunohistochemistry. We identified significant relationships between copper transporter levels and brain copper concentrations, supporting a role for these proteins in copper transport in the human brain. Interestingly, the substantia nigra contained twice as much copper than that in other brain regions, suggesting an important role for copper in this brain region. Furthermore, ATP7A levels were significantly greater in the cerebellum, compared with other brain regions, supporting an important role for ATP7A in cerebellar neuronal health. This study provides novel data regarding copper regulation in the human brain, critical to understand the mechanisms by which brain copper levels can be altered, leading to neurological disease.
24829669##2012-10-18##Etiology and complications of liver cirrhosis in children:report of a single center from southern iran.##
23416828##2013-2-19##Wilson's disease in children with blindness: an atypical presentation.##Wilson's disease (WD) is an autosomal recessive disease affecting copper metabolism causing copper induced organ damage. Common organs involved are liver and central nervous system. But RBC, eye, kidneys and bone may also be affected. In WD main defect remains in copper transporter protein p type ATPase resulting from gene mutation in chromosome 13. Neurological manifestations in WD develop due to deposition of copper in different brain areas like basal ganglia, cerebral cortex, corticospinal and corticobulbar pathway. Different types of neurological manifestations develop in WD but visual impairment is very rare. A 14 years old boy of WD presented to us with blindness, tremor and slurred speech along with end stage liver disease. Blindness was thought to be due to optic neuropathy which reversed after drug treatment.
23466863##2013-3-8##Panda with "Bright eyes" in Wilson's disease.##
23503979##2011-7-20##[Wilson's disease in the child: apropos of 20 cases].##
22721972##2012-4-9##Selective slowing of downward saccades in Wilson's disease.##
24358170##2013-8-20##Evolution of exchangeable copper and relative exchangeable copper through the course of Wilson's disease in the Long Evans Cinnamon rat.##
24058603##2013-3-19##Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPOI, TOPΟ-IIA, TOPOIIB and C-MYC genes in patients with small cell lung cancer (SCLC) who received first line therapy with cisplatin and etoposide.##
23505552##2012-10-18##Novel bioimaging techniques of metals by laser ablation inductively coupled plasma mass spectrometry for diagnosis of fibrotic and cirrhotic liver disorders.##
23529326##2013-3-27##Correlations between anthropometric and serologic elements of metabolic syndrome and histopathologic features of nonalcoholic fatty liver disease.##
24244969##2013-11-20##The link between copper and Wilson's disease.##Wilson's disease (hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of copper metabolism leading to copper accumulation in the liver and extrahepatic organs such as the brain and cornea. Patients may present with combinations of hepatic, neurological and psychiatric symptoms. Copper is the therapeutic target for the treatment of Wilson's disease. But how did copper come to be linked with Wilson's disease? The answer encompasses a study of enzootic neonatal ataxia in lambs in the 1930s, the copper-chelating properties of British Anti-Lewisite, and the chemical analysis for copper of the organs of deceased Wilson's disease patients in the mid-to-late 1940s. Wilson's disease is one of a number of copper-related disorders where loss of copper homeostasis as a result of genetic, nutritional or environmental factors affects human health.
23738435##2013-6-7##The treatment of Wilson's disease, a rare genetic disorder of copper metabolism.##Wilson's disease is a rare autosomal recessive disease characterised by the deposition of copper in the brain, liver; cornea, and other organs. The overload of copper inevitably leads to progressive liver and neurological dysfunction. Copper overload in patients with Wilson's disease is caused by impairment to the biliary route for excretion of dietary copper A combination of neurological, psychiatric and hepatic symptoms can make the diagnosis of Wilson's disease challenging. Most symptoms appear in the second and third decades of life. The disease affects between one in 30,000 and one in 100,000 individuals, and is fatal if left untreated. Five drugs are currently available to treat Wilson's disease: British Anti-Lewisite; D-penicillamine; trientine; zinc sulfate or acetate; and ammonium tetrathiomolybdate. Each drug can reduce copper levels and/or transform copper into a metabolically inert and unavailable form in the patient. The discovery and introduction of these five drugs owes more to the inspiration of a few dedicated physicians and agricultural scientists than to the resources of the pharmaceutical industry.
23682437##2013-5-21##Acute hepatic failure among hospitalized Thai children.##We conducted a hospital-based study from June 2002 to December 2006 of Thai children aged 1-15 years with acute hepatic failure (AHF) to determine the causes and outcomes. Eleven children were included in the study. Hepatitis B virus was the cause of AHF in one child, infection-associated hemophagocytic syndrome was the cause in 1 child, Wilson's disease was the cause in 1 child and dengue fever was suspected to be the cause in 2 children. In 6 children the cause of AHF was unknown. Jaundice was reported in 9 of 11 children. Ten of 11 children had mild to moderate encephalopathy on admission. Five of 11 children died due to AHF. No liver transplantations were performed among the children in this study. Further studies into the relationship between dengue infection and AHF are needed.
24032090##2013-4-17##The neuropsychiatry of hyperkinetic movement disorders: insights from neuroimaging into the neural circuit bases of dysfunction.##
24557965##2014-2-22##Determining the frequency and severity of malnutrition and correlating it with the severity of liver cirrhosis.##
23043908##2012-6-25##Characteristics of neurological Wilson's disease without Kayser-Fleischer ring.##
22609346##2012-2-5##Myelopathy secondary to copper deficiency as a complication of treatment of Wilson's disease.##Wilson's Disease (WD) is an autosomal recessive disorder of copper metabolism resulting in a pathological accumulation of this metal, initially in the liver and later in other organs, mainly brain. Treatment with copper chelating agents and zinc salts results in a depletion of copper deposits and prevents or reverses the clinical manifestations. Copper deficiency may cause haematological and neurological changes, the latter principally being polyneuropathy and myelopathy. We report a patient with WD who developed a myelopathy associated with a deficiency of copper following prolonged treatment with D-penicillamine and zinc salts.
23565442##2013-4-9##Refractory rickets due to Fanconi's Syndrome secondary to Wilson's disease.##Renal tubular disorders are an important cause of refractory rickets. Wilson's disease, an inherited disorder of copper metabolism has varied presentations. We present a case of refractory rickets due to Fanconi's syndrome attributable to Wilson's disease. An adolescent girl presented with pain in the hip and knee joints and a knock-knee deformity since six years. She had received multiple doses of cholecalciferol with little improvement. There was no history of seizures, polyuria, jaundice, intake of drugs, or similar complaints in the family. Examination revealed a severely short stature with widening of the wrist joint and genu valgum. Examination of the central nervous system (CNS) was normal. Skeletal radiographs showed features suggestive of rickets at the hip and knee joints. Routine biochemistry was normal, 25-hydroxyvitamin D [25(OH)D] was adequate (57.1 ng/dL), with normal corrected calcium (9.24 mg/dL), low phosphate (2.76 mg/dL), elevated bone-specific alkaline phosphatase, and normal renal functions. Twenty-four-hour urine revealed phosphaturia, kaliuresis, and glucosuria with normal blood sugars and aminoaciduria. Blood gas analysis revealed normal anion gap metabolic acidosis with a urine pH of 7. Ammonium chloride (NH4CL) challenge test revealed proximal tubular acidosis. A search for causes revealed Kayser-Fleischer rings. The diagnosis of Wilson's disease was confirmed by low serum ceruloplasmin levels (6.5 mg/dL; normal: 18-35 mg/dL) with high 24-hour urine copper levels (433 mcg; normal: 20-50 mcg). She was started on a replacement of alkali, phosphate, calcium, and vitamin D, with zinc acetate for Wilson's disease. Rickets as a presenting feature of Wilson's disease has been reported rarely. Recognition of this entity is important, as treatment of the primary condition may improve tubular function as well.
22941676##2012-3-7##Genetics of Wilson's disease: a clinical perspective.##Hepatic Wilson's disease is often a difficult diagnosis to confirm. This review examines the current role of genetic tests for Wilson's disease and is aimed at clinicians caring for patients with this disease. We discuss how genetic testing is carried out for Wilson's disease, indications for these tests, and genetic counseling for the family. In contrast to the advances in diagnosis of Wilson's disease by testing for ATP7B mutations, genotype-phenotype correlations are not yet sufficiently established. The non-Wilsonian copper overload syndromes causing cirrhosis in children are another important area for study. The review also identifies further areas for research into the genetics of Wilson's disease in India.
22820477##2012-7-3##Familial screening in Wilson's disease: think at the previous generation!##
24010089##2012-12-26##Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism that results in accumulation of copper primarily in the liver, brain and cornea. Mutations in the WD gene, ATP7B, cause failure of copper excretion from hepatocyte into bile and a defective synthesis of ceruloplasmin. More than 500 mutations are now recognized, scattered throughout the ATP7B gene. Since WD has protean clinical presentations, awareness of WD in clinical practice is important for the early diagnosis and prevention of accumulated copper toxicity. Molecular genetic testing is playing an increasingly important role in the diagnosis of WD in uncertain cases and family screening. Siblings should be screened for WD once an index case has been diagnosed. Discrimination of heterozygotes from asymptomatic patients is essential to avoid inappropriate lifelong therapy for heterozygotes. Genetic testing, either by haplotype analysis or by mutation analysis, is the only definite solution for differentiating heterozygote carriers from affected asymptomatic patients. Routine genetic testing, because of the multitude of documented mutations, has been thought to be impractical until recently. However, genetic testing is now being more actively applied to the diagnosis of WD, particularly in young children in whom conventional biochemical diagnosis has much limitation and only genetic testing is able to confirm WD. Because advancement of modern biochemical technology now allows more rapid, easier, and less expensive mutation detection, direct DNA sequencing could be actively considered as the primary mode of diagnostic investigation rather than a supplementary test to the conventional biochemical tests. This review will focus on the recent advancement of molecular genetics and genetic diagnosis of WD in very young children on the basis of research data of the Seoul National University Children's Hospital and recent literature.
23425886##2013-2-22##Meeting Report: Rare disease in south-eastern Europe, 15-17 November 2012, Skopje, Republic of Macedonia.##(Full text is available at http://www.manu.edu.mk/prilozi).Under the auspices of the European Academy of Paediatrics, the first Rare Disease in South-Eastern Europe (SEE) meeting was held on November 15-17 2012, at the Macedonian Academy of Sciences and Arts, Skopje (MASA). This was a manifestation in honour of the 45 years since its establishment, under the guidance of the G.D. Efremov Research Centre for Genetic Engineering and Bio-technology. The Macedonian Chamber of Doctors granted 20 CME credit points for the meeting. The meeting started with talks on the importance of rare diseases in general (Liesbeth Siderius, The Netherlands, John Dodge, UK) and in Macedonia (Zoran Gucev, Velibor Tasic, Dijana Plasevska-Karanfilska, Momir Polenakovic). The importance of having registries for RDs, team work, additional education and international collaboration was stressed as being especially important. All speakers, as well as the NGO patient organization (Slavica Stojanovska, Vesna Stojmenska) underlined the need for comprehensive societal efforts in tackling this emerging social and medical problem. Surgical problems regarding the ear and hearing were finely exposed in the presentation by Ilija Filipce (Macedonia). At least 80% of RDs are genetic in their origin. Anna Tylki-Szymanska (Poland) spoke about Lysosomal acid lipase deficiency, Wolman disease and cholesteryl ester storage disease, while Agnieszka Jurecka (Poland) introduced the audience to the natural history of mucopolysaccharidosis type VI. Especially insightful presentations were those describing the genetics of abnormal vertebral segmentation and the Notch signalling pathway (Peter Turnpenny, UK) and the overgrowth syndromes in their interesting and exciting relationship to human cancer (Between Mendel and cancer - PI3K/AKT-related overgrowth syndromes, Robert Sample, UK). The genetics and the clinical features of the pituitary were addressed by several prominent scientists. The genetic causes of IGF-I deficiency and insensitivity were presented by Jan-Maarten Wit (The Netherlands), while the defects within pituitary growth factors and their phenotypes in infancy and adolescence was brilliantly presented by Roland Pfaeffle (Germany). In addition, the fine aspects of the septo-optic dysplasia were presented by Liljana Saranac (Serbia). The ever growing body of genetic insights was enriched by the fundamental findings in epigenetics (genomic imprinting anomalies) presented by Yves Le Bouc (France) with his talk on the Beckwith-Wiedemann overgrowth syndrome (BWS) and the Russell-Silver (RSS) syndrome. As, rather unfortunately, patients with Gaucher's disease (GD) are not treated in Macedonia, Gaucher disease was a separate section at the RD meeting at MASA. GD as a model disorder for targeted therapy (Patrik Deegan, UK) and the therapeutic options in Gaucher's disease (Deborah Elstein, Israel) introduced the public to the basic and the newest available therapeutic options. Regional collaboration was especially stressed in the talk on the laboratory diagnosis of lysosomal storage diseases in Bulgaria, by Ivanka Sinegirska from Sofia, Bulgaria. Arunas Valiulis (Lithuania) talked about the EU Leonardo Project, Building a Network of Management of Alpha-1 Antitrypsin Deficiency in Central / Eastern Europe, further pointing towards the need for international and especially European collaboration on the particular form of RD. As the first patient(s) with Fabry's disease have been discovered in Macedonia the talk on Fabry enzyme replacement therapy (ERT) (Patrik Deegan, UK) was especially insightful. The molecular diagnosis and treatment of Wilson's disease is always a difficult clinical situation, as stressed by Georgios Laudianos, Italy. Insights on primary hyperoxaluria type III were given by Yaacov Frishberg (Israel), especially interesting were the presentations on atypical haemolitic uremic syndrome (Zoltan Prohaska, Hungary), hypouricaemia (Ivan Sebesta, Prague, Czech Republic; Dganit Dinour, Israel; and Velibor Tasic, Macedonia). Alport's Disease (Gordana Petrusevska, Macedonia), Autism (Nada Pop-Jordanova, Macedonia), progressive familial and benign recurrent inrahepatic cholestasis (Viktorija Chaloska-Ivanova, Macedonia) and a comprehensive survey on patients with primary immune deficiency diseases in Macedonia (Kristina Mironska, Macedonia) were also presented. Several groups have also contributed with their posters (27) on different RDs. The meeting was attended by 128 delegates from 21 countries. In addition, there were conclusions and proposed modifications for further progress in the development of diagnosis and treatment of RDs. The meeting and ita organization were rated by delegates and lecturers as an exceptional scientific success. Of particular importance also is the fact of the intensive collaboration of SEE countries and SEE and the EU countries. It was also an opportunity to reconsider the state of the organizational, educational and scientific integration of SEE and the EU on the rather specific field of RDs.
23188863##2012-11-29##Is blinking of the eyes affected in extrapyramidal disorders? An interesting observation in a patient with Wilson disease.##Blinking of eye is a routine human activity which seldom attracts any attention of clinicians in health and disease. There is experimental evidence that blink rate is affected in extrapyramidal disorders affecting the balance of these neurotransmitters. However, no observations regarding blink rate in Wilson disease (WD) have been reported previously. We report a patient of WD with an increased spontaneous blink rate. A 24-year-old lady presented complaining of tremulousness of both upper limbs and head for 2 years, dysphagia and difficulty in speaking for 1.5 years and abnormal behaviour for last 1 year. We observed that her blink rate at rest was 32/min. Serum ceruloplasmin level was low (0.08 g/l). The patient was started on therapy with D-penicillamine, zinc sulphate, levodopa-carbidopa and trihexiphenidyl. At 1-month follow-up, patient's tremors were markedly decreased and blink rate at rest was decreased to 12/min.
23210912##2012-9-26##Advance in the pathogenesis and treatment of Wilson disease.##Wilson disease is an autosomal recessive disorder of copper metabolism. Diagnosis depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Genetic analysis for mutations within ATP7B is a convincing diagnostic tool. The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake. Medical therapy is effective but WD is not yet curable. Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure, although evaluation of its long-term effect are still in need.
23180946##2012-3-31##Celiac disease markers in patients with liver diseases: a single center large scale screening study.##
23109455##2012-10-31##Response to different therapeutic approaches in Wilson disease. A long-term follow up study.##
23396027##2013-2-12##Wilson disease in 71 patients followed for over two decades in a tertiary center in Saudi Arabia: a retrospective review.##
23014265##2012-9-28##Neuro-ophthalmology of movement disorders.##
22158007##2011-12-08##Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease.##The ideal gene therapy for metabolical liver disorders would target hepatocytes before the onset of disease and be durable, non-toxic and non-immunogenic. Early gestational gene transfer can achieve such goals. Here, we demonstrate that prenatal gene transfer of human Atp7b reduces liver pathology and improves biochemical markers in Atp7b(-/-) mice, a murine model of Wilson's disease (WD). Following prenatal injection of lentivirus vector containing the human Atp7b gene under the transcriptional control of a liver-specific promoter, the full-length ATP7B was detectable in mouse livers for the entire duration of experiments (20 weeks after birth). In contrast to a marked pathology in non-injected animals, livers from age-matched treated mice consistently demonstrated normal gross and histological morphology. Hepatic copper content was decreased in the majority of treated mice, although remaining copper levels varied. Improvement of hepatic copper metabolism was further apparent from the presence of copper-bound ceruloplasmin in the sera and normalization of the mRNA levels for HMG CoA-reductase. With this approach, the complete loss of copper transport function can be ameliorated, as evident from phenotypical improvement in treated Atp7b(-/-) mice. This study provides proof of principle for in utero gene therapy in WD and other liver-based enzyme deficiencies.
22718095##2012-1-17##Therapeutic plasma exchange for fulminant hepatic failure secondary to Wilson's disease.##Wilson's disease (WD) is an autosomal-recessive disorder of impaired copper metabolism resulting in accumulation of copper primarily in the liver but ultimately in many organs and tissues. A small number of patients with WD initially present with fulminant hepatic failure (FHF), hypercupremia, and intravascular hemolysis. The therapeutic goals for these patients include quickly removing the copper and preparing the patient for liver transplantation. Here, we report on a 6-year-old male with WD in FHF with anemia, renal insufficiency, and coagulopathy. The patient received a series of therapeutic plasma exchanges (TPE) as adjunctive therapy to remove copper and stabilize his coagulopathy and anemia until a transplant was possible. A total of five single plasma volume (1500 mL) TPE were performed over the course of 11 days with plasma as the replacement fluid. Laboratory results demonstrated temporary improvement after each procedure. Liver transplantation was performed 12 days after beginning TPE and 35 days after admission to the hospital. TPE was a successful adjunctive therapy to bridge this patient with WD to transplantation.
22940187##2012-6-3##Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors γ and α expressions in the liver of Wilson's disease.##
22093921##2011-11-17##Successful liver transplantation following veno-arterial extracorporeal membrane oxygenation in a child with fulminant Wilson disease and severe pulmonary hemorrhage: a case report.##Massive pulmonary hemorrhage and other serious cardiopulmonary diseases in patients with fulminant hepatitis result not only in graft failure but also mortality after LT. ECMO is used to treat children with cardiorespiratory failure refractory to conventional intensive care. We describe a five-yr-old girl with genetically confirmed fulminant Wilson disease and severe pulmonary hemorrhage who underwent successful primary LT following veno-arterial ECMO. To our knowledge, this is the first report of successful primary LT in a patient using veno-arterial ECMO. The present case demonstrates that ECMO, as a bridging modality to LT, may be necessary to manage both massive pulmonary hemorrhage and possible graft loss because of hypoxemia.
22806248##2012-7-2##Establishment of hepatic and neural differentiation platforms of Wilson's disease specific induced pluripotent stem cells.##The combination of disease-specific human induced pluripotent stem cells (iPSC) and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases. Wilson's disease (WD) is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene. WD affects multiple organs with primary manifestations in the liver and central nervous system (CNS). In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes, we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages. Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B. Combining with directed cell differentiation strategies, we successfully differentiated WD iPSC into hepatocyte-like cells, neural stem cells and neurons. Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells. Hence we established a platform for studying both hepatic and neural abnormalities of WD, which may provide a new tool for tissue-specific disease modeling and drug screening in the future.
22943453##2012-9-4##Non-invasive evaluation of hepatic manifestation in Wilson disease with transient elastography, ARFI, and different fibrosis scores.##
23677665##2013-5-15##Recognition and treatment of neurologic Wilson's disease.##As Wilson's disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilson's disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilson's disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective.
23275849##2012-1-4##Presentation of Epilepsy in a Patient with Wilson's Disease and Developmental Venous Anomaly (Venous Angioma) in the Brain.##Intracranial developmental venous anomalies (DVAs), also called venous angiomas, and Wilson's disease are both considered rare disorders with varying degrees of neurologic and systemic manifestations; yet the coexistence of the two disorders is considered extremely rare, bearing in mind the low prevalence of each disorder. Epilepsy is a recognised presentation in these disorders and will be the focus of discussion in our report of a 21-year-old male patient who, based on a clinical examination and laboratory and neuroimaging results, was diagnosed with both Wilson's disease and DVA. He presented initially at Sultan Qaboos University Hospital, Oman with tremors and writing difficulties in the right hand followed by the development of epilepsy, and was treated medically by de-coppering and antiepileptic medications. We also present a brief literature review of both disorders, their association with epilepsy, and treatment options. Family screening for patients with Wilson's disease is pivotal in preventing unfavourable outcomes.
23112546##2011-11-11##Dietary copper triggers onset of fulminant hepatitis in the Long-Evans cinnamon rat model.##
22981378##2011-3-20##Functional significance of the copper transporter ATP7 in peptidergic neurons and endocrine cells in Drosophila melanogaster.##The Drosophila ATP7 copper transporter has sequence homology to the human copper transporters ATP7A and ATP7B, which are defective in Menkes and Wilson disease, respectively. We show here that in Drosophila ATP7 is expressed by many peptidergic neurons. As C-terminal amidation of neuropeptides depends on the copper-containing enzyme PHM, it seemed likely that in the absence of ATP7 the activity of PHM might be compromised. Indeed, inhibition of ATP7 expression by RNAi led to a decrease in mature amidated neuropeptides and the appearance of C-terminally Gly-extended neuropeptides. The strength of this effect differed from one cell type to another; it was very pronounced for AKH and corazonin, but much less so for SIFamide and myosuppressin. Nevertheless, down-regulation of ATP7 specifically in the SIFamide-expressing neurons resulted in male-male courtship behavior.
22898812##2012-8-16##Molecular events initiating exit of a copper-transporting ATPase ATP7B from the trans-Golgi network.##The copper-transporting ATPase ATP7B has a dual intracellular localization: the trans-Golgi network (TGN) and cytosolic vesicles. Changes in copper levels, kinase-mediated phosphorylation, and mutations associated with Wilson disease alter the steady-state distribution of ATP7B between these compartments. To identify a primary molecular event that triggers ATP7B exit from the TGN, we characterized the folding, activity, and trafficking of the ATP7B variants with mutations within the regulatory N-terminal domain (N-ATP7B). We found that structural changes disrupting the inter-domain contacts facilitate ATP7B exit from the TGN. Mutating Ser-340/341 in the N-ATP7B individually or together to Ala, Gly, Thr, or Asp produced active protein and shifted the steady-state localization of ATP7B to vesicles, independently of copper levels. The Ser340/341G mutant had a lower kinase-mediated phosphorylation under basal conditions and no copper-dependent phosphorylation. Thus, negative charges introduced by copper-dependent phosphorylation are not obligatory for ATP7B trafficking from the TGN. The Ser340/341A mutation did not alter the overall fold of N-ATP7B, but significantly decreased interactions with the nucleotide-binding domain, mimicking consequences of copper binding to N-ATP7B. We propose that structural changes that specifically alter the inter-domain contacts initiate exit of ATP7B from the TGN, whereas increased phosphorylation may be needed to maintain an open interface between the domains.
23243681##2012-12-18##Fulminant Wilson disease.##
22843330##2012-7-31##D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis.##D-Penicillamine (3,3-dimethyl-D-cysteine; DP) is an FDA-approved redox-active D-cysteine-derivative with antioxidant, disulfide-reducing, and metal chelating properties used therapeutically for the control of copper-related pathology in Wilson's disease and reductive cystine-solubilization in cystinuria. Based on the established sensitivity of metastatic melanoma cells to pharmacological modulation of cellular oxidative stress, we tested feasibility of using DP for chemotherapeutic intervention targeting human A375 melanoma cells in vitro and in vivo. DP treatment induced caspase-dependent cell death in cultured human metastatic melanoma cells (A375, G361) without compromising viability of primary epidermal melanocytes, an effect not observed with the thiol-antioxidants N-acetyl-L-cysteine (NAC) and dithiothreitol. Focused gene expression array analysis followed by immunoblot detection revealed that DP rapidly activates the cytotoxic unfolded protein response (UPR; involving phospho-PERK, phospho-eIF2α, Grp78, CHOP, and Hsp70) and the mitochondrial pathway of apoptosis with p53 upregulation and modulation of Bcl-2 family members (involving Noxa, Mcl-1, and Bcl-2). DP (but not NAC) induced oxidative stress with early impairment of glutathione homeostasis and mitochondrial transmembrane potential. SiRNA-based antagonism of PMAIP1 expression blocked DP-induced upregulation of the proapoptotic BH3-only effector Noxa and prevented downregulation of the Noxa-antagonist Mcl-1, rescuing melanoma cells from DP-induced apoptosis. Intraperitoneal administration of DP displayed significant antimelanoma activity in a murine A375 xenograft model. It remains to be seen if melanoma cell-directed induction of UPR and apoptosis using DP or improved DP-derivatives can be harnessed for future chemotherapeutic intervention.
22810201##2012-2-29##In vivo detection of copper ions by magnetic resonance imaging using a prion-based contrast agent.##Abnormal distributions of transition metals inside the body are potential diagnostic markers for several diseases, including Alzheimer's disease, Parkinson's disease, Wilson's disease, and cancer. In this article, we demonstrate that P57/Gd, a novel prion-based contrast agent, can selectively image tissues with excessive copper accumulation using magnetic resonance imaging (MRI). P57/Gd selectivity binds copper(II) over other physiologically relevant cations such as zinc, iron, manganese, and calcium. To simulate a metabolic copper disorder, we treated mice with an intraperitoneal injection of a CuSO(4) solution to induce a renal copper overload. The MRI signal intensities from the renal cortex and medulla of copper spiked animals that were administered P57/Gd were found to correlate with the ex vivo copper concentrations determined by inductively coupled plasma mass spectrometry.
23125884##2011-10-12##Longitudinal analysis of serum miR-122 in a rat model of Wilson's disease.##PURPOSE: MicroRNA-122 (miR-122) has recently been shown to represent a novel biomarker of liver disease. However, the presence of serum miR-122 after liver injury was mostly studied at singular time points. The course of serum miR-122 was determined at consecutive time points during the onset of disease. METHODS: Fulminant hepatitis was induced by a high-copper diet in Long-Evans Cinnamon (LEC) rats that were used as models for Wilson's disease (WD). Levels of serum miR-122, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and liver histology were determined. RESULTS: Toxic copper given to isolated hepatocytes induced release of miR-122 into the tissue culture medium. Levels of serum miR-122 were highly elevated (21.9 ± 5) in LEC rats after high-copper diet in fulminant hepatitis, whereas healthy rats showed low (<0.6) baseline levels of miR-122. Levels of miR-122 in the serum of LEC rats after high-copper diet continuously increased for about 4 weeks prior to the onset of fulminant hepatitis. In most of the animals (77.8%), significantly increased levels of miR-122 were detected about 2 weeks (13.7 ± 2 days) earlier as compared to hepatitis-associated serum markers ALT, AST, and bilirubin. Analysis of miR-122 in survivors after cell-based therapy of WD demonstrated a rapid decrease of miR-122 levels following hepatocyte transplantation. miR-122 expression in the serum was normalized to baseline levels in most of the (4/5) survivors. CONCLUSION: Our results suggest that longitudinal analysis of miR-122 allows detection of severe liver disease at an early stage and might be excellently suited to monitor therapy, at least when severe liver disease can be restored as observed after cell-based therapy of WD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12072-012-9348-5) contains supplementary material, which is available to authorized users.
23580823##2013-4-13##Etiologic and epidemiologic study of hepatocellular carcinoma in West Azarbaijan of Iran (2006-2011).##
24644489##2011-8-27##Idiopathic Thrombocytopenia and Neurologic Manifestations in A Young Female Leading to the Diagnosis of Wilson's Disease.##We present a 19-year-old patient with hematologic and neurologic manifestations associated with Wilson's disease. Idiopathic thrombocytopenia was diagnosed in October 2009. Bone marrow aspiration was normal. Gradually her neurologic and psychiatric symptoms emerged, dysarthria, writing apraxia, learning difficulties, emotionalism and eventually dystonia of hands. The serum ceruloplasmin was low, and the Kayser Fleischer's ring was positive. MRI of the brain showed abnormality in the bilateral basal ganglia, brain stem and superior cerebellar peduncles without post-contrast enhancement.
22170165##2011-12-16##Imaging copper metabolism imbalance in Atp7b (-/-) knockout mouse model of Wilson's disease with PET-CT and orally administered 64CuCl2.##
23801921##2012-5-8##Physiology and pathophysiology of eryptosis.##Abstract available from the publisher.
22854969##2012-8-1##Distinctive features of catalytic and transport mechanisms in mammalian sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) and Cu+ (ATP7A/B) ATPases.##Ca(2+) (sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA)) and Cu(+) (ATP7A/B) ATPases utilize ATP through formation of a phosphoenzyme intermediate (E-P) whereby phosphorylation potential affects affinity and orientation of bound cation. SERCA E-P formation is rate-limited by enzyme activation by Ca(2+), demonstrated by the addition of ATP and Ca(2+) to SERCA deprived of Ca(2+) (E2) as compared with ATP to Ca(2+)-activated enzyme (E1·2Ca(2+)). Activation by Ca(2+) is slower at low pH (2H(+)·E2 to E1·2Ca(2+)) and little sensitive to temperature-dependent activation energy. On the other hand, subsequent (forward or reverse) phosphoenzyme processing is sensitive to activation energy, which relieves conformational constraints limiting Ca(2+) translocation. A "H(+)-gated pathway," demonstrated by experiments on pH variations, charge transfer, and Glu-309 mutation allows luminal Ca(2+) release by H(+)/Ca(2+) exchange. As compared with SERCA, initial utilization of ATP by ATP7A/B is much slower and highly sensitive to temperature-dependent activation energy, suggesting conformational constraints of the headpiece domains. Contrary to SERCA, ATP7B phosphoenzyme cleavage shows much lower temperature dependence than EP formation. ATP-dependent charge transfer in ATP7A and -B is observed, with no variation of net charge upon pH changes and no evidence of Cu(+)/H(+) exchange. As opposed to SERCA after Ca(2+) chelation, ATP7A/B does not undergo reverse phosphorylation with P(i) after copper chelation unless a large N-metal binding extension segment is deleted. This is attributed to the inactivating interaction of the copper-deprived N-metal binding extension with the headpiece domains. We conclude that in addition to common (P-type) phosphoenzyme intermediate formation, SERCA and ATP7A/B possess distinctive features of catalytic and transport mechanisms.
22426664##2012-1-4##Are irreversible morphological [corrected] signs of portal hypertension in neurological form of Wilson's disease associated with treatment delay? A pilot study.##Aim of this study was to evaluate the rate of morphological liver and spleen abnormalities in patients with neurological clinical presentation of Wilson's disease (WD). Fourteen patients with neurological presentation of WD divided into group A (5 patients who initiated chelating therapy <24 months from the first symptoms) and group B (9 patients whose therapy started ≥24 months after the initial symptoms) underwent abdominal MRI examination. Abnormal findings on abdominal MRI were present in 28% of patients with neurological form of WD. Significant hepatosplenomegaly was present in none of the patients from group A and in 4 (44%) patients from group B. In addition, macronodular liver cirrhosis and peritoneal effusion were evident in two and one patient from group B, respectively, and in none of the patients from group A. Our results suggest that severe portal hypertension and liver damage in patients with neurological presentation of WD might be reversible or do not even develop if chelating treatment is initiated <2 years after the onset of symptoms.
22983845##2012-9-18##Copper imbalances in ruminants and humans: unexpected common ground.##Ruminants are more vulnerable to copper deficiency than humans because rumen sulfide generation lowers copper availability from forage, increasing the risk of conditions such as swayback in lambs. Molybdenum-rich pastures promote thiomolybdate (TM) synthesis and formation of unabsorbable Cu-TM complexes, turning risk to clinical reality (hypocuprosis). Selection pressures created ruminant species with tolerance of deficiency but vulnerability to copper toxicity in alien environments, such as specific pathogen-free units. By contrast, cases of copper imbalance in humans seemed confined to rare genetic aberrations of copper metabolism. Recent descriptions of human swayback and the exploratory use of TM for the treatment of Wilson's disease, tumor growth, inflammatory diseases, and Alzheimer's disease have created unexpected common ground. The incidence of pre-hemolytic copper poisoning in specific pathogen-free lambs was reduced by an infection with Mycobacterium avium that left them more responsive to treatment with TM but vulnerable to long-term copper depletion. Copper requirements in ruminants and humans may need an extra allowance for the "copper cost" of immunity to infection. Residual cuproenzyme inhibition in TM-treated lambs and anomalies in plasma copper composition that appeared to depend on liver copper status raise this question "can chelating capacity be harnessed without inducing copper-deficiency in ruminants or humans?" A model of equilibria between exogenous (TM) and endogenous chelators (e.g., albumin, metallothionein) is used to predict risk of exposure and hypocuprosis; although risk of natural exposure in humans is remote, vulnerability to TM-induced copper deficiency may be high. Biomarkers of TM impact are needed, and copper chaperones for inhibited cuproenzymes are prime candidates.
22422381##2012-3-14##Clinico-radiological spectrum of bilateral temporal lobe hyperintensity: a retrospective review.##Bilateral temporal lobe hyperintensity (BTH) is a commonly encountered MRI finding in a wide spectrum of clinical conditions and often poses a diagnostic challenge to the radiologist. The purpose of this paper is to elucidate several diseases that manifest as BTH on MRI, based on a retrospective review of cranial MRI of 65 cases seen in our institution between October 2007 and September 2010. We found BTH in different clinical scenarios that included infective diseases (herpes simplex virus, congenital cytomegalovirus infection), epileptic syndrome (mesial temporal sclerosis), neurodegenerative disorders (Alzheimer's disease, frontotemporal dementia, Type 1 myotonic dystrophy), neoplastic conditions (gliomatosis cerebri), metabolic disorders (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, Wilson's disease, hyperammonemia), dysmyelinating disease (megalencephalic leukoencephalopathy with subcortical cysts), and vascular (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and paraneoplastic (limbic encephalitis) disorders. The conventional MRI findings with advanced MRI such as diffusion-weighted imaging, susceptibility-weighted imaging and MR spectroscopy along with laboratory results are potentially helpful in distinguishing the different clinical conditions and thus affect the early diagnosis and clinical outcome.
22569595##2012-3-25##HBV and HCV infections in Wilson's disease patients: copper overload could be protective?##
22863441##2011-10-17##Kayser-Fleischer ring in Wilson's disease: a cohort study.##
23547415##2013-4-4##Wilson's disease presenting with hypokalemia, hypoparathyroidism and renal failure.##Wilson's disease (WD) is not as rare as once believed, and has a wide range of presentations with equally wide range of age of onset. Sometimes the primary presentation might be unusual and may require a thorough investigation to avoid a misdiagnosis. Our case presented with uncontrolled seizures, severe hypokalemia, renal failure, and hypoparathyroidism. After being diagnosed as WD and treated for the same patient made a remarkable recovery.
22763723##2012-7-05##Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study.##Wilson disease (WD), a disorder of copper metabolism is caused by mutations in the ATP7B gene, a copper transporting ATPase. In the present study we describe a novel mutation in exon 9 of the ATP7B gene. The ATP7B gene was analyzed for mutations by denaturing HPLC and direct sequencing. DNA from 100 healthy blood donors from the same geographic area was examined as control. Sixteen (7.4%) out of the 216 patients diagnosed with WD in Austria carried the newly identified R816S(c.2448G>T) point mutation in exon 9 (4 male, age: 19 (6-30) years, median (range)). One patient was homozygous for R816S(c.2448G>T). Thirteen patients were compound heterozygotes (p.H1069Q(c.3207C>A)/R816S(c.2448G>T) (N=6), P539L/R816S(c.2448G>T) (N=3), each one G710S/R816S(c.2448G>T), P767P(2299insC)/R816S(c.2448G>T), W779G/R816S(c.2448G>T), T1220M/R816S(c.2448G>T)). In two patients no second mutation was identified. Interestingly, all but three of the patients originated within a distinct geographical area in Austria. Eleven patients presented with hepatic disease, 3 patients with neurological disease and 2 were asymptomatic sisters of an index case. A liver biopsy was available in 14 patients. Three patients showed advanced liver disease with liver transplantation for acute hepatic failure in two. The remaining patients had only mild histological changes, most commonly steatosis. Chronic hepatitis was described in five patients. Kayser-Fleischer ring was present in five patients. None of the 100 healthy controls carried the mutation. We describe a novel mutation in the ATP7B gene, occurring in patients originated from a distinct geographical area in Austria associated with a variable course of the disease.
22926781##2012-2-21##Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder.##
23342748##2013-1-25##[Nephrotic syndrome after treatment with d-penicillamine in a pediatric patient with Wilson's disease].##We describe a case of nephrotic syndrome (NS) after a 7 months treatment with D-penicillamine in a 14 years old girl with Wilson's disease, with a prompt regression at the discontinuation of the drug. Kidney function, proteinuria in particular, must be always monitored during the chelating therapy, and the drug must be discontinued as soon as signs of renal injury are detected.
23006462##2012-9-26##Presentation, diagnosis and outcome of predominantly hepatic Wilson's disease in adult Saudi patients: a single centre experience.##
22774841##2012-7-7##Common local founder effects for Wilson's disease and hereditary hemochromatosis; mutation studies of a large family.##
23050060##2012-7-15##The molecular basis of memory.##We propose a tripartite biochemical mechanism for memory. Three physiologic components are involved, namely, the neuron (individual and circuit), the surrounding neural extracellular matrix, and the various trace metals distributed within the matrix. The binding of a metal cation affects a corresponding nanostructure (shrinking, twisting, expansion) and dielectric sensibility of the chelating node (address) within the matrix lattice, sensed by the neuron. The neural extracellular matrix serves as an electro-elastic lattice, wherein neurons manipulate multiple trace metals (n > 10) to encode, store, and decode coginive information. The proposed mechanism explains brains low energy requirements and high rates of storage capacity described in multiples of Avogadro number (N(A) = 6 × 10(23)). Supportive evidence correlates memory loss to trace metal toxicity or deficiency, or breakdown in the delivery/transport of metals to the matrix, or its degradation. Inherited diseases revolving around dysfunctional trace metal metabolism and memory dysfunction, include Alzheimer's disease (Al, Zn, Fe), Wilson's disease (Cu), thalassemia (Fe), and autism (metallothionein). The tripartite mechanism points to the electro-elastic interactions of neurons with trace metals distributed within the neural extracellular matrix, as the molecular underpinning of "synaptic plasticity" affecting short-term memory, long-term memory, and forgetting.
22889306##2012-2-9##613 cases of splenic rupture without risk factors or previously diagnosed disease: a systematic review.##
22648419##2012-5-30##Functional partnership of the copper export machinery and glutathione balance in human cells.##Cells use the redox properties of copper in numerous physiologic processes, including antioxidant defense, neurotransmitter biosynthesis, and angiogenesis. Copper delivery to the secretory pathway is an essential step in copper utilization and homeostatic maintenance. We demonstrate that the glutathione/glutathione disulfide (GSH/GSSG) pair controls the copper transport pathway by regulating the redox state of a copper chaperone Atox1. GSSG oxidizes copper-coordinating cysteines of Atox1 with the formation of an intramolecular disulfide. GSH alone is sufficient to reduce the disulfide, restoring the ability of Atox1 to bind copper; glutaredoxin 1 facilitates this reaction when GSH is low. In cells, high GSH both reduces Atox1 and is required for cell viability in the absence of Atox1. In turn, Atox1, which has a redox potential similar to that of glutaredoxin, becomes essential for cell survival when GSH levels decrease. Atox1(+/+) cells resist short term glutathione depletion, whereas Atox1(-/-) cells under the same conditions are not viable. We conclude that GSH balance and copper homeostasis are functionally linked and jointly maintain conditions for copper secretion and cell proliferation.
23087754##2012-5-12##Hypercalciuria and nephrocalcinosis as early feature of Wilson disease onset: description of a pediatric case and literature review.##
22561748##2012-1-11##Killing me softly - suicidal erythrocyte death.##Similar to nucleated cells, erythrocytes may undergo suicidal death or eryptosis, which is characterized by cell shrinkage, cell membrane blebbing and cell membrane phospholipid scrambling. Eryptotic cells are removed and thus prevented from undergoing hemolysis. Eryptosis is stimulated by Ca(2+) following Ca(2+) entry through unspecific cation channels. Ca(2+) sensitivity is enhanced by ceramide, a product of acid sphingomyelinase. Eryptosis is triggered by hyperosmolarity, oxidative stress, energy depletion, hyperthermia and a wide variety of xenobiotics and endogenous substances. Eryptosis is inhibited by nitric oxide, catecholamines and a variety of further small molecules. Erythropoietin counteracts eryptosis in part by inhibiting the Ca(2+)-permeable cation channels but by the same token may foster formation of erythrocytes, which are particularly sensitive to eryptotic stimuli. Eryptosis is triggered in several clinical conditions such as iron deficiency, diabetes, renal insufficiency, myelodysplastic syndrome, phosphate depletion, sepsis, haemolytic uremic syndrome, mycoplasma infection, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase-(G6PD)-deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, and Wilson's disease. Enhanced eryptosis is observed in mice with deficient annexin 7, cGMP-dependent protein kinase type I (cGKI), AMP-activated protein kinase AMPK, anion exchanger AE1, adenomatous polyposis coli APC and Klotho as well as in mouse models of sickle cell anemia and thalassemia. Eryptosis is decreased in mice with deficient phosphoinositide dependent kinase PDK1, platelet activating factor receptor, transient receptor potential channel TRPC6, janus kinase JAK3 or taurine transporter TAUT. If accelerated eryptosis is not compensated by enhanced erythropoiesis, clinically relevant anemia develops. Eryptotic erythrocytes may further bind to endothelial cells and thus impede microcirculation.
22484412##2012-2-10##Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis.##Wilson's disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.
22684688##2012-1-23##Measurement of peroxiredoxin-4 serum levels in rat tissue and its use as a potential marker for hepatic disease.##Peroxiredoxin (Prx)-4, a secretable endoplasmic reticulum (ER)-resident isoform of the mammalian Prx family, functions as a thioredoxin-dependent peroxidase. It is acknowledged that Prx-4 plays a role in the detoxification of hydrogen peroxide, and potentially other peroxides, which may be generated during the oxidative folding of proteins and oxidative stress in the ER. The present study was undertaken in order to specifically quantify the tissue levels of Prx-4. To accomplish this, an enzyme-linked immunosorbent assay was developed using a specific polyclonal antibody produced by immunizing a rabbit with native recombinant rat Prx-4 protein. The assay was used to detect Prx-4 in the range of 0.1 and 10 ng/ml, and to investigate tissue distribution in rats. Using this immunoassay, we found that the serum levels of Prx-4 were substantially lower in asymptomatic Long-Evans Cinnamon rats, a rat model of Wilson's disease, compared to normal rats. In addition, the treatment of rat hepatoma cells with N-acetylcysteine led to a significant increase in the release of Prx-4 protein into the medium; thus, it appears likely that the secretion of Prx-4 is associated with the redox state within cells. These results suggest that serum Prx-4 has potential for use as a biomarker for hepatic oxidative stress.
22581771##2012-5-11##Endogenous formation and repair of oxidatively induced G[8-5 m]T intrastrand cross-link lesion.##Exposure to reactive oxygen species (ROS) can give rise to the formation of various DNA damage products. Among them, d(G[8-5 m]T) can be induced in isolated DNA treated with Fenton reagents and in cultured human cells exposed to γ-rays, d(G[8-5m]T) can be recognized and incised by purified Escherichia coli UvrABC nuclease. However, it remains unexplored whether d(G[8-5 m]T) accumulates in mammalian tissues and whether it is a substrate for nucleotide excision repair (NER) in vivo. Here, we found that d(G[8-5 m]T) could be detected in DNA isolated from tissues of healthy humans and animals, and elevated endogenous ROS generation enhanced the accumulation of this lesion in tissues of a rat model of Wilson's disease. Additionally, XPA-deficient human brain and mouse liver as well as various types of tissues of ERCC1-deficient mice contained higher levels of d(G[8-5 m]T) but not ROS-induced single-nucleobase lesions than the corresponding normal controls. Together, our studies established that d(G[8-5 m]T) can be induced endogenously in mammalian tissues and constitutes a substrate for NER in vivo.
22965522##2012-9-12##Is central pontine myelinolysis a sign of pre-symptomatic neurologic form of Wilson disease?##
22800610##2012-1-30##Wilson disease in a Nigerian child: a case report.##
22919193##2012-1-08##Ocular signs in Wilson disease.##
22665589##2012-6-6##Studying human disease genes in Caenorhabditis elegans: a molecular genetics laboratory project.##Scientists routinely integrate information from various channels to explore topics under study. We designed a 4-wk undergraduate laboratory module that used a multifaceted approach to study a question in molecular genetics. Specifically, students investigated whether Caenorhabditis elegans can be a useful model system for studying genes associated with human disease. In a large-enrollment, sophomore-level laboratory course, groups of three to four students were assigned a gene associated with either breast cancer (brc-1), Wilson disease (cua-1), ovarian dysgenesis (fshr-1), or colon cancer (mlh-1). Students compared observable phenotypes of wild-type C. elegans and C. elegans with a homozygous deletion in the assigned gene. They confirmed the genetic deletion with nested polymerase chain reaction and performed a bioinformatics analysis to predict how the deletion would affect the encoded mRNA and protein. Students also performed RNA interference (RNAi) against their assigned gene and evaluated whether RNAi caused a phenotype similar to that of the genetic deletion. As a capstone activity, students prepared scientific posters in which they presented their data, evaluated whether C. elegans was a useful model system for studying their assigned genes, and proposed future directions. Assessment showed gains in understanding genotype versus phenotype, RNAi, common bioinformatics tools, and the utility of model organisms.
22669981##2012-6-4##Progressive familial intrahepatic cholestasis type 3: overlapping presentation with Wilson disease.##
23032833##2012-10-4##Analysis of clinical and biochemical spectrum of Wilson disease patients.##
23037674##2012-10-6##Catatonia: a rare presenting symptom of Wilson's disease.##
22366147##2011-11-30##Two cases of ankylosing spondylitis and Wilson's disease in the same patient. Only a fortuitous association?##
22692182##2012-6-13##A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism.##The copper-transporting ATPase ATP7B has an essential role in human physiology, particularly for the liver and brain function. Inactivation of ATP7B is associated with a severe hepato-neurologic disorder, Wilson disease (WD). Hundreds of WD related mutations have been identified in ATP7B to date. The low frequency and the compound-heterozygous nature of causative mutations complicate the analysis of individual mutants and the establishment of genotype-phenotype correlations. To facilitate studies of disease-causing mutations and mechanistic understanding of WD, we have homology-modelled the ATP7B core (residues 643-1377) using the recent structure of the bacterial copper-ATPase LCopA as a template. The model, supported by evolutionary conservation and hydrophobicity analysis, as well as existing and new mutagenesis data, allows molecular interpretations of experimentally characterized clinical mutations. We also illustrate that structure and conservation can be used to grade potential deleterious effects for many WD mutations, which were clinically detected but have not yet been experimentally characterized. Finally, we compare the structural features of ATP7B and LCopA and discuss specific features of the eukaryotic copper pump.
22565294##2012-5-8##A systems approach implicates nuclear receptor targeting in the Atp7b(-/-) mouse model of Wilson's disease.##Wilson's disease (WD) is an inherited disorder of copper metabolism characterized by liver disease and/or neurologic and psychiatric pathology. The disease is a result of mutation in ATP7B, which encodes the ATP7B copper transporting ATPase. Loss of copper transport function by ATP7B results in copper accumulation primarily in the liver, but also in other organs including the brain. Studies in the Atp7b(-/-) mouse model of WD revealed specific transcript and metabolic changes that precede development of liver pathology, most notably downregulation of transcripts in the cholesterol biosynthetic pathway. In order to gain insight into the molecular mechanisms of transcriptomic and metabolic changes, we used a systems approach analysing the pre-symptomatic hepatic nuclear proteome and liver metabolites. We found that ligand-activated nuclear receptors FXR/NR1H4 and GR/NR3C1 and nuclear receptor interacting partners are less abundant in Atp7b(-/-) hepatocyte nuclei, while DNA repair machinery and the nucleus-localized glutathione peroxidase, SelH, are more abundant. Analysis of metabolites revealed an increase in polyol sugar alcohols, indicating a change in osmotic potential that precedes hepatocyte swelling observed later in disease. This work is the first application of quantitative Multidimensional Protein Identification Technology (MuDPIT) to a model of WD to investigate protein-level mechanisms of WD pathology. The systems approach using "shotgun" proteomics and metabolomics in the context of previous transcriptomic data reveals molecular-level mechanisms of WD development and facilitates targeted analysis of hepatocellular copper toxicity.
22807186##2012-7-19##A new treatable genetic disorder of manganese metabolism causing dystonia-parkinsonism and cirrhosis: the "new" Wilson's disease?##
22735241##2012-6-28##Neurological symptoms, genotype-phenotype correlations and ethnic-specific differences in Bulgarian patients with Wilson disease.##
22327203##2012-2-13##Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators.##Wilson's disease is an orphan disease due to copper homeostasis dysfunction. Mutations of the ATP7B gene induces an impaired functioning of a Cu-ATPase, impaired Cu detoxification in the liver and copper overload in the body. Indeed, even though copper is an essential element, which is used as cofactor by many enzymes playing vital roles, it becomes toxic when in excess as it promotes cytotoxic reactions leading to oxidative stress. In this perspective, human copper homeostasis is first described in order to explain the mechanisms promoting copper overload in Wilson's disease. We will see that the liver is the main organ for copper distribution and detoxification in the body. Nowadays this disease is treated life-long by systemic chelation therapy, which is not satisfactory in many cases. Therefore the design of more selective and efficient drugs is of great interest. A strategy to design more specific chelators to treat localized copper accumulation in the liver will then be presented. In particular we will show how bioinorganic chemistry may help in the design of such novel chelators by taking inspiration from the biological copper cell transporters.
22837979##2011-2-25##Neuromuscular Electrical Stimulation Therapy for Dysphagia Caused by Wilson's Disease.##Wilson's disease is an autosomal recessive disorder of abnormal copper metabolism. Although dysphagia is a common complaint of patients with Wilson's disease and pneumonia is an important cause of death in these patients, management of swallowing function has rarely been reported in the context of Wilson's disease. Hence, we report a case of Wilson's disease presenting with dysphagia. A 33-year-old man visited our hospital with a complaint of difficulty in swallowing, since about last 7 years and which had worsened since the last 2-3 months. He was diagnosed with Wilson's disease about 13 years ago. On the initial VFSS, reduced hyoid bone movement, impaired epiglottic movement and moderate amount of residue in the valleculae during the pharyngeal phase were noted. After 10 sessions of neuromuscular electrical stimulation for 1 hour per day, decreased amount of residue was observed in the valleculae during the pharyngeal phase on the follow-up VFSS.
22699536##2011-11-15##Jaw-opening oromandibular dystonia secondary to Wilson's disease treated with botulinum toxin type A.##We have reported a case series of five patients with jaw-opening oromandibular dystonia secondary to Wilson's disease (WD), in which the patients were treated with botulinum toxin type A (BTX-A). In all cases, dystonia score was partially reduced three weeks after injections. The most common side effect was transient mild dysphagia. This preliminary study showed that jaw-opening oromandibular dystonia in WD may be partially responsive to the use of BTX-A.
22720274##2012-6-22##Wilson disease: Canadian perspectives on presentation and outcomes from an adult ambulatory setting.##
22720273##2012-6-22##Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum.##The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another.
22541062##2012-3-14##Other genetic liver diseases in children.##Wilson disease is rare but proteiform, and should be suspected in any child with liver disease and older than 3 years of age. The treatment is very efficient, and must be taken life-long. Fifteen percent of patients with alpha-1-antitrypsin deficiency develop a neonatal jaundice, and 3% a cirrhosis in childhood. There is no specific treatment except liver transplantation. Five percent of cystic fibrosis patients develop a cirrhosis, with a very slow progression. Milder abnormalities are frequent, as well as biliary stones. Liver disease in ciliopathies may be a congenital hepatic fibrosis, with risks of portal hypertension and cholangitis, or a more variable biliary disease. Gilbert disease is frequent and benign. Crigler-Najjar syndrome is rare, severe, and may be an indication for liver or liver-cell transplantation.
22521558##2012-2-22##Non-alcoholic fatty liver disease in children.##Non-alcoholic fatty liver disease is increasingly prevalent in children, together with obesity. Transaminases, tests for insulin resistance, ultrasonography and MRI are variably used as surrogates markers of steatosis. Other liver diseases, such as Wilson disease, should be excluded. A liver biopsy is performed in selected cases: young children, familial history of severe disease, inconclusive tests for other pathologies, suspected advanced fibrosis, hypertransaminasemia despite weight loss and in clinical trials. Weight reduction, and changes in lifestyle, are the front-line treatment. Drug therapy is under evaluation.
22500664##2011-2-24##Clinical efficacy and safety of Chinese herbal medicine for Wilson's disease: a systematic review of 9 randomized controlled trials.##Wilson's disease is an autosomal recessive disorder of copper metabolism. Despite being treatable, there is no universally accepted treatment regimen. Currently, various Chinese herbal medicines (CHMs) are widely used in the treatment of Wilson's disease in China, but there is a lack of reliable scientific evidence for the effectiveness of such therapies. The objective of this systematic review is to assess the clinical efficacy and safety of CHM as an alternative or/and adjuvant therapy for Wilson's disease. A systematic literature search in different medical databases was performed to identify randomized controlled trials comparing CHM as monotherapy or CHM as adjuvant therapy with western conventional medical therapy in the treatment of Wilson's disease. A total of 687 participants were included in nine eligible studies. The main findings are that CHM as monotherapy or adjuvant therapy for Wilson's disease may be able to improve the clinical symptoms, to promote the urinary copper excretion, to ameliorate liver function and/or liver cirrhosis, and has fewer adverse effects in comparison with western conventional medication. Furthermore, CHM generally appeared to be safe and well tolerated in patients with Wilson's disease. However, the evidence presented in this review are insufficient to warrant a clinical recommendation due to the generally low methodological quality of the included studies. In conclusion, CHM seems to be beneficial and safe for Wilson's disease, but high-quality evidences are still needed to further evaluate this therapy. Therefore, additional well-designed, randomized, placebo-controlled clinical trials are needed.
22261353##2011-6-9##Non-invasive assessment of hepatic fibrosis in a series of patients with Wilson's Disease.##
22433793##2012-3-22##The diagnostic value of multimodal evoked potentials in the determination of subclinical neurological involvement of Wilson's disease.##
22720308##2012-6-22##The His1069Gln mutation in the ATP7B gene in Romanian patients with Wilson's disease referred to a tertiary gastroenterology center.##
22577234##2012-5-10##PET with 64Cu-histidine for noninvasive diagnosis of biliary copper excretion in Long-Evans cinnamon rat model of Wilson disease.##
22677543##2012-3-1##Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis.##ATP7B mutations result in Cu storage in the liver and brain in Wilson disease (WD). Atox1 and COMMD1 were found to interact with ATP7B and involved in copper transport in the hepatocyte. To understand the molecular etiology of WD, we analyzed ATP7B, Atox1 and COMMD1 genes. Direct sequencing of (i) ATP7B gene was performed in 112 WD patients to identify the spectrum of disease-causing mutations in the French population, (ii) Atox1 gene was performed to study the known polymorphism 5'UTR-99T>C in 78 WD patients with two ATP7B mutations and (iii) COMMD1 gene was performed to detect the nucleotide change c.492GAT>GAC. MLPA (Multiplex Ligation-dependent Probe Amplification) analysis was performed in WD patients presenting only one ATP7B mutation. Among our 112 WD unrelated patients, 83 different ATP7B gene mutations were identified, 27 of which were novel. Two ATP7B mutations were identified in 98 WD cases, and one mutation was identified in 14 cases. In two of these 14 WD patients, we identified the deletion of exon 4 of the ATP7B gene by MLPA technique. In 78 selected patients of the cohort with two mutations in ATP7B, we have examined genotype-phenotype correlation between the detected changes in Atox1 and COMMD1 genes, and the presentation of the WD patients. Based on the data of this study, no major role can be attributed to Atox1 and COMMD in the pathophysiology or clinical variation of WD.
22664333##2012-3-2##Discovery of human zinc deficiency: 50 years later.##Essentiality of zinc for humans and its deficiency was recognized in 1963. During the past 50 years, it has become apparent that deficiency of zinc in humans is prevalent. Nutritional deficiency of zinc may affect nearly 2 billion subjects in the developing world. Consumption of cereal proteins high in phytate decreases the availability of zinc for absorption. Conditioned deficiency of zinc is also very common. Growth retardation, hypogonadism in males, rough skin, impaired immunity, neuro-sensory disorder and cognitive impairment are some of the clinical manifestations of zinc deficiency. Zinc is involved in many biochemical functions. Over 300 enzymes require zinc for their activation and nearly 2000 transcription factors require zinc for gene expression. Zinc is essential for cell mediated immunity. Zinc is also an effective antioxidant and anti-inflammatory agent. In therapeutic dosages, zinc has been used for the treatment of acute diarrhea in infants and children, common cold, Wilson's disease, sickle cell disease and for prevention of blindness in patients with age related macular degeneration.
22565015##2012-2-13##Copper dysfunction in Alzheimer's disease: from meta-analysis of biochemical studies to new insight into genetics.##The involvement of body copper metabolism in the development of Alzheimer's disease (AD) - the most common form of dementia - is a deeply investigated issue in recent years. Copper is essential for life, but in excess it can be toxic. Recently, it has been hypothesized that copper toxicity may be a contributory factor in the etiology of the neurodegenerative disease AD. Studies on copper evaluation in AD vs. healthy controls collected in the latest 30 years and merged in a meta-analysis demonstrate that serum copper is slightly increased in AD. A specific form of copper, the copper non-bound to ceruloplasmin, or 'free' copper, seems to best characterize this increase in copper in AD patients. Clinical studies from us and other groups have demonstrated that free copper is associated with the typical deficits of AD, incipient AD and mild cognitive impairment, and specific cerebrospinal markers. Moreover, very recent data addressing molecular processes underlying copper dysfunction in AD have indicated that genetic variations of K832R and R952K Single Nucleotide Polymorphisms (SNPs) of the Wilson's disease gene ATP7B are associated also with sporadic AD. Specifically, ATP7B encodes for the protein ATPase 7B which controls free copper status in the body, and both R allele in K832R and K allele in R952K ATP7B SNPs are associated with an increased risk of having AD. Even though copper dysfunction cannot be assumed as a determinant of the disease, its causative, rather than associated, role in AD pathology as risk factor can be claimed.
23082426##2012-10-23##Concurrent massive breast enlargement, myasthenia gravis and dermopathy as manifestations of penicillamine toxicity in a Wilson's disease patient.##Penicillamine toxicity in Wilson's disease has been well reported but rarely seen now as newer agents are being used. We present a case who developed multiple rare complications of Penicillamine concurrently. Our patient is one of three siblings on Penicillamine, she was the only one who developed massive breast enlargement four months after commencing Penicillamine therapy, as well as dermatological adverse reactions and myasthenia gravis three more months later. All the adverse effects improved soon after substitution of the offending agent with Trientine.
22718296##2011-5-27##Liver structures of a patient with idiopathic copper toxicosis.##This is the first report describing the liver structures of a Japanese patient with idiopathic copper toxicosis, which should be differentiated from hepatolenticular degeneration of Wilson disease. An 11-year-old Japanese boy presented with ascites associated with biochemical liver damage. Involvement of hepatitis virus was ruled out by laboratory tests. Because urinary copper excretion was increased, Wilson disease was highly suspected, but the serum level of ceruloplasmin was normal, and Kayser-Fleischer rings were not detected by slit lamp examination. Brain images were within normal limits. ATP7B analysis was negative for mutations. Liver specimen showed cirrhosis associated with chronic active hepatitis. Almost all hepatocytes were positive for orcein-stained granules. Mallory bodies were found in some hepatocytes. Fatty change was minimal, and there were no glycogenated nuclei in the parenchyma. Combined regimens of trientine and zinc for 6 months improved the decompensated state of liver function. After 2.5 years of treatment, a second liver biopsy was performed. The post-treatment liver showed complete disappearance of portal inflammation and remarkable decrease in cuprothionein granules. Mallory bodies disappeared from the parenchyma. An abundance of hepatocellular Mallory bodies and heavy copper loading limited to the liver may be specific to idiopathic copper toxicosis.
21993972##2011-8-4##Gross hematuria in a case of Wilson disease: answers.##
22260451##2011-5-19##Brucella infection with pancytopenia after pediatric liver transplantation.##Brucellosis is considered the most widespread zoonosis in the world. It has been reported that the prevalence of seropositivity among the Turkish population varies from 3% to 14%. We present a case of brucellosis after pediatric liver transplantation. A 15-year-old boy with the diagnosis of neuro Wilson's disease underwent deceased-donor liver transplantation. The postoperative immunosuppressive protocol consisted of steroids and tacrolimus. Two months after the operation the patient experienced fever to 40°C. The patient complained of poor appetite, headache, and diarrhea. He had had pancytopenia. Despite administration of appropriate antibiotics, antiviral and antifungal agents, fever persisted for > 1 month. Multiple blood, urine, stool, and sputum cultures were negative. Bone marrow aspirate revealed hypocellularity. Liver biopsy was performed, but rejection was not observed on biopsy specimen. Brucella serology was positive and Brucella agglutination titer was 1:320. Bone marrow culture was positive for Brucella but blood culture was negative. The patient was then treated with oral doxycycline and rifampin for 8 weeks. No previous case report about Brucella infection after liver transplantation has appeared in the literature, to our knowledge; our case is presented as the first. Bone marrow hypoplasia is a rare feature of Brucella infection. Our patient with brucellosis and pancytopenia had had hypocellular bone marrow. The clinical and hematologic findings resolved with treatment of the infection. Brucella infection should be suspected in liver transplanted recipients with fever of unknown origin, especially in a recipient who has lived in an endemic area. Brucella also should be considered as a possible diagnosis in patients with pancytopenia.
22737053##2012-6-25##Endocrine symptoms as the initial manifestation of Wilson's disease.##Wilson's disease is a rare genetic disorder of copper metabolism. The difference in copper tissue accumulation is responsible for the various clinical manifestations of this disorder. If left untreated, Wilson's disease progresses to hepatic failure, severe neurological disability, and even death. Due to the complex clinical picture of Wilson's disease, its diagnosis relies on a high index of suspicion. In our paper, we present endocrine symptoms suggesting the presence of insulinoma and hyperprolactinemia as the initial clinical manifestation of Wilson's disease in a young female. Zinc acetate treatment resulted in the disappearance of hypoglycemia, galactorrhea, and menstrual abnormalities.
22646910##2012-3-24##Bipolar disorders and Wilson's disease.##
22578168##2012-5-21##Dynamic multibody protein interactions suggest versatile pathways for copper trafficking.##As part of intracellular copper trafficking pathways, the human copper chaperone Hah1 delivers Cu(+) to the Wilson's Disease Protein (WDP) via weak and dynamic protein-protein interactions. WDP contains six homologous metal binding domains (MBDs) connected by flexible linkers, and these MBDs all can receive Cu(+) from Hah1. The functional roles of the MBD multiplicity in Cu(+) trafficking are not well understood. Building on our previous study of the dynamic interactions between Hah1 and the isolated fourth MBD of WDP, here we study how Hah1 interacts with MBD34, a double-domain WDP construct, using single-molecule fluorescence resonance energy transfer (smFRET) combined with vesicle trapping. By alternating the positions of the smFRET donor and acceptor, we systematically probed Hah1-MBD3, Hah1-MBD4, and MBD3-MBD4 interaction dynamics within the multidomain system. We found that the two interconverting interaction geometries were conserved in both intermolecular Hah1-MBD and intramolecular MBD-MBD interactions. The Hah1-MBD interactions within MBD34 are stabilized by an order of magnitude relative to the isolated single-MBDs, and thermodynamic and kinetic evidence suggest that Hah1 can interact with both MBDs simultaneously. The enhanced interaction stability of Hah1 with the multi-MBD system, the dynamic intramolecular MBD-MBD interactions, and the ability of Hah1 to interact with multiple MBDs simultaneously suggest an efficient and versatile mechanism for the Hah1-to-WDP pathway to transport Cu(+).
22883114##2012-8-14##[Wilson's disease in decision-making functions of Iowa gambling task].##
22076732##2011-10-11##Metal element excretion in 24-h urine in patients with Wilson disease under treatment of D-penicillamine.##Wilson disease is an inherited autosomal recessive disorder causing copper accumulation and consequent toxicity. D-Penicillamine, a potent metal chelator, is an important therapy for Wilson disease. To investigate the changes of metal elements under the treatment of D-penicillamine, we determined the levels of Cu, Zn, Mg, Ca, Fe, Se, Mn, Pb, Hg, Cd, As, Tl, and Al by ICP-MS in 24-h urine of 115 Wilson disease patients who had received treatment with D: -penicillamine for 1 month to 22 years at maintenance doses, as well as 115 age-matched, healthy controls. The levels of Cu, Mg, Ca, Zn, Hg, Pb, Tl, Cd, and Mn in the 24-h urine of the cases were significantly higher than those of the controls (P < 0.05), and the observed increases in the levels of Mg, Ca, and Zn were directly correlated with the treatment duration with Pearson Correlation Coefficient (R) of 0.356 (Mg), 0.329 (Ca), and 0.313 (Zn), respectively (P < 0.05). On the other hand, the levels of Al and As in the 24-h urine were lower than those of the controls (P < 0.05) and were negatively correlated with the treatment time with R of -0.337 (Al) and -0.398 (As), respectively, (P < 0.05). Thus, this study indicates that the levels of metal elements may be altered in patients with Wilson disease under the treatment of D-penicillamine.
22395570##2012-3-8##Metals and the liver.##
22464590##2011-10-17##How do patients with rare diseases experience the medical encounter? Exploring role behavior and its impact on patient-physician interaction.##
22139496##2011-8-9##Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms.##
22459168##2011-11-28##The CXXC motifs in the metal binding domains are required for ATP7B to mediate resistance to cisplatin.##The copper (Cu) exporter ATP7B mediates resistance to cisplatin (cDDP) but details of the mechanism are unknown. We explored the role of the CXXC motifs in the metal binding domains (MBDs) of ATP7B by investigating binding of cDDP to the sixth metal binding domain (MBD6) or a variant in which the CXXC motif was converted to SXXS. Platinum measurement showed that cDDP bound to wild type MBD6 but not to the SXXS variant. Wild type ATP7B rendered ovarian 2008 cells resistant to cDDP. In 2008 and in HEK293T cells, wild type ATP7B trafficked from TGN to peripheral locations in response to Cu or cDDP. A variant in which the CXXC motifs in all 6 MBDs were converted to SXXS localized correctly to the TGN but failed to traffic when exposed to either Cu or cDDP. Deletion of either the first 5 MBDs or all 6 MBDs resulted in failure to localize to the TGN. Neither the SXXS variant nor the deletion variant was able to mediate resistance to cDDP. We conclude that cDDP binds to the CXXC motifs of ATP7B and that this interaction is essential to the trafficking of ATP7B and to its ability to mediate resistance to cDDP.
22292432##2012-1-31##Wilson's disease: does iron metabolism impact phenotypic presentation?##
22301700##2012-2-03##Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia.##Biliary atresia (BA) is a neonatal disorder characterized by aggressive fibroinflammatory obliteration of the biliary tract. Approximately 20 percent of BA patients demonstrate left-right laterality defects (syndromic BA). Cilia participate in important physiological functions in cholangiocytes, and as some ciliopathies have been associated with both laterality defects and hepatic fibrosis, we hypothesized that patients with syndromic BA exhibit abnormalities of cholangiocyte cilia that disrupt cholangiocyte homeostasis. Nine BA specimens were studied, including pre-Kasai diagnostic biopsies (n=7) and liver explants (n=2). Five specimens were from patients with laterality defects. These were compared with normal pediatric livers, as well as livers affected by primary sclerosing cholangitis, Wilson's disease, and cardiac cirrhosis. Biopsy sections were stained with antibodies against keratin 19 (a cholangiocyte marker) and acetylated α-tubulin (a cilia marker) and were visualized by confocal microscopy. Computer-assisted relative quantification was used to compare staining of cilia within bile ducts among samples. Surprisingly, cilia in BA specimens were significantly shorter, abnormal in their orientation, and less abundant compared with normal liver and disease controls regardless of the presence of a laterality defect. There are significant abnormalities of cholangiocyte cilia in both syndromic and non-syndromic BA livers compared with normal livers and livers affected by other cholestatic diseases. Although this may result from severe cholestasis or inflammation, it may also reflect common mechanistic pathways in different forms of BA and may have important implications for understanding the progression of the disease.
22824716##2012-7-25##Acute extrapyramidal syndrome and seizures as heralding manifestation of Wilson disease.##
22221592##2011-10-7##Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation.##
22139498##2012-2-1##Serum 'free' copper in Wilson disease.##
22071549##2011-10-18##Zinc and human health: an update.##The importance of micronutrients in health and nutrition is undisputable, and among them, zinc is an essential element whose significance to health is increasingly appreciated and whose deficiency may play an important role in the appearance of diseases. Zinc is one of the most important trace elements in the organism, with three major biological roles, as catalyst, structural, and regulatory ion. Zinc-binding motifs are found in many proteins encoded by the human genome physiologically, and free zinc is mainly regulated at the single-cell level. Zinc has critical effect in homeostasis, in immune function, in oxidative stress, in apoptosis, and in aging, and significant disorders of great public health interest are associated with zinc deficiency. In many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, autoimmune diseases, aging, age-related degenerative diseases, and Wilson's disease, the concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress, and lead to the generation of inflammatory cytokines. In these diseases, oxidative stress and chronic inflammation may play important causative roles. It is therefore important that status of zinc is assessed in any case and zinc deficiency is corrected, since the unique properties of zinc may have significant therapeutic benefits in these diseases. In the present paper, we review the zinc as a multipurpose trace element, its biological role in homeostasis, proliferation and apoptosis and its role in immunity and in chronic diseases, such as cancer, diabetes, depression, Wilson's disease, Alzheimer's disease, and other age-related diseases.
23029640##2012-10-3##Structural models of the human copper P-type ATPases ATP7A and ATP7B.##The human copper exporters ATP7A and ATP7B contain domains common to all P-type ATPases as well as class-specific features such as six sequential heavy-metal binding domains (HMBD1-HMBD6) and a type-specific constellation of transmembrane helices. Despite the medical significance of ATP7A and ATP7B related to Menkes and Wilson diseases, respectively, structural information has only been available for isolated, soluble domains. Here we present homology models based on the existing structures of soluble domains and the recently determined structure of the homologous LpCopA from the bacterium Legionella pneumophila. The models and sequence analyses show that the domains and residues involved in the catalytic phosphorylation events and copper transfer are highly conserved. In addition, there are only minor differences in the core structures of the two human proteins and the bacterial template, allowing protein-specific properties to be addressed. Furthermore, the mapping of known disease-causing missense mutations indicates that among the heavy-metal binding domains, HMBD5 and HMBD6 are the most crucial for function, thus mimicking the single or dual HMBDs found in most copper-specific P-type ATPases. We propose a structural arrangement of the HMBDs and how they may interact with the core of the proteins to achieve autoinhibition.
21974938##2011-6-7##Liver biopsy is a superior diagnostic method in some patients showing the typical laboratory features of autoimmune hepatitis.##
22169274##2011-6-23##Urinary copper excretion before and after oral intake of d-penicillamine in parents of patients with Wilson's disease.##
22480881##2012-4-7##Defining Wilson disease phenotypes: from the patient to the bench and back again.##
22240481##2011-3-27##Diverse functional properties of Wilson disease ATP7B variants.##
22269206##2011-5-21##Low ceruloplasmin in a patient with Niemann-Pick type C disease.##We present a 28-year-old woman with a diagnosis of Niemann-Pick type C disease which was initially diagnosed as Wilson disease due to low serum ceruloplasmin and elevated free copper. This report supports the hypothesis that NPC1 could play a role in copper metabolism.
22019423##2011-9-14##Feasibility of RNA studies on illegitimate transcription for molecular characterization of splicing mutations in the ATP7B gene: a case report.##Approximately 520 Wilson disease-causing mutations in the ATP7B gene have been described to date. In this study we report DNA and RNA analyses carried out for molecular characterization of a consensus sequence splicing mutation found in homozygosity in a Swiss Wilson disease patient. RNA analysis of 1946 +6 T→C in both the peripheral lymphoblasts and liver resulted in the production in the propositus of only an alternative transcript lacking exons 6, 7, and 8 resulting most likely in alterations of cell biochemistry and disease. The patient presents an early form of severe hepatic disease characterized by hepatosplenomegaly, reduced hepatic function, anemia and thrombocytopenia indicating that 1946 +6 T→C is a severe mutation. Since identical results were obtained from both peripheral lymphoblasts and liver they also suggest that RNA studies of illegitimate transcripts can be safely used for molecular characterization of ATP7B splicing mutations, thus improving genetic counseling and diagnosis of Wilson disease. Moreover these studies, contribute to reveal the exact molecular mechanisms producing Wilson disease.
22706746##2012-6-19##From suspicion of liver metastases to the diagnosis of Wilson disease in a patient with seminoma.##Wilson disease is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, kidneys, and cornea due to inadequate biliary copper excretion. It should be considered especially in young patients who have findings of liver disease with unexplained etiology. Clinical presentation of the disease can be variable, and different types of parenchymal changes of the liver can be seen on imaging modalities. Multiple nodular lesions mimicking metastases can be detected. This condition can obligate physicians to screen for a malignant disease. Moreover, it may cause misdiagnosis as advanced stage of disease when coexistent with a malignancy. The coexistence of Wilson disease with some malignant diseases has been reported; however, coexistence with seminoma was not reported before. Approximately 40% of testicular cancers are pure seminoma. Liver metastases are rare in seminoma. In this article, a case of Wilson cirrhosis is reported. The patient was first followed with diagnosis of seminoma with suspicion of liver metastases.
22706740##2012-6-19##Acute liver failure in children: 20-year experience.##
22435386##2012-3-23##Images in clinical medicine. Kayser-Fleischer rings in Wilson's disease.##
22283484##2012-2-2##Controlled photonic manipulation of proteins and other nanomaterials.##The ability to controllably handle the smallest materials is a fundamental enabling technology for nanoscience. Conventional optical tweezers have proven useful for manipulating microscale objects but cannot exert enough force to manipulate dielectric materials smaller than about 100 nm. Recently, several near-field optical trapping techniques have been developed that can provide higher trapping stiffness, but they tend to be limited in their ability to reversibly trap and release smaller materials due to a combination of the extremely high electromagnetic fields and the resulting local temperature rise. Here, we have developed a new form of photonic crystal "nanotweezer" that can trap and release on-command Wilson disease proteins, quantum dots, and 22 nm polymer particles with a temperature rise less than ~0.3 K, which is below the point where unwanted fluid mechanical effects will prevent trapping or damage biological targets.
22261259##2011-6-7##[Diagnosis and care of Wilson disease with neurological revelation].##Wilson disease is an autosomal recessive disease that produces a copper accumulation in many organs, initially in the liver, progressing to liver cirrhosis, and in the brain, with different neurologic symptoms. Diagnosis is based on clinical, biochemical, and genetic tests. Different treatments based on chelating agents may help reduce the disease's spontaneous morbidity and mortality. We describe three patients who presented Wilson disease before 18 years of age, with initial neurologic symptoms between 1998 and 2010. After comparison with literature reports, their clinical symptoms, progression, and care allowed us to propose a treatment algorithm. Neurologic symptoms are present in 35% of the patients with Wilson disease such as dystonia, extrapyramidal syndrome, dysarthria, dysphagia, and psychiatric symptoms. The time to diagnosis remains too long and may account for the increased severity of the illness encountered and problems treating these patients. The first treatment choice must be triethylenetetramine, which causes fewer side effects of initial worsening of symptoms compared to D-penicillamine. Zinc therapy is the first treatment for asymptomatic patients or those on maintenance treatment. Finally, liver transplantation is a potential treatment even if the patient presents severe neurological disability because it may improve clinical symptoms. However, further research is warranted on this matter.
21982967##2011-8-31##Honeycomb appearance of the liver in Wilson's disease.##
21838703##2011-12-22##Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment.##Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
22228371##2012-1-10##Fulminant liver failure in Wilson's disease with histologic features of postinfantile giant cell hepatitis; cytomegalovirus as the trigger for both?##Giant cell hepatitis is a well-known histological feature of several neonatal and infantile liver diseases. In contrast, postinfantile giant cell hepatitis is rarely identified in adult liver biopsies. It has been associated with varying etiologies, mainly viral infections, drug toxicity, and autoimmunity. Here, we report an 18-year-old, previously healthy man with acute liver failure, who showed giant cell hepatitis in a liver biopsy. There was no evidence of viral hepatitis A-E, autoimmunity, and no drug history. Diagnostic work-up revealed Wilson's disease as the underlying disease. As syncytial giant cell formation is thought to be a uniform reaction pattern not related to any specific etiology, copper toxicity in Wilson's disease might cause giant cell formation. In contrast, our patient recalled a recent cytomegalovirus infection, which was confirmed serologically. Therefore, the giant cell formation might also be a fingerprint of an intercurrent cytomegalovirus infection as the common trigger for both giant cell hepatitis and decompensation of Wilson's disease.
22407412##2012-3-9##[Mild cognitive impairment and depressive symptoms in patients with Wilson's disease under long-term therapy].##
23056859##2010-11-18##Atomic Absorption Spectrometry in Wilson's Disease and Its Comparison with Other Laboratory Tests and Paraclinical Findings.##
22340672##2011-11-28##EASL Clinical Practice Guidelines: Wilson's disease.##This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers in the diagnosis and management of patients with Wilson's disease. The goal is to describe a number of generally accepted approaches for diagnosis, prevention, and treatment of Wilson's disease. Recommendations are based on a systematic literature review in the Medline (PubMed version), Embase (Dialog version), and the Cochrane Library databases using entries from 1966 to 2011. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system used in other EASL CPGs was used and set against the somewhat different grading system used in the AASLD guidelines (Table 1A and B). Unfortunately, there is not a single randomized controlled trial conducted in Wilson's disease which has an optimal design. Thus, it is impossible to assign a high or even a moderate quality of evidence to any of the questions dealt with in these guidelines. The evaluation is mostly based on large case series which have been reported within the last decades.
22024248##2011-4-28##Transcranial sonography in Wilson's disease.##Transcranial sonography (TCS) has been recently recognized as a reliable and sensitive tool in detecting basal ganglia (BG) abnormalities in several movement disorders, where different patterned hyperechogenic lesions were demonstrated. The aim of this study was to investigate changes in TCS in a larger group of clinically stable patients with Wilson's disease (WD), and to correlate them with demographic and clinical data. TCS was conducted in 54 consecutive, clinically stable patients with WD who were classified as predominantly neurologic or hepatic form of the disease and were adequately assessable by TCS from both sides. TCS revealed significantly higher prevalence of SN (p = 0.007) and LN hyperechogenicity (0.001) in WD patients when compared to controls. Moderate to marked SN hyperechogenicity was found in 31.5% of WD patients (in 42% and 7% of those with neurologic and hepatic form of WD, respectively) and in 8% of healthy controls. Disease severity correlated with the hyperechogenicity of SN (r = 0.303; p = 0.029) and with the width of the third ventricle (r = 0.351; p = 0.011). There is only one report of TCS in WD previous to our study. Both studies proved the ability of TCS to detect accumulation of copper and probably other trace metals, such as iron and manganese, in the BG of WD patients.
22730635##2012-6-27##Good response with zinc acetate monotherapy in an adolescent affected by severe Wilson disease.##We describe a 17-year-old girl with haemolytic anaemia as presentation of Wilson disease. The diagnosis was based on the findings of < 20 mg/dl ceruloplasmin serum level, Kayser-Fleischer ring and Coombs-negative haemolytic anaemia. Genetic testing revealed the presence of the H1069Q heterozygous mutation. The patient was treated with Zinc acetate monotherapy, with good response, maintened after 22 months. This case emphasizes the importance of recognizing atypical clinical presentation of Wilson disease, which must always be considered in patients with Coombs-negative haemolytic anaemia. The good clinical response to treatment with zinc acetate monotherapy in our case might lend to consider the use of zinc monotherapy as initial therapy also in symptomatic patients with Wilson disease under close clinical observation. Clinical trials are needed to provide evidence for use of zinc monotherapy as first-line therapy in symptomatic patients with Wilson disease.
22424165##2011-12-1##Wilson's disease--treatment of psychiatric manifestations in pregnancy.##
22410050##2012-3-14##Liver transplantation for Wilson's disease in pediatric patients: decision making and timing.##Transplantation for Wilson's disease occupies 1/3 of the cases for metabolic diseases in Japan. At the end of 2009, 109 transplantations had been performed including three deceased donor cases in the Japanese registry. We herein discuss problems of transplantation for Wilson's disease as well as its indication, timing, and social care. We retrospectively reviewed four fulminant cases and two chronic cases who underwent living donor liver transplantation. There were two boys and two girls. Four adolescents of average age 11.3 years underwent living donor liver transplantation. Duration from onset to transplantation ranged from 10 to 23 days. Average Model for End-stage Liver Disease (MELD) score was 27.8 (range=24-31). All patients were administrated chelates prior to transplantation. MELD, New Wilson's index, Japanese scoring for liver transplantation, and liver atrophy were useful tools for transplantation decision making; however, none of them was an independent decisive tool. Clinical courses after transplantation were almost uneventful. One girl, however, developed an acute rejection episode due to noncompliance at 3 years after transplantation. All patients currently survive without a graft loss. No disease recurrence had been noted even using living related donors. Two adults evaluated for liver transplantation were listed for deceased donor liver transplantation. Both candidates developed cirrhosis despite long-term medical treatment. There were no appropriate living donors for them. There are many problems in transplantation for Wilson's disease. The indications for liver transplantation should be considered individually using some decision-making tools. The safety of the living donor should be paid the most attention.
22075048##2011-6-27##New novel mutation of the ATP7B gene in a family with Wilson disease.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The WD gene codes for a copper transporting P-type ATPase (ATP7B) are located on chromosome 13q14.3. Mutation of this gene disrupts copper homeostasis, resulting in the accumulation of copper in the liver, brain, kidneys and corneas and copper toxication at these sites. Since the detection of the WD gene in 1993, approximately 300 disease-specific muations have been identified. We recently evaluated a Korean family with WD. The proband, a 17-year-old boy, visited our hospital due to abnormal behaviors including generalized slow movement, dysphagia, drooling and ataxia. Laboratory results revealed decreases in serum copper and ceruloplasmin and an increase in urinary excretion of copper. He had liver cirrhosis, brain lesions and Kayser-Fleischer corenal rings. Molecular genetic analysis of the ATP7B gene demonstrated that he was heterozygous for deletion mutation c.2697_2723del27 in exon 11. Further study of family members revealed that his father and younger brother had the same mutation. The c.2697_2723del27 deletion mutation in exon 11 has not yet been reported as a causative muation of WD and is an in-frame deletion not expected to lead to a frame shift. Therefore, we report a novel mutation of the ATP7B gene in a family with WD.
22014607##2011-6-30##Widespread cerebral cortical mineralization in Wilson's disease detected by susceptibility-weighted imaging.##Signal abnormalities of cortical gray matter, compared with the deep nuclear structures, have received less attention in Wilson's disease (WD). They nearly always accompanied white matter signal change, and commonly are associated with epilepsy and psychiatric features. We report herein two cases diagnosed as WD who, in addition to characteristic deep nuclear lesions on MR imaging, had widespread cerebral cortical paramagnetic signals dramatically detected by susceptibility-weighted imaging. T2-weighted MR images did not show any cortico-subcortical hyperintense lesions. To our knowledge, these findings have not been described before and may help to further characterize the disease.
22308360##2012-1-30##Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model.##Copper is an essential metal nutrient that is tightly regulated in the body because loss of its homeostasis is connected to severe diseases such as Menkes and Wilson diseases, Alzheimer's disease, prion disorders, and amyotrophic lateral sclerosis. The complex relationships between copper status and various stages of health and disease remain challenging to elucidate, in part due to a lack of methods for monitoring dynamic changes in copper pools in whole living organisms. Here we present the synthesis, spectroscopy, and in vivo imaging applications of Coppersensor 790, a first-generation fluorescent sensor for visualizing labile copper pools in living animals. Coppersensor 790 combines a near-infrared emitting cyanine dye with a sulfur-rich receptor to provide a selective and sensitive turn-on response to copper. This probe is capable of monitoring fluctuations in exchangeable copper stores in living cells and mice under basal conditions, as well as in situations of copper overload or deficiency. Moreover, we demonstrate the utility of this unique chemical tool to detect aberrant increases in labile copper levels in a murine model of Wilson disease, a genetic disorder that is characterized by accumulation of excess copper. The ability to monitor real-time copper fluxes in living animals offers potentially rich opportunities to examine copper physiology in health and disease.
22083169##2011-11-16##Evolving perspectives in Wilson disease: diagnosis, treatment and monitoring.##Wilson disease (WD), the autosomal recessively inherited copper overload disorder, remains a diagnostic and therapeutic challenge. In the last decade, direct sequencing of the affected gene ATP7B became commercially available, but interpretation of the results still requires careful attention. Thus, a combination of tests reflecting the disturbed copper metabolism is needed to make the final diagnosis. Because of the low disease frequency, the existing treatment concepts are not based on controlled trails. Here, recent outcome reports of larger cohort studies challenge the recommended therapies and call for individualized treatment strategies. The notion, that certain medical regimens may either be insufficient to upkeep copper homeostasis or may lead to a clinically relevant overtreatment, demand a continuous monitoring of patients even after decades of therapy. In this article, we review current diagnostic and therapeutic approaches in WD.
22170460##2011-12-15##Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population.##Although many studies have been performed to identify mutations in Korean patients with various autosomal-recessive Mendelian disorders (AR-MDs), little is known about the carrier frequencies of AR-MDs in the Korean population. Twenty common mutations from six AR-MDs, including Wilson disease (WD), non-syndromic hearing loss (NSHL), glycogen storage disease type Ia (GSD Ia), phenylketonuria (PKU), congenital hypothyroidism (CH), and congenital lipoid adrenal hyperplasia (CLAH) were selected to screen for based on previous studies. A total of 3057 Koreans were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry followed by confirmation using the Sanger sequencing. We found 201 and 8 carriers with either one or two mutations in different genes, respectively, yielding a total carrier frequency of 1 in 15 (6.7%). Of the six AR-MDs, NSHL has the highest carrier frequency followed by WD, CH, CLAH, GSD Ia, and PKU. As carrier screening tests are becoming prevalent and the number of mutations known and tested is rising, a priori data on the carrier frequencies in different ethnic groups is mandatory to plan a population screening program and to estimate its efficiency. In light of this, the present results can be used as a basis to establish a screening policy for common AR-MRs in the Korean population.
22293421##2012-2-2##Metallothionein (MT) 1/2 expression in MT 1/2 and MT 3 knock-out mice and Long-Evans Cinnamon (LEC) rats.##Metallothionein (MT) is known to be involved in various physiological roles and diseases. However, a standard method for MT measurement has not been established until recently. Therefore, we have developed an easy and specific enzyme-linked immunosorbent assays (ELISA) to determine MT-1 and MT-2. In order to evaluate the method we developed, MT-1/2 in liver, kidney and brain was determined in wild type (WT), MT-1/2 knockout (KO) and MT-3 KO mice, with and without Cd treatment. MT 1/2 in urine was determined in genetically disordered LEC rats (an animal model of Wilson disease). MT-1/2 concentrations in the liver, kidney and brain in MT-1/2 KO mice were significantly lower compared to those of WT and MT-3 KO mice. MT-1/2 concentrations in the livers of WT mice significantly increased with Cd administration, but not in MT-1/2 KO mice. Similar results were observed by immunohistochemical staining. To confirm the molecular weight (MW) of MT detected in organs by the ELISA, analysis with a Sephadex G-75 was performed. Two peaks of MT-1/2 (MW small and large) were detected in WT and MT-3 KO mice. The small MT peak was mostly depleted in MT 1/2-KO mice, while a large MT peak remained. A significant increase in MT-1/2 concentration was detected in the urine of LEC rats with age and especially at the hepatitis stage. In conclusion, MT-1/2 ELISA and immunohistochemical staining was highly correlated with MT-1/2 determination in experimental animal specimens and could be a robust analytical tool for physiological and toxicological studies.
22140056##2011-12-6##Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease.##The outcome of consecutive hepatocyte transplants was explored in a rat model of Wilson's disease before the onset of fulminant hepatitis without preconditioning regimens. Rats received a high-copper diet in order to induce a rapid induction of liver failure. Sham-operated rats (15/15) developed jaundice and fulminant hepatitis, and they died within 4 weeks of first transplantation. Despite the continuation of a high dietary copper challenge, long-term survival was observed for a notable proportion of the transplanted animals (7/18). All survivors displayed normalized levels of hepatitis-associated serum markers and ceruloplasmin oxidase activity by posttransplant days 50 and 98, respectively. The liver copper concentrations, the liver histology, and the expression of marker genes were significantly restored within 4 months of transplantation in comparison with the control group. The high expression of a copper transporter gene (ATPase Cu++ transporting beta polypeptide) in the livers of the survivors indicated a high rate of repopulation by donor hepatocytes. Our data suggest that repeated cell transplantation can overcome the limitations of a single therapy session in rats with severe hepatic disease by functionally restoring the host liver without preconditioning.
21788094##2011-2-10##Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy.##
22147205##2011-8-29##Canine models of copper toxicosis for understanding mammalian copper metabolism.##Hereditary forms of copper toxicosis exist in man and dogs. In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B. Forms of copper toxicosis for which no causal gene is known yet are recognized as well, often in young children. Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered. Genetic studies in the Bedlington terrier, a dog breed affected with copper toxicosis, identified COMMD1, a gene that was previously unknown to be involved in copper metabolism. Besides the Bedlington terrier, a number of other dog breeds suffer from hereditary copper toxicosis and show similar phenotypes to humans with copper storage disorders. Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases. This article reviews the work that has been done on the Bedlington terrier, summarizes what was learned from studies into COMMD1 function, describes hereditary copper toxicosis phenotypes in other dog breeds, and discusses the opportunities for genome-wide association studies on copper toxicosis in the dog to contribute to the understanding of mammalian copper metabolism and copper metabolism disorders in man.
22350045##2012-2-22##Wilson's disease treated with penicillamine and lupus erythematosus: related or distinct entities?##Systemic lupus erythematosus (SLE) has been reported to be associated to Wilson's disease, as a complication of treatment with penicillamine. Even though drug-induced lupus erythematosus (DILE) has some features in common with SLE, they are distinct entities. We report the case of a young girl who at the age of five had a diagnosis of Wilson's disease and she started therapy with penicillamine. Eight years after the beginning of therapy, she developed proteinuria, which was considered to be related to penicillamine. Two years later, she developed arthritis, malar rash and laboratory findings suggestive for lupus erythematosus. At the beginning her symptoms, due to the known association between penicillamine and DILE, were thought to be related to this treatment. In this hypothesis, she was referred to the Rheumatology Centre; zinc acetate was substituted for penicillamine and she started naproxen for the treatment of arthritis. Anyway, the subsequent clinical course and laboratory findings led us to a diagnosis of idiopathic SLE. A renal biopsy detected massive mesangiocapillary proliferation with subendothelial deposits (wire loops) and duplication of glomerular basement membrane (active diffuse global proliferative lupus nephritis, class IV G A). To our knowledge, this is the first report of an association between Wilson's disease and SLE.
21327972##2011-2-18##Positron emission tomography of copper metabolism in the Atp7b-/- knock-out mouse model of Wilson's disease.##
22447258##2012-3-23##Sleep disorders in chronic liver disease.##Sleep-related complaints and disturbances are increasingly recognized in the setting of chronic liver disease and have recently been shown to be an important prognostic factor in patients with advanced chronic liver disease. This article reviews the literature surrounding sleep disturbances and disorders in a variety of types of chronic liver disease. This includes the association of sleep disturbances with hepatitis C and antiviral therapy, primary biliary cirrhosis, and Wilson disease as well as the circadian rhythm abnormalities present in cirrhosis and hepatic encephalopathy. The association between chronic liver disease, particularly nonalcoholic fatty liver disease, and sleep-disordered breathing is also reviewed in detail.
22312450##2011-6-3##Liver transplantation for Wilson disease.##The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options may include hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD.
22130675##2011-11-30##Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B.##ATP7A and ATP7B are copper-transporting P(1B)-type ATPases (Cu-ATPases) that are critical for regulating intracellular copper homeostasis. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and copper toxicity disorders, Menkes and Wilson diseases, respectively. Clusterin and COMMD1 were previously identified as interacting partners of these Cu-ATPases. In this study, we confirmed that clusterin and COMMD1 interact to down-regulate both ATP7A and ATP7B. Overexpression and knockdown of clusterin/COMMD1 decreased and increased, respectively, endogenous levels of ATP7A and ATP7B, consistent with a role in facilitating Cu-ATPase degradation. We demonstrate that whereas the clusterin/ATP7B interaction was enhanced by oxidative stress or mutation of ATP7B, the COMMD1/ATP7B interaction did not change under oxidative stress conditions, and only increased with ATP7B mutations that led to its misfolding. Clusterin and COMMD1 facilitated the degradation of ATP7B containing the same Wilson disease-causing C-terminal mutations via different degradation pathways, clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway. Furthermore, endogenous ATP7B existed in a complex with clusterin and COMMD1, but these interactions were neither competitive nor cooperative and occurred independently of each other. Together these data indicate that clusterin and COMMD1 represent alternative and independent systems regulating Cu-ATPase quality control, and consequently contributing to the maintenance of copper homeostasis.
21917273##2011-4-17##Gender differences in Wilson's disease.##
22243965##2011-9-20##Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin.##Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.
23326792##2012-2-25##Mismanagement of Wilson's disease as psychotic disorder.##Wilson's disease (WD) or hepatolenticular degeneration is an inherited neurodegenerative disorder of copper metabolism (autosomal recessive, chromosome13). Psychiatric disorders in WD include dementia, characterized by mental slowness, poor concentration, and memory impairment. Symptoms may progress rapidly, especially in younger patients, but are more often gradual in development with periods of remission and exacerbation. Delusional disorder and schizophrenia-like psychosis are rare forms of psychiatric presentation. In this report, the patient with WD presented by psychosis symptoms and treated mistaken as schizophrenia for almost ten years. Although he has treated with antipsychotics, he had periods of remissions and relapses and never was symptoms free. Since psychosis can be the manifestation of medical diseases such as WD, overall view of these patients is necessary and medical diseases should be considered as a differential diagnosis.
22269222##2012-1-20##Mechanisms and significance of eryptosis, the suicidal death of erythrocytes.##Eryptosis, the suicidal death of erythrocytes, is characterized by erythrocyte shrinkage, blebbing, and phospholipid scrambling of the cell membrane. Eryptosis is triggered by increased cytosolic Ca(2+) activity, which may result from Ca(2+) entry through PGE(2)-activated Ca(2+)-permeable cation channels. The Ca(2+) sensitivity of the scrambling machinery is enhanced by ceramide, which is formed by an acid sphingomyelinase, an enzyme stimulated by platelet-activating factor. Eryptosis is enhanced in a variety of clinical conditions such as sickle-cell anemia, β-thalassemia, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome, phosphate depletion, iron deficiency, sepsis, hemolytic uremic syndrome, renal insufficiency, diabetes, malaria, mycoplasma infection, and Wilson's disease. Eryptosis is enhanced in mouse models of sickle cell anemia and thalassemia, as well as in mice lacking functional annexin 7, cGMP-dependent protein kinase type I, AMP-activated protein kinase, Janus kinase 3, anion exchanger 1, adenomatous polyposis coli, or Klotho. Eryptosis is triggered by osmotic shock, oxidative stress, energy depletion, hyperthermia, and a myriad of small molecules. Eryptosis is inhibited by a variety of substances including nitric oxide and catecholamines. Erythropoietin counteracts eryptosis in part by inhibiting the Ca(2+)-permeable cation channels. Excessive erythropoietin concentrations lead, however, to formation of erythrocytes, which are particularly sensitive to eryptotic stimuli. Accelerated eryptosis may be compensated by enhanced erythropoiesis, which is apparent from reticulocytosis. If the compensation is not sufficient, clinically relevant anemia develops. Beyond that, adhesion of eryptotic erythrocytes to the vascular wall may lead to impairment of microcirculation.
22147193##2011-6-29##MTP -493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients.##The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8% of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3% of the patients with fibrosis grade 1+2 (OR = 1.8; 95%CI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95%CI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.
22606437##2011-11-30##Unexplained findings of kayser-fleischer-like rings in a patient with cryptogenic cirrhosis.##Cryptogenic cirrhosis (CC) is defined as cirrhosis occurring in an individual without an identifiable cause of liver disease, such as excessive alcohol consumption, viral hepatitis infection, hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, chronic intake of medications that could induce cirrhosis, alpha-1-antitrypsin deficiency, Wilson's disease, or any other rare cause of cirrhosis according to the clinical context. Cryptogenic cirrhosis is a common cause of liver-related morbidity and mortality in the United States. Nonalcoholic fatty liver disease is now recognized as the most common cause of cryptogenic cirrhosis. A biopsy specimen is also important for detecting histological advanced disease, which may be clinically silent and undetected by liver-related tests or diagnostic imaging. We are presenting an unusual case of a patient with cryptogenic cirrhosis found to have Kayser-Fleischer-like rings without evidence of Wilson's disease.
21824720##2010-5-13##Characterizing paramagnetic signal in a patient with Wilson's disease by susceptibility-weighted imaging.##
23049615##2012-5-7##Quality of Life and Psychiatric Symptoms in Wilson's Disease: the Relevance of Bipolar Disorders.##
22473403##2011-9-30##Wilson's disease: an analysis of 28 Brazilian children.##
22455587##2011-10-10##Selective divalent copper chelation for the treatment of diabetes mellitus.##Oxidative stress and mitochondrial dysfunction have been identified by many workers as key pathogenic mechanisms in ageing-related metabolic, cardiovascular and neurodegenerative diseases (for example diabetes mellitus, heart failure and Alzheimer's disease). However, although numerous molecular mechanisms have been advanced to account for these processes, their precise nature remains obscure. This author has previously suggested that, in such diseases, these two mechanisms are likely to occur as manifestations of a single underlying disturbance of copper regulation. Copper is an essential but highly-toxic trace metal that is closely regulated in biological systems. Several rare genetic disorders of copper homeostasis are known in humans: these primarily affect various proteins that mediate intracellular copper transport processes, and can lead either to tissue copper deficiency or overload states. These examples illustrate how impaired regulation of copper transport pathways can cause organ damage and provide important insights into the impact of defects in specific molecular processes, including those catalyzed by the copper-transporting ATPases, ATP7A (mutated in Menkes disease), ATP7B (Wilson's disease), and the copper chaperones such as those for cytochrome c oxidase, SCO1 and SCO2. In diabetes, impaired copper regulation manifests as elevations in urinary CuII excretion, systemic chelatable-CuII and full copper balance, in increased pro-oxidant stress and defective antioxidant defenses, and in progressive damage to the blood vessels, heart, kidneys, retina and nerves. Linkages between dysregulated copper and organ damage can be demonstrated by CuII-selective chelation, which simultaneously prevents/reverses both copper dysregulation and organ damage. Pathogenic structures in blood vessels that contribute to binding and localization of catalytically-active CuII probably include advanced glycation end products (AGEs), as well as atherosclerotic plaque: the latter probably undergoes AGE-modification itself. Defective copper regulation mediates organ damage through two general processes that occur simultaneously in the same individual: elevation of CuII-mediated pro-oxidant stress and impairment of copper-catalyzed antioxidant defence mechanisms. This author has proposed that diabetes-evoked copper dysregulation is an important new target for therapeutic intervention to prevent/reverse organ damage in diabetes, heart failure, and neurodegenerative diseases, and that triethylenetetramine (TETA) is the first in a new class of anti-diabetic molecules, which function by targetting these copper-mediated pathogenic mechanisms. TETA prevents tissue damage and causes organ regeneration by acting as a highly-selective CuII chelator which suppresses copper-mediated oxidative stress and restores anti-oxidant defenses. My group has employed TETA in a comprehensive programme of nonclinical studies and proof-of-principle clinical trials, thereby characterizing copper dysregulation in diabetes and identifying numerous linked cellular and molecular mechanisms though which TETA exerts its therapeutic actions. Many of the results obtained in nonclinical models with respect to the molecular mechanisms of diabetic organ damage have not yet been replicated in patients' tissues so their applicability to the human disease must be considered as inferential until the results of informative clinical studies become available. Based on evidence from the studies reviewed herein, trientine is now proceeding into the later stages of pharmaceutical development for the treatment of heart failure and other diabetic complications.
23046650##2012-10-11##Regulation of copper transporters in human cells.##Copper is essential for normal growth and development of human organisms. The role of copper as a cofactor of important metabolic enzymes, such as cytochrome c oxidase, superoxide dismutase, lysyl oxidase, dopamine-β-hydroxylase, and many others, has been well established. In recent years, new regulatory roles of copper have emerged. Accumulating evidence points to the involvement of copper in lipid metabolism, antimicrobial defense, neuronal activity, resistance of tumor cells to platinum-based chemotherapeutic drugs, kinase-mediated signal transduction, and other essential cellular processes. For many of these processes, the precise mechanism of copper action remains to be established. Nevertheless, it is increasingly clear that many regulatory and signaling events are associated with changes in the intracellular localization and abundance of copper transporters, as well as distinct compartmentalization of copper itself. In this review, we discuss current data on regulation of the localization and abundance of copper transporters in response to metabolic and signaling events in human cells. Regulation by kinase-mediated phosphorylation will be addressed along with the emerging area of the redox-driven control of copper transport. We highlight mechanistic questions that await further testing.
23930071##2013-8-10##D-penicillamine induced membranous glomerulonephritis in a child with Wilson's disease.##
25013635##2014-7-12##Two-year experience of orthotopic liver transplantation in afzalipoor hospital, kerman, southeastern iran.##
22790141##2012-7-1##Resolution of cranial MRI and SPECT abnormalities in a patient with Wilson's disease following oral zinc monotherapy.##A 38-year-old woman with Wilson's disease developed neurological deterioration after 25 years of low-dose penicillamine administration. She showed an akinetic-rigid syndrome and cerebellar motor ataxia. Brain MRI showed increased signal intensity at the bilateral pons, midbrain, putamen, and thalamus. 123I-IMP-SPECT revealed a diffuse reduction of cerebral blood flow at the bilateral cerebral hemisphere including the basal ganglia. After the patient's regimen was changed to zinc therapy, her neurological condition gradually improved, and she showed almost complete recovery within two years. Serial MRI and SPECT studies showed a marked improvement in the lesions.
22356903##2012-2-24##Association of K832R and R952K SNPs of Wilson's disease gene with Alzheimer's disease.##Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson's disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12-2.60); p = 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19-2.80); p = 0.006] ATP7B SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D' = 0.79) and controls (D' = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD.
22258517##2012-1-20##Copper hypothesis in the missing hereditability of sporadic Alzheimer's disease: ATP7B gene as potential harbor of rare variants.##Sporadic Alzheimer's disease (LOAD) is the most common form of dementia and has a high heritability. The genes associated with LOAD explain a small proportion of the genetic contribution to LOAD, leaving several genetic risk factors to be identified. Some authors have suggested a shift from the paradigm "common disease-common gene variants", which is currently the basis for genome-wide association studies, to a "common disease-multiple rare gene variants" hypothesis aimed at identifying rarer allele variants with large effect size on LOAD onset, suggesting that they may account for the 'missing' heritability of LOAD. Recent studies have demonstrated the connection between copper imbalance and LOAD. Some studies have pointed out the pivotal role of 'free' copper, the portion of serum copper non-bound to ceruloplasmin. Free copper has been already identified as a biological marker of Wilson's disease (WD), the paradigmatic disease of free copper toxicosis or accumulation. The ATP7B gene controls free copper levels, and its mutations cause WD. The paradigm shift to "common disease-multiple rare variants" may suitably fit the ATP7B gene; the high heterogeneity of the ATP7B gene may have hidden multiple rare variants with large effect sizes for LOAD. Demonstrating that the ATP7B gene harbors rare variants which may account for some of the missing hereditability of LOAD would support previous evidence of copper involvement in LOAD from a new and totally different perspective and would bring almost immediate benefits in the clinical community in terms of early diagnosis, treatment efficacy, LOAD prevention, and cost savings.
21832955##2011-8-12##Manifestations and evolution of Wilson disease in pediatric patients carrying ATP7B mutation L708P.##
21832954##2011-8-12##Wilson disease: lessons from an island population.##
21691224##2011-6-22##Acute on chronic liver disease in children from the developing world: recognition and prognosis.##
23430908##2011-7-5##Homozygosity for Non-H1069Q Missense Mutations in ATP7B Gene and Early Severe Liver Disease: Report of Two Families and a Meta-analysis.##Most patients with Wilson's disease (WD) are compound heterozygote, which complicates establishing genotype-phenotype correlations. We identified five patients who presented with early and/or severe hepatic disease who are homozygous for W939C missense mutation on exon 12 of ATP7B. We therefore conducted a meta-analysis to determine the phenotype of patients homozygous for missense or nonsense mutations in all ATP7B exons.The meta-analysis showed that 69% and 31% of patients are homozygous for H1069Q and non-H1069Q mutations, respectively. Compared to patients with H1069Q, those with non-H1069Q mutations were significantly more likely to have a hepatic phenotype, severe liver disease, a mixed phenotype, and less likely to have a neurologic phenotype. Compared to patients with nonsense mutations, those with non-H1069Q ones were equally likely to present with a hepatic phenotype and to have severe liver disease. Mean age at symptom onset in the non-H1069Q versus the H1069Q group was 15.5 versus 20.5years (p<0.001).Our data suggest that mutation W939C and other non-H1069Q missense mutations are associated with early disease onset, a hepatic phenotype, and a high risk of hepatic failure in homozygous patients. Early identification of such patients by genetic screening is important for timely initiation of treatment and prevention of complications.
23430866##2010-5-6##Liver failure with coagulopathy, hyperammonemia and cyclic vomiting in a toddler revealed to have combined heterozygosity for genes involved with ornithine transcarbamylase deficiency and Wilson disease.##A girl with a 2 month history of cyclic episodes of vomiting, diarrhea, and lethargy lasting 2-3 days each presented with acute hepatopathy (ALT 3,500 IU/L) with coagulopathy (PT 55 s) and hyperammonemia (207 μmol/L) at age 1½ years. Biochemical and molecular analyzes revealed ornithine transcarbamylase (OTC) deficiency. While laboratory signs of mild hepatocellular dysfunction are common in OTC deficiency, substantial liver failure with coagulopathy is generally not seen, although four others cases have been reported, three of which presented with cyclic vomiting. Further evaluation in our case revealed elevated urine (198.8 μg/g creatinine) and liver (103 μg/g dry weight) copper content, and a heterozygous mutation in the Wilson disease gene, ATP7B. Our patient, now aged 5 years, has remained in excellent health with normal growth and development on fasting avoidance, a modified vegan diet, and sodium phenylbutyrate.These five cases demonstrate that generalized liver dysfunction/failure is a potential serious complication of OTC deficiency, although not a common one, and suggests that an ALT and PT should be obtained in OTC patients during episodes of hyperammonemia. Cyclic vomiting is a known presentation of OTC deficiency; it is not known if comorbid liver failure predisposes toward this phenotype. We propose that the heterozygote state in ATP7B increases the liver copper content, thus predisposing our patient with OTC deficiency to develop liver failure during a hyperammonemic episode. Our present case is an example of the opportunity of molecular diagnostics to identify putative modifier genes in patients with atypical presentations of genetic disorders.
22098612##2011-1-31##Iron metabolism and the role of HFE gene polymorphisms in Wilson disease.##
22522855##2012-4-24##[Magnetic resonance images in Wilson's disease].##
22217972##2012-1-6##Acute liver failure as the initial manifestation of Wilson disease triggered by human parvovirus b19 infection.##
23166778##2012-7-2##Retinal neurodegeneration in Wilson's disease revealed by spectral domain optical coherence tomography.##
22879914##2012-4-11##COMMD1-deficient dogs accumulate copper in hepatocytes and provide a good model for chronic hepatitis and fibrosis.##New therapeutic concepts developed in rodent models should ideally be evaluated in large animal models prior to human clinical application. COMMD1-deficiency in dogs leads to hepatic copper accumulation and chronic hepatitis representing a Wilson's disease like phenotype. Detailed understanding of the pathogenesis and time course of this animal model is required to test its feasibility as a large animal model for chronic hepatitis. In addition to mouse models, true longitudinal studies are possible due to the size of these dogs permitting detailed analysis of the sequence of events from initial insult to final cirrhosis. Therefore, liver biopsies were taken each half year from five new born COMMD1-deficient dogs over a period of 42 months. Biopsies were used for H&E, reticulin, and rubeanic acid (copper) staining. Immunohistochemistry was performed on hepatic stellate cell (HSC) activation marker (alpha-smooth muscle actin, α-SMA), proliferation (Ki67), apoptosis (caspase-3), and bile duct and liver progenitor cell (LPC) markers keratin (K) 19 and 7. Quantitative RT-PCR and Western Blots were performed on gene products involved in the regenerative and fibrotic pathways. Maximum copper accumulation was reached at 12 months of age, which coincided with the first signs of hepatitis. HSCs were activated (α-SMA) from 18 months onwards, with increasing reticulin deposition and hepatocytic proliferation in later stages. Hepatitis and caspase-3 activity (first noticed at 18 months) increased over time. Both HGF and TGF-β1 gene expression peaked at 24 months, and thereafter decreased gradually. Both STAT3 and c-MET showed an increased time-dependent activation. Smad2/3 phosphorylation, indicative for fibrogenesis, was present at all time-points. COMMD1-deficient dogs develop chronic liver disease and cirrhosis comparable to human chronic hepatitis, although at much higher pace. Therefore they represent a genetically-defined large animal model to test clinical applicability of new therapeutics developed in rodent models.
22802922##2012-2-21##Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load.##Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson's disease (WD), this function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b(-/-) mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b(-/-) livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr1(-/-) knockouts, which have normal ATP7B function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD.
22629446##2011-8-11##Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice.##Wilson disease (WD) is characterized by the accumulation of copper arising from a mutation in the ATP7B gene. Penicillamine (PA) makes 10-50% of the patients with neurologic symptoms neurologically worse at the early stage of administration. The aim of this study was to determine how the copper metabolism changes and whether the change impairs the brain of toxic milk (tx) mice, an animal model of WD, during the PA administration. The free copper and protein-bound copper concentrations in the serum, cortex and basal ganglia of tx mice with PA administration for 3 days, 10 days and 14 days, respectively, were investigated. The expression of copper transporters, ATP7A and CTR1,was analyzed by real-time quantitative PCR, immunofluorescence and Western blot. Then SOD, MDA and GSH/GSSG were detected to determine whether the oxidative stress changed correspondingly. The results revealed the elevated free copper concentrations in the serum and brain, and declined protein-bound copper concentrations in the brain of tx mice during PA administration. Meanwhile, transiently increased expression of ATP7A and CTR1 was observed generally in the brain parenchyma by immunofluorescence, real-time quantitative PCR and Western blot. Additionally, ATP7A and CTR1 were observed to locate mainly at Golgi apparatus and cellular membrane respectively. Intense staining of ATP7A in the choroid plexus was found in tx mice on the 3rd and 10th day of PA treatment, but rare staining of ATP7A and CTR1 in the blood-brain barrier (BBB). Decreased GSH/GSSG and increased MDA concentrations were also viewed in the cortex and basal ganglia. Our results suggested the elevated free copper concentrations in the brain might lead to the enhanced oxidative stress during PA administration. The increased free copper in the brain might come from the copper mobilized from brain parenchyma cells but not from the serum according to the ATP7A and CTR1 expression analysis.
22574136##2012-1-30##In vitro thermodynamic dissection of human copper transfer from chaperone to target protein.##Transient protein-protein and protein-ligand interactions are fundamental components of biological activity. To understand biological activity, not only the structures of the involved proteins are important but also the energetics of the individual steps of a reaction. Here we use in vitro biophysical methods to deduce thermodynamic parameters of copper (Cu) transfer from the human copper chaperone Atox1 to the fourth metal-binding domain of the Wilson disease protein (WD4). Atox1 and WD4 have the same fold (ferredoxin-like fold) and Cu-binding site (two surface exposed cysteine residues) and thus it is not clear what drives metal transfer from one protein to the other. Cu transfer is a two-step reaction involving a metal-dependent ternary complex in which the metal is coordinated by cysteines from both proteins (i.e., Atox1-Cu-WD4). We employ size exclusion chromatography to estimate individual equilibrium constants for the two steps. This information together with calorimetric titration data are used to reveal enthalpic and entropic contributions of each step in the transfer process. Upon combining the equilibrium constants for both steps, a metal exchange factor (from Atox1 to WD4) of 10 is calculated, governed by a negative net enthalpy change of ∼10 kJ/mol. Thus, small variations in interaction energies, not always obvious upon comparing protein structures alone, may fuel vectorial metal transfer.
23289267##2013-1-8##[Wilson disease as the significant risk factor of surgical treatment--clinical case report].##Wilson Disease (W ) is a rare inborn disorder of cooper metabolism. In approximately 40% of cases signs and symptoms of abnormal liver functions are observed due to hepatic inflammation, cirrhosis or insufficiency. The mainstay treatment is the conservative treatment with zinc (eg Zincteral) or penicillamine. The Authors present a patient with WD who underwent surgery because of an advanced rectal prolapse (laparotomy, rectal mobilization, rectopexy, the partial sigmoid colon resection with the primary anastomosis). The postoperative course was complicated by anastomotic leakage and a subsequent diffuse peritonitis. The patient required relaparotomy and three weeks treatment in the intensive therapy unit. The Authors consider the WD as a significant risk factor for surgical patients. Surgical treatment of patients with WD should be least invasive.
21920437##2011-4-4##Severe dysfunction of respiratory chain and cholesterol metabolism in Atp7b(-/-) mice as a model for Wilson disease.##Wilson disease (WD) is caused by mutations of the WD gene ATP7B resulting in copper accumulation in different tissues. WD patients display hepatic and neurological disease with yet poorly understood pathomechanisms. Therefore, we studied age-dependent (3, 6, 47weeks) biochemical and bioenergetical changes in Atp7b(-/-) mice focusing on liver and brain. Mutant mice showed strongly elevated copper and iron levels. Age-dependently decreasing hepatic reduced glutathione levels along with increasing oxidized to reduced glutathione ratios in liver and brain of 47weeks old mice as well as elevated hepatic and cerebral superoxide dismutase activities in 3weeks old mutant mice highlighted oxidative stress in the investigated tissues. We could not find evidence that amino acid metabolism or beta-oxidation is impaired by deficiency of ATP7B. In contrast, sterol metabolism was severely dysregulated. In brains of 3week old mice cholesterol, 8-dehydrocholesterol, desmosterol, 7-dehydrocholesterol, and lathosterol were all highly increased. These changes reversed age-dependently resulting in reduced levels of all previously increased sterol metabolites in 47weeks old mice. A similar pattern of sterol metabolite changes was found in hepatic tissue, though less pronounced. Moreover, mitochondrial energy production was severely affected. Respiratory chain complex I activity was increased in liver and brain of mutant mice, whereas complex II, III, and IV activities were reduced. In addition, aconitase activity was diminished in brains of Atp7b(-/-) mice. Summarizing, our study reveals oxidative stress along with severe dysfunction of mitochondrial energy production and of sterol metabolism in Atp7b(-/-) mice shedding new light on the pathogenesis of WD.
21950517##2011-9-27##Cognitive and psychiatric phenotypes of movement disorders in children: a systematic review.##
21997183##2011-7-26##Identification of high-copper-responsive target pathways in Atp7b knockout mouse liver by GSEA on microarray data sets.##The mutation of the Wilson's disease protein ATP7B has been widely used to study the direct link between hepatic high copper and development of liver pathology. Several studies have used gene expression profiling of high-copper effects to identify the key genes in the process, but few focused on the involved pathways and the coexpression patterns of associated pathways. We used a microarray data set from the public database library of GEO (Gene Expression Omnibus), which is associated with liver transcriptome in the early stages of copper accumulation in the mouse model of Wilson's disease under Atp7b knockout. To be more powerful than conventional single-gene methods in the study of complex diseases, we applied gene set enrichment analysis (GSEA) on the data sets and performed candidate transcription factors selection. As a result, 16 upregulated pathways such as tryptophan metabolism and cell cycle and 15 downregulated pathways such as TCA cycle and PPAR signaling pathway were identified as high-copper-responsive target pathways in Atp7b knockout mouse liver, and most of them had not been reported on previously. Finally, coexpression networks of related pathways were constructed with the significant core genes and transcription factors such as SREBP1 and PPARG. The results of our study may help us better understand the molecular mechanisms of high-copper effects in mice liver in genome-wide.
22170272##2011-12-16##The Wilson films--Wilson's disease.##
21370261##2009-11-10##A film of patients with movement disorders made in Queen Square, London in the Mid-1920s by Samuel Alexander Kinnier Wilson.##
21999650##2011-10-18##Medical management of chronic liver diseases (CLD) in children (part II): focus on the complications of CLD, and CLD that require special considerations.##Treatment of the causes of many chronic liver diseases (CLDs) may not be possible. In this case, complications must be anticipated, prevented or at least controlled by the best available therapeutic modalities. There are three main goals for the management of portal hypertension: (i) prevention of the first episode of variceal bleeding largely by non-selective β-adrenoceptor antagonists, which is not generally recommended in children; (ii) control of bleeding by using a stepwise approach from the least to most invasive strategies; (iii) and prevention of re-bleeding using bypass operations, with particular enthusiasm for the use of meso-Rex bypass in the pediatric population. Hepatic encephalopathy management also consists of three main aspects: (i) ruling out other causes of encephalopathy; (ii) identifying and treating precipitating factors; and (iii) starting empiric treatment with drugs such as lactulose, rifaximin, sodium benzoate, and flumazenil. Treatment of mild ascites and peripheral edema should begin with the restriction of sodium and water, followed by careful diuresis, then large-volume paracentesis associated with colloid volume expansion in severe cases. Empiric broad spectrum antimicrobial therapy should be used for the treatment of spontaneous bacterial peritonitis, bacterial and fungal sepsis, and cholangitis, after taking appropriate cultures, with appropriate changes in therapy after sensitivity testing. Empirical therapies continue to be the standard practice for pruritus; these consist of bile acid binding agents, phenobarbital (phenobarbitone), ursodeoxycholic acid, antihistamines, rifampin (rifampicin), and carbamazepine. Partial external biliary diversion can be used in refractory cases. Once hepatorenal syndrome is suspected, treatment should be initiated early in order to prevent the progression of renal failure; approaches consist of general supportive measures, management of concomitant complications, screening for sepsis, treatment with antibiotics, use of vasopressin analogs (terlipressin), and renal replacement therapy if needed. Hepatopulmonary syndrome and portopulmonary hypertension are best managed by liver transplantation. Provision of an adequate caloric supply, nutrition, and vitamin/mineral supplements for the management of growth failure, required vaccinations, and special care for ensuring psychologic well-being should be ensured. Anticoagulation might be attempted in acute portal vein thrombosis. Some CLDs, such as extrahepatic biliary atresia (EHBA), Crigler-Najjar syndrome, and Indian childhood cirrhosis, require special considerations. For EHBA, Kasai hepatoportoenterostomy is the current standard surgical approach in combination with nutritional therapy and supplemental fat and water soluble vitamins, minerals, and trace elements. In type 1 Crigler-Najjar syndrome, extensive phototherapy is the mainstay of treatment, in association with adjuvant therapy to bind photobilirubin such as calcium phosphate, cholestyramine, or agar, until liver transplantation can be carried out. Treating Indian childhood cirrhosis with penicillamine early in the course of the disease and at doses similar to those used to treat Wilson disease decreases the mortality rate by half. New hopes for the future include extracorporeal liver support devices (the molecular adsorbent recirculating system [MARS®] and Prometheus®), hepatocyte transplantation, liver-directed gene therapy, genetically engineered enzymes, and therapeutic modalities targeting fibrogenesis. Hepapoietin, a naturally occurring cytokine that promotes hepatocyte growth, is under extensive research.
21999649##2011-10-18##Medical management of chronic liver diseases in children (part I): focus on curable or potentially curable diseases.##The management of children with chronic liver disease (CLD) mandates a multidisciplinary approach. CLDs can be classified into 'potentially' curable, treatable non-curable, and end-stage diseases. Goals pertaining to the management of CLDs can be divided into prevention or minimization of progressive liver damage in curable CLD by treating the primary cause; prevention or control of complications in treatable CLD; and prediction of the outcome in end-stage CLD in order to deliver definitive therapy by surgical procedures, including liver transplantation. Curative, specific therapies aimed at the primary causes of CLDs are, if possible, best considered by a pediatric hepatologist. Medical management of CLDs in children will be reviewed in two parts, with part I (this article) specifically focusing on 'potentially' curable CLDs. Dietary modification is the cornerstone of management for galactosemia, hereditary fructose intolerance, and certain glycogen storage diseases, as well as non-alcoholic steatohepatitis. It is also essential in tyrosinemia, in addition to nitisinone [2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione] therapy, as well as in Wilson disease along with copper-chelating agents such as D-penicillamine, triethylenetetramine dihydrochloride, and ammonium tetrathiomolybdate. Zinc and antioxidants are adjuvant drugs in Wilson disease. New advances in chronic viral hepatitis have been made with the advent of oral antivirals. In children, currently available drugs for the treatment of chronic hepatitis B virus infection are standard interferon (IFN)-α-2, pegylated IFN-α-2 (PG-IFN), and lamivudine. In adults, adefovir and entecavir have also been licensed, whereas telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine, and thymosin α-1 are currently undergoing clinical testing. For chronic hepatitis C virus infection, the most accepted treatment is PG-IFN plus ribavirin. Corticosteroids, with or without azathioprine, remain the basic strategy for inducing remission in autoimmune hepatitis. Ciclosporin (cyclosporine) and other immune suppressants may be used for patients who do not achieve remission, or who have significant side effects, with corticosteroid/azathioprine therapy. The above therapies can prevent, or at least minimize, progression of liver damage, particularly if started early, leading to an almost normal quality of life in affected children.
22286624##2012-1-31##Acute Gallbladder Hydrops and Arthritis: unusual initial manifestations of Wilson's Disease (WD): Case Report.##(Full text is available at http://www.manu.edu.mk/prilozi). Wilson disease (WD) is an autosomal recessive disorder, in which copper is deposited in the liver, brain, cornea and kidneys. The clinical presentation is variable, with fully expressed disease manifesting cirrhosis, neurologic damage and Kayser-Fleischer (K-F) ring on the cornea. A 24-year-old patient developed right upper quadrant pain with a palpable mass and a swelling of the right talocrural articulation. X-rays were uneventful, but the routine examination of hepatic enzymes discovered a 6-8 fold increase in SGPT, SGOT and AST. Antibodies for hepatitis B, C were normal, as well as the ANA, ANCA, antimytochondrial and anti-smooth muscle antibodies. Ultrasound of the abdomen re-vealed extremely dilated hepatic, cystic ducts as well as gallbladder. A large, oedematous gallbladder with yellow green bile was removed, the liver was found to be cirrhotic, but as the operative bleeding was abundant a biopsy was not done. Serum ceruloplasmin was low [0.160 g/l (normal 0.204-0.407)], serum copper 12.7 µmol/l (11.0-24.4), transaminasis: always very high, in the last months normal/slightly elevated. Urine copper: 1.0 µmol/24h (> 9.44). As first seen the proband had tremor, dysarthria, dystonia and K-F ring on the cornea. After 10 months of treatment with penicillamine his transaminases normalized, the tremor, dysarthria, dystonia initially got worse and then ameliorated. The coagulation times are ameliorated, but not yet normalized. Mutational analysis has shown that the proband is homozygote for c.3207 C- > A, p.H1069Q while his parents are heterozygotes. His sister is a healthy non-carrier. In brief, we describe an unusual presentation of WD, with gallbladder hydrops and talocrural arthritis in a patient with complete clinical manifestations of the disease. Key words: Wilson disease, Kayser-Fleischer rings, gallbladder hydrops. arthritis, p.H1069Q mutation.
21878323##2011-6-30##Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis.##Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism. Failure to diagnose WD can be dramatic leading to irreversible damages. The molecular genetic analysis of ATP7B gene is the reference test for diagnosis but the number of reported mutations of the ATP7B gene is on the rise. The analysis is cumbersome and requires tedious work. Other clinical and biological tests are proposed but it is often difficult to interpret some patients' results. A rapid and reliable biological test for WD diagnosis is still needed. Analytical reliability of Exchangeable copper (CuEXC) determination procedure is examined by studying the repeatability, the short term stability and stability in frozen serum. Relative exchangeable copper (REC=CuEXC/total copper%) is proposed and evaluated as a new diagnostic test and compared to classic tests used for WD diagnosis. Sixteen new Wilson disease patients were diagnosed in our institution between January 2009 and May 2011. The different biological tests used for WD diagnosis yielded lower sensitivity and specificity compared to our new biomarker, the REC. We show that REC is an excellent discriminatory tool for the diagnosis of WD offering 100% sensitivity and 100% specificity.
22046940##2011-11-4##Causes and evaluation of mildly elevated liver transaminase levels.##Mild elevations in levels of the liver enzymes alanine transaminase and aspartate transaminase are commonly discovered in asymptomatic patients in primary care. Evidence to guide the diagnostic workup is limited. If the history and physical examination do not suggest a cause, a stepwise evaluation should be initiated based on the prevalence of diseases that cause mild elevations in transaminase levels. The most common cause is nonalcoholic fatty liver disease, which can affect up to 30 percent of the population. Other common causes include alcoholic liver disease, medication-associated liver injury, viral hepatitis (hepatitis B and C), and hemochromatosis. Less common causes include α(1)-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic conditions (e.g., thyroid disorders, celiac disease, hemolysis, muscle disorders) can also cause elevated liver transaminase levels. Initial testing should include a fasting lipid profile; measurement of glucose, serum iron, and ferritin; total iron-binding capacity; and hepatitis B surface antigen and hepatitis C virus antibody testing. If test results are normal, a trial of lifestyle modification with observation or further testing for less common causes is appropriate. Additional testing may include ultrasonography; measurement of α(1)-antitrypsin and ceruloplasmin; serum protein electrophoresis; and antinuclear antibody, smooth muscle antibody, and liver/kidney microsomal antibody type 1 testing. Referral for further evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for six months or more.
22204029##2011-12-30##Wilson's disease only presenting with isolated unilateral resting tremor.##
22104638##2011-11-23##Oxcarbazepine-responsive paroxysmal kinesigenic dyskinesia in Wilson disease.##A 22-year-old man presented with a 2-year history of tremor of the upper limbs associated to behavioral disorders. A magnetic resonance imaging of the brain showed hyperintensity in the right frontoparietal region, basal ganglia, particularly in the caudate nucleus, midbrain, and pons in T2 sequences, fluid-attenuated inversion recovery, and diffusion. Serum ceruloplasmin levels were 4 mg/dL (range, 20-45 mg/dL), and 24-hour urine cooper excretion was increased up to 223 µg (10-40 µg/24 hours). Slit lamp examination demonstrated the presence of a Kayser-Fleischer ring and penicillamine treatment started. Four months later, he developed episodes of paroxysmal dystonic posturing of his left arm, which increased in frequency reaching 2 or 3 attacks per hour. They were triggered by voluntary movements and forced him to adopt an abnormal flexion of the left forearm over the left bicep and were preceded by a tightening sensation of the left forearm muscles. Episodes completely remitted with oxcarbazepine.
21757286##2011-2-16##Positive outcome in a patient with Wilson's disease treated with reduced zinc dosage in pregnancy.##
22308153##2011-6-26##Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease.##
22234080##2012-1-12##Reversal of liver cirrhosis in autoimmune hepatitis.##Liver cirrhosis is generally considered irreversible but there are reports in which there is documented reversal of fibrosis/cirrhosis in various clinical conditions like Wilson's disease, hemochromatosis, primary biliary cirrhosis and autoimmune hepatitis. The subgroup of patients with autoimmune hepatitis that will have reversal of cirrhosis is not known. We present two cases with documented liver cirrhosis that had reversal of cirrhosis after treatment with immunosuppressive agents. We postulate that patients presenting with acute hepatitis and no other fibrogenic factors have higher chances of reversal of liver cirrhosis as compared to those presenting as chronic liver injury.
22093324##2010-9-13##Antioxidants as therapeutic agents for liver disease.##Oxidative stress is commonly associated with a number of liver diseases and is thought to play a role in the pathogenesis of chronic hepatitis C, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), haemochromatosis and Wilson's disease. Antioxidant therapy has thus been considered to have the possibility of beneficial effects in the management of these liver diseases. Despite this promise, antioxidants have produced mixed results in a number of clinical trials of efficacy. This review summarizes the results of clinical trials of antioxidants as sole or adjuvant therapy of chronic hepatitis C, alcoholic liver disease and non-alcoholic steatohepatitis (NASH). Overall, the most promising results to date are for vitamin E therapy of NASH but some encouraging results have been obtained with antioxidant therapy of acute alcoholic hepatitis as well. Despite evidence for small reductions of serum alanine aminotransferase, there is as yet no convincing evidence that antioxidant therapy itself is beneficial to patients with chronic hepatitis C. Problems such as small sample size, short follow up duration, inadequate endpoints, failure to demonstrate tissue delivery and antioxidant efficacy, and heterogeneous nature of the 'antioxidant' compounds used have complicated interpretation of results of the clinical studies. These limitations and their implications for future trial design are discussed.
21956703##2011-8-16##Copper deficiency in Wilson's disease: an avoidable complication of treatment.##
21956287##2011-4-6##Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal.##The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.
22169730##2011-12-16##[Prognosis and treatment of fulminant Wilson's disease].##
22229202##2012-1-11##[Cryopreserved iliac vein for reconstruction of middle hepatic vein in living donor right liver transplantation].##
22322054##2012-2-11##[Values of serum copper and serum free copper in the diagnosis and monitoring of Wilson's disease and its carriers].##
21596401##2010-10-31##[Neurological complications of Wilson's disease].##
21965752##2011-10-4##Thiamine supplementation attenuated hepatocellular carcinoma in the Atp7b mouse model of Wilson's disease.##
22142743##2011-12-7##Miscellaneous non-inflammatory musculoskeletal conditions. Musculoskeletal conditions associated with Wilson's disease.##Wilson's disease (WD) is a rare disease, defined as an autosomal recessive disorder characterised by release of free copper and dramatic accumulation of intracellular hepatic copper with subsequent hepatic and central nervous system abnormalities. Mutations of the ATP7B gene are responsible for the metabolic dysfunction. Small open studies have reported spinal radiological abnormalities including scoliosis, diffuse bone demineralisation, osteochondritis and occasionally fracture. Prevalence of osteoporosis in young adult patients is debated, ranging from 10%, with normal mean Z-score values, to 43% in adults. Past history of spinal or peripheral fractures might be present in 50% of patients. Articular disorders include arthralgias of large joints, such as knee pain, rare effusions, early onset of radiological features of osteoarthritis and associated osteochondritis of the knee joint. Radiological chondrocalcinosis, an unusual feature in young adults, has to be confirmed. Few patients may develop drug-induced lupus with arthralgias, positive anti-nuclear and anti-histone antibodies, secondary to D-penicillamine, the major copper chelator used in WD. In this orphan disease, small retrospective studies cannot allow ascertaining definite WD-related articular and bone manifestations. However, such clinical and radiological abnormalities are occasionally the first symptoms leading to diagnosis. Physicians should be aware that unexplained joint pain and effusion, or even radiological features of osteoarthritis, of the large joints in adolescents could suggest WD and lead to copper survey.
21883362##2011-8-23##Rapid onset of argyria induced by a silver-containing dietary supplement.##We describe a 53-year-old man in good general health who presented with an 8-month history of progressive gray hyperpigmentation of the face. He denied using any prescription medications; however, he admitted to taking a herbal supplement. Clinically, the differential diagnosis included hemochromatosis, Wilson's disease and hyperpigmentation secondary to supplement use. Punch biopsies from the left forehead and preauricular region showed heavily sun-damaged skin with a minimal inflammatory infiltrate. Closer inspection, however, revealed minute scattered black/brown particles distributed in the basement membrane zone of eccrine and sebaceous glands. Similar particles were also present in hair follicles, blood vessels and arrector pili muscles. The particles did not stain with Gomori methenamine silver, Fontana-Masson or iron stains. Electron microscopy with energy-dispersive x-ray analysis showed numerous particles, less than 1 µm in greatest dimension, which showed peaks for silver and sulfur. This analytical result confirmed the impression of argyria. Further history revealed that the patient had indeed been taking a silver supplement for several months under the premise that it would boost his immune system. This case is unique in that the patient's hyperpigmentation developed in a short period of time as compared with other reports in the medical literature.
21396415##2011-2-14##Polymorphism of methylenetetrahydrofolate reductase as disease modifier - a déjà-vu in Wilson disease?##
21334398##2010-2-23##Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease.##
22145502##2011-12-8##Analysis of exon 8 of ATP7B gene in Thai patients with Wilson disease.##
20660913##2010-7-26##Corpus callosum abnormalities in Wilson's disease.##
21970993##2011-10-6##Zinc monotherapy from time of diagnosis for young pediatric patients with presymptomatic Wilson disease.##In 4 young pediatric patients with presymptomatic Wilson disease, we found zinc monotherapy beginning at time of diagnosis to be safe and highly effective for follow-up intervals between 1 and 2 years. Such maintenance therapy with zinc can maintain urinary copper excretion between 1 and 3 μg · kg(-1) · day.
21801185##2011-8-25##DNA capturing machinery through spore-displayed proteins.##
21925265##2011-6-1##DNA and RNA studies for molecular characterization of a gross deletion detected in homozygosity in the NH2-terminal region of the ATP7B gene in a Wilson disease patient.##Wilson disease is an autosomal recessive disorder caused by defective function of the copper transporting protein ATP7B. Approximately 520 Wilson disease-causing mutations have been described to date. In this study we report the use of DNA and RNA analysis for molecular characterization of a gross deletion of the ATP7B gene detected in homozygosity in a Wilson disease patient. The c.51+384_1708-953del mutation spans an 8798 bp region of the ATP7B gene from exon 2 to intron 4. The results obtained suggest that the combination of DNA and RNA analyses can be used for molecular characterization of gross ATP7B deletions, thus improving genetic counselling and diagnosis of Wilson disease. Moreover these studies, help to better establish the molecular mechanisms producing Wilson disease.
20509019##2010-5-29##[Wilson's disease and Westphal-Strümpell pseudosclerosis: conceptual history in German-speaking countries].##The article investigates the hitherto little elaborated conceptual history of Wilson's hepatolenticular degeneration and Westphal's pseudosclerosis from the mid-nineteenth century up to present day, mainly in German-speaking countries. This disease exemplifies how neurological diseases have come into existence and also demonstrates how clinical descriptions of a few isolated cases merge into a nosological diagnosis, how recognized therapeutic measures are developed and how the underlying genetic causes are identified. For some time German-speaking neurologists were in disagreement about whether or not a disease described by Carl Westphal in 1883 was identical with one described by and later named after Kinnier Wilson. This article presents the publications by Adolf Strümpell, Alois Alzheimer, August Bostroem and Walther Spielmeyer as the major contributions of German-speaking specialists to a deeper understanding of an illness and investigates whether or not the two disease concepts represent identical illnesses or not. From 1970 onwards the "Morbus Wilson Center" in Leipzig became important for the development of recognized therapeutic measures and their application in medical practice in Eastern Germany (the former GDR) and its findings have been incorporated in the present Guidelines of the German Society for Neurology published in 2008 for the treatment of Wilson's disease.
22054275##2011-11-8##Association of Wilson disease with neurofibromatosis.##
21987877##2011-10-13##[A primer on Wilson disease for the general practitioner].##Wilson disease (WD) is an inherited disorder of hepatic copper excretion leading to toxic accumulation of copper in the liver as well as the brain, cornea, and other organs. The defect is due to mutations of the copper-transporting ATPase ATP7B. Clinical manifestations are highly variable and comprise acute liver failure, chronic hepatitis and cirrhosis as well as neurological or psychiatric symptoms. The Kayser-Fleischer corneal ring is pathognomonic but absent in about 50% of patients with hepatic manifestations alone. A high index of suspicion in clinically compatible situations is key, with a combination of laboratory tests allowing the diagnosis of WD. Treatment is based on the use of chelating agents, D-penicillamine or trientine. Liver transplantation should be considered for patients with acute liver failure or advanced cirrhosis.
22055589##2011-5-2##A clinical study of Wilson's disease: The experience of a single Egyptian Paediatric Hepatology Unit.##
22102982##2011-11-22##Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review.##Homeostasis of metal ions such as Zn(2+) is essential for proper brain function. Moreover, the list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn(2+)-levels is long and steadily growing, including Parkinson's and Alzheimer's disease as well as schizophrenia, attention deficit and hyperactivity disorder, depression, amyotrophic lateral sclerosis, Down's syndrome, multiple sclerosis, Wilson's disease and Pick's disease. Furthermore, alterations in Zn(2+)-levels are seen in transient forebrain ischemia, seizures, traumatic brain injury and alcoholism. Thus, the possibility of altering Zn(2+)-levels within the brain is emerging as a new target for the prevention and treatment of psychiatric and neurological diseases. Although the role of Zn(2+) in the brain has been extensively studied over the past decades, methods for controlled regulation and manipulation of Zn(2+) concentrations within the brain are still in their infancy. Since the use of dietary Zn(2+) supplementation and restriction has major limitations, new methods and alternative approaches are currently under investigation, such as the use of intracranial infusion of Zn(2+) chelators or nanoparticle technologies to elevate or decrease intracellular Zn(2+) levels. Therefore, this review briefly summarizes the role of Zn(2+) in psychiatric and neurodegenerative diseases and highlights key findings and impediments of brain Zn(2+)-level manipulation. Furthermore, some methods and compounds, such as metal ion chelation, redistribution and supplementation that are used to control brain Zn(2+)-levels in order to treat brain disorders are evaluated.
21610751##2011-5-25##Clinical presentation and mutations in Danish patients with Wilson disease.##This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were consistently indicative of WND, with the exception of the 24-h urine-Cu test, which is always outside the normal range. Mutations were identified in 100% of the screened ATP7B alleles (70 unrelated), including five novel mutations: p.1021K; p.G1158V; p.L1304F; IVS20-2A>G; Ex5_6del. In all, 70% of mutations were found in exons 8, 14, 17, 18, and 20. The most frequent mutation, p.H1069Q, comprised 18%. We propose a new and simple model that correlates genotype and age of onset. By assuming that the milder of two mutations is 'functionally dominant' and determines the age of onset, we classified 25/27 mutations as either severe (age of onset <20 years) or moderate (age of onset >20 years), and correctly predicted the age of onset in 37/39 patients. This method should be tested in other Wilson populations.
21707886##2011-6-28##Potential of the international scoring system for the diagnosis of Wilson disease to differentiate Japanese patients who need anti-copper treatment.##
21796144##2011-7-28##Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation.##This study was designed to investigate the molecular basis and the correlation between genotype and phenotype in the southern Chinese patients with Wilson's disease (WD). Genotypes of the ATP7B gene in 73 WD patients were examined by denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. A total of 38 different disease-causing mutations were identified, including 10 novel mutations: missense mutations (p.Gln707Arg, p.Cys1079Phe, p.Gly1149Glu, p.Ser855Tyr, p.Ala874Pro and p.Ser921Arg), nonsense mutation (p.Arg1228Stop), splice-site mutations (2121+3A>T and 3244-2A>G) and frameshift mutation (1875_1876insAATT). We found that a pair of siblings carried the same genotype but different clinical type, and two patients were found to have three mutations. In addition, we compared the clinical data for p.Arg778Leu homozygotes and compound heterozygotes. Our research has enriched the mutation spectrum of the ATP7B gene in the Chinese population and can serve as the basis for genetic counseling and clinical/prenatal diagnosis to prevent WD in China.
22428436##2012-3-21##[Pediatric steatohepatitis: is it only obesity?].##We describe the case of an 11-year-old obese child with nonalcoholic steatohepatitis and Wilson's disease. Nonalcoholic steatohepatitis, although frequently found in patients with obesity, can also be caused by other etiologies, including Wilson's disease, which must therefore always be ruled out in the obese child.
21690256##2011-6-20##A practical guide to the differential diagnosis of tremor.##Tremor is, by definition, a rhythmic oscillation of a body part. It is the most prevalent movement disorder in clinical medicine, so doctors working in many specialities and in general practice can expect to encounter it. Most tremors can be classified on the basis of four observable clinical characteristics: anatomical pattern; the relative prominence of the tremor at rest, on maintaining a posture, and with action; tremor frequency; and tremor amplitude. A resting tremor suggests Parkinson's disease, and the diagnosis then depends on a judgement about whether the patient has other signs of parkinsonism. The most common causes of postural tremor are physiological tremor, essential tremor and drug-induced tremor. The differential diagnosis may also include dystonic tremor and psychogenic tremor, while metabolic tremor caused by thyrotoxicosis should be considered in any recent-onset postural tremor. Wilson's disease and fragile X-associated tremor/ataxia syndrome are rarer conditions that may present with tremor and are very important to identify. There is a small but genuine diagnostic grey zone between Parkinson's disease and more benign tremor disorders such as essential tremor and dystonic tremor, in which resting and postural tremor coexist with mild or equivocal non-tremor parkinsonian signs. The authors review clinical features and investigational techniques that may help to discriminate this group of hard-to-classify tremors.
21751376##2011-3-5##Proteomic analysis of the hepatic tissue of Long-Evans Cinnamon (LEC) rats according to the natural course of Wilson disease.##Copper-induced toxicity is important in the pathogenic process of Wilson's disease (WD). Using Long-Evans Cinnamon (LEC) rats, an animal model of WD, the study was undertaken to identify proteins involved in the process of WD and to investigate their functional roles in copper-induced hepatotoxicity. In early stages, expression levels of mitochondrial matrix proteins including agmatinase, isovaleryl coenzyme A dehydrogenase, and cytochrome b5 were downregulated. As mitochondrial injuries progressed, along with subsequent apoptotic processes, expressions of malate dehydrogenase 1, annexin A5, transferrin, S-adenosylhomocysteine hydrolase, and sulfite oxidase 1 were differentially regulated. Notably, the expression of malate dehydrogenase 1 was downregulated while the annexin A5 was overexpressed in an age-dependent manner, indicating that these proteins may be involved in the WD process. In addition, pronounced under-expression of S-adenosylhomocysteine hydrolase in elderly LEC rats, also involved in monoamine neurotransmitter metabolism, indicates that this protein might be related to the development of neurological manifestations in WD. The results of our study help to understand the pathogenic process of WD in hepatic tissues, identifying the important proteins associated with the disease process of WD, and to investigate the molecular pathogenic process underlying the development of neurological manifestations in WD.
21622540##2011-5-27##The pattern of urinary copper excretion and its response to treatment in patients with Wilson's disease.##
21854603##2011-5-6##Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil.##
21593220##2011-5-18##Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin.##Directed hepatocyte differentiation from human induced pluripotent stem cells (iPSCs) potentially provides a unique platform for modeling liver genetic diseases and performing drug-toxicity screening in vitro. Wilson's disease is a genetic disease caused by mutations in the ATP7B gene, whose product is a liver transporter protein responsible for coordinated copper export into bile and blood. Interestingly, the spectrum of ATP7B mutations is vast and can influence clinical presentation (a variable spectrum of hepatic and neural manifestations), though the reason is not well understood. We describe the generation of iPSCs from a Chinese patient with Wilson's disease that bears the R778L Chinese hotspot mutation in the ATP7B gene. These iPSCs were pluripotent and could be readily differentiated into hepatocyte-like cells that displayed abnormal cytoplasmic localization of mutated ATP7B and defective copper transport. Moreover, gene correction using a self-inactivating lentiviral vector that expresses codon optimized-ATP7B or treatment with the chaperone drug curcumin could reverse the functional defect in vitro. Hence, our work describes an attractive model for studying the pathogenesis of Wilson's disease that is valuable for screening compounds or gene therapy approaches aimed to correct the abnormality. In the future, once relevant safety concerns (including the stability of the mature liver-like phenotype) and technical issues for the transplantation procedure are solved, hepatocyte-like cells from similarly genetically corrected iPSCs could be an option for autologous transplantation in Wilson's disease.
22688476##2012-6-13##Renal tubular acidosis due to Wilson's disease presenting as metabolic bone disease.##Two sisters presented with lower limb deformity and difficulty in walking without support. Both had short stature; however, neurodevelopment and secondary sexual characters were normal. Abdominal examination revealed splenomegaly and ophthalmic examination showed presence of Kayser-Fleischer (K-F) rings. Diagnosis of Wilson's disease was confirmed with low serum copper and ceruloplasmin levels. Further investigations revealed urinary acidification defect with hypercalciuria pointing towards distal renal tubular acidosis. Both patients were started on copper chelation therapy and showed gradual radiographic improvement in osteopaenia.
22687675##2012-6-13##Behavioural and psychiatric disorders in paediatric Wilson's disease.##An 11-year-old boy was treated since 6-years-old with methylphenidate for combined attention deficit and hyperactivity disorder. At age nine his behaviour had worsened and he started to have phobias. One year later persistent hypertransaminasemia was found. Physical examination showed a dysdiadocokinesia. Laboratory investigation revealed a low caeruloplasmin and augmented basal urinary copper with a positive postpenicillamine test. Liver biopsy showed high liver copper (853 µg/g) and brain MRI was normal. D-penicillamine and zinc acetate were started without side effects. ATP7B gene mutation was confirmed after treatment initiation.
21709497##2011-6-29##Evaluation of Cuprimine® and Syprine® for decorporation of radioisotopes of cesium, cobalt, iridium and strontium.##Cuprimine® and Syprine® are therapeutics approved by the USFDA to treat copper overload in Wilson Disease (a genetic defect in copper transport) by chelation and accelerated excretion of internally-deposited copper. These oral therapeutics are based on the respective active ingredients D-penicillamine (DPA) and N,N'-bis (2-aminoethyl) -1,2-ethanediamine dihydrochloride (Trien). Cuprimine is considered the primary treatment, although physicians are increasingly turning to Syprine as a first-line therapy. Both drugs exhibit oral systemic activity and low toxicity; their biological effects and safety are established. Previous in vivo studies using a rodent animal model established the decorporation potential of Cuprimine and Syprine for (60)Co and (210)Po. Currently these studies are being expanded to evaluate the in vivo decorporation efficacy of these drugs for several additional radionuclides. In this report, results of this investigation are discussed using the radionuclides (137)Cs, (60)Co, (192)Ir and (85)Sr. Short-term 48-h pilot studies were undertaken to evaluate DPA and Trien for their in vivo decorporation potential using male Wistar-Han rats. In these studies, a radionuclide solution was administered to the animals by intravenous (IV) injection, followed by a single IV dose of either DPA or Trien. Control animals received the radionuclide alone. Results show effective decorporation of (60)Co by DPA within the time frame evaluated. DPA and Trien were also modestly effective in decorporation of (137)Cs and (85)Sr, respectively. The study did not find DPA or Trien effective for decorporation of (192)Ir. Based on these encouraging findings, further studies to evaluate the dose-response profiles and timing of the chelator administration post exposure to radionuclides are warranted.
21813384##2011-8-5##Efficacy of liver transplantation for acute hepatic failure: a single-center experience.##
21538440##2010-12-22##Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database.##
22355993##2012-2-24##Neurological Wilson disease in children: a three years experience from Multan.##
21641265##2010-11-24##Prognostic significance of neurologic examination findings in Wilson disease.##
21600834##2010-11-25##Wilson's disease in consecutive generations of one family.##
21901661##2011-9-7##Atypical presentation of Wilson disease.##A 15-year-old Caucasian female on human chorionic gonadotropin (HCG) diet presented with fever, cholestasis, coagulopathy, hemolytic anemia, and acute renal dysfunction. Imaging of the biliary system and liver were normal. She responded to intravenous antibiotics, vitamin K and blood transfusions but experienced relapse upon discontinuation of antibiotics. She had remission with reinstitution of antibiotics. Liver biopsy revealed pronounced bile ductular reaction, bridging fibrosis, and hepatocytic anisocytosis and anisonucleosis with degenerative enlarged eosinophilic hepatocytes, suggestive of Wilson disease. Diagnosis of Wilson disease was further established based on the low serum ceruloplasmin, increased urinary and hepatic copper and presence of Kayser-Fleischer rings. The multisystem involvement of the liver, kidney, blood, and brain are consistent with Wilson disease; however, the clinical presentation of cholangitis and reversible coagulopathy is uncommon, and may result from concurrent acute cholangitis and/or the HCG diet regimen the patient was on.
21901655##2011-9-7##Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment.##Nearly a century after Dr. Samuel Alexander Kinnier Wilson composed his doctoral thesis on the pathologic findings of "lenticular degeneration" in the brain associated with cirrhosis of the liver we know that the underlying molecular basis for this autosomal recessive inherited disorder that now bears his name is mutation of a copper transporting ATPase, ATP7B, an intracellular copper transporter mainly expressed in hepatocytes. Loss of ATP7B function is the basis for reduced hepatic biliary copper excretion and reduced incorporation of copper into ceruloplasmin. During the intervening years, there was recognition of the clinical signs, histologic, biochemical features, and mutation analysis of ATP7B that characterize and enable diagnosis of this disorder. These include the presence of signs of liver or neurologic disease and detection of Kayser-Fleischer rings, low ceruloplasmin, elevated urine and hepatic copper, and associated histologic changes in the liver. Medical therapies and liver transplantation can effectively treat patients with this once uniformly fatal disorder. The earlier detection of the disease led to the initiation of treatment to prevent disease progression and reverse pathologic findings if present, and family screening to detect the disorder in first-degree relatives is warranted. Gene therapy and hepatocyte cell transplantation for Wilson disease has only been tested in animal models but represent future areas for study. Despite all the advances we still have to consider the diagnosis of Wilson disease to test patients for this disorder and properly establish the diagnosis before committing to life-long treatment.
21901654##2011-9-7##Pathology of the liver in copper overload.##Copper accumulation in the liver is associated with cellular and apoptotic injury. Wilson disease is the most well-characterized disorder of disordered copper metabolism. Other less-common disorders include Indian childhood cirrhosis, endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. The histopathologic spectrum of the liver in Wilson disease is extremely variable and overlaps among the different entities, though this review will focus on the pathology of Wilson disease. The findings lack specificity, although characteristic findings are observed. Unlike other disorders of copper overload, the pathologic changes are typically sequential, ranging from little or no significant findings to cirrhosis with or without widespread hepatocellular damage. Steatosis and glycogenated nuclei are frequent. Staining of copper is an unreliable method of diagnosis of Wilson disease, whether there are minimal histologic abnormalities or chronic liver disease. Copper and copper-associated protein accumulation may also be seen in chronic biliary obstructive processes.
21901653##2011-9-7##Clinical molecular diagnosis of Wilson disease.##Wilson disease is an autosomal recessive disorder of copper transport characterized by toxic accumulation of copper in the liver, brain, and other organs. It is lethal if untreated, but effective treatment is available. The broad spectrum of clinical manifestations, including hepatic and neuropsychiatric symptoms, can present over a large age range, contributing to difficulty in recognition of this disease. The diagnosis has traditionally rested on measurements of ceruloplasmin and copper in urine and liver, but it remains a challenge due to ambiguous biochemical results that can overlap with healthy carriers. Although hepatic copper concentration has been the gold standard for diagnosis, direct sequencing of the ATP7B gene is sensitive, specific, and can obviate the need for invasive liver biopsy. In this article, the authors review the sensitivity, limitations, and pitfalls of ATP7B sequencing in the diagnosis of Wilson disease. ATP7B sequencing should be standard practice in the diagnosis of Wilson disease.
22087377##2011-4-24##A Novel Splice-site Allelic Variant is Responsible for Wilson Disease in an Omani Family.##
21681837##2010-11-23##Detection of single nucleotide polymorphisms by a gold nanowire-on-film SERS sensor coupled with S1 nuclease treatment.##Single nucleotide polymorphisms (SNPs) can serve as important biomarkers for genetic diseases, for which accurate detection of SNPs is essential for early diagnosis. We have developed a novel SNP sensor by combining a Au nanowire-on-film surface-enhanced Raman scattering (SERS) platform with S1 nuclease reaction. The combined sensor system provides reproducible SERS signals only in the presence of perfectly matched target DNAs, to probe DNAs as a result of single-stranded DNA-specific degradation by S1 nuclease. Furthermore, point mutations in DNA causing Wilson disease and Avellino corneal dystrophy were successfully identified by this sensor, thereby indicating its practical ability to diagnose genetic diseases.
21770477##2011-7-21##Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimer's disease.##This article reviews recent evidence, much of which has been generated by my group's research programme, which has identified for the first time a previously unknown copper-overload state that is central to the pathogenesis of diabetic organ damage. This state causes tissue damage in the blood vessels, heart, kidneys, retina and nerves through copper-mediated oxidative stress. This author now considers this copper-overload state to provide an important new target for therapeutic intervention, the objective of which is to prevent or reverse the diabetic complications. Triethylenetetramine (TETA) has recently been identified as the first in a new class of anti-diabetic molecules through the original work reviewed here, thus providing a new use for this molecule, which was previously approved by the US FDA in 1985 as a second-line treatment for Wilson's disease. TETA acts as a highly selective divalent copper (Cu(II)) chelator that prevents or reverses diabetic copper overload, thereby suppressing oxidative stress. TETA treatment of diabetic animals and patients has identified and quantified the interlinked defects in copper metabolism that characterize this systemic copper overload state. Copper overload in diabetes mellitus differs from that in Wilson's disease through differences in their respective causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess copper. Elevated pathogenetic tissue binding of copper occurs in diabetes. It may well be mediated by advanced-glycation endproduct (AGE) modification of susceptible amino-acid residues in long-lived fibrous proteins, for example, connective tissue collagens in locations such as blood vessel walls. These AGE modifications can act as localized, fixed endogenous chelators that increase the chelatable-copper content of organs such as the heart and kidneys by binding excessive amounts of catalytically active Cu(II) in specific vascular beds, thereby focusing the related copper-mediated oxidative stress in susceptible tissues. In this review, summarized evidence from our clinical studies in healthy volunteers and diabetic patients with left-ventricular hypertrophy, and from nonclinical models of diabetic cardiac, arterial, renal and neural disease is used to construct descriptions of the mechanisms by which TETA treatment prevents injury and regenerates damaged organs. Our recent phase II proof-of-principle studies in patients with type 2 diabetes and in nonclinical models of diabetes have helped to define the pathogenetic defects in copper regulation, and have shown that they are reversible by TETA. The drug tightly binds and extracts excess systemic Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic copper deficiency, even after prolonged use. Its physicochemical properties, which are pivotal for its safety and efficacy, clearly differentiate it from all other clinically available transition metal chelators, including D-penicillamine, ammonium tetrathiomolybdate and clioquinol. The studies reviewed here show that TETA treatment is generally effective in preventing or reversing diabetic organ damage, and support its ongoing development as a new medicine for diabetes. Trientine (TETA dihydrochloride) has been used since the mid-1980s as a second-line treatment for Wilson's disease, and our recent clinical studies have reinforced the impression that it is likely to be safe for long-term use in patients with diabetes and related metabolic disorders. There is substantive evidence to support the view that diabetes shares many pathogenetic mechanisms with Alzheimer's disease and vascular dementia. Indeed, the close epidemiological and molecular linkages between them point to Alzheimer's disease/vascular dementia as a further therapeutic target where experimental pharmacotherapy with TETA could well find further clinical application.
21734698##2011-7-8##Structural biology: a platform for copper pumps.##
21454443##2011-3-31##Critical roles for the COOH terminus of the Cu-ATPase ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking.##ATP7A and ATP7B are copper-transporting P-type ATPases that are essential to eukaryotic copper homeostasis and must traffic between intracellular compartments to carry out their functions. Previously, we identified a nine-amino acid sequence (F37-E45) in the NH(2) terminus of ATP7B that is required to retain the protein in the Golgi when copper levels are low and target it apically in polarized hepatic cells when copper levels rise. To understand further the mechanisms regulating the intracellular dynamics of ATP7B, using multiple functional assays, we characterized the protein phenotypes of 10 engineered and Wilson disease-associated mutations in the ATP7B COOH terminus in polarized hepatic cells and fibroblasts. We also examined the behavior of a chimera between ATP7B and ATP7A. Our results clearly demonstrate the importance of the COOH terminus of ATP7B in the protein's copper-responsive apical trafficking. L1373 at the end of transmembrane domain 8 is required for protein stability and Golgi retention in low copper, the trileucine motif (L1454-L1456) is required for retrograde trafficking, and the COOH terminus of ATP7B exhibits a higher sensitivity to copper than does ATP7A. Importantly, our results demonstrating that four Wilson disease-associated missense mutations behaved in a wild-type manner in all our assays, together with current information in the literature, raise the possibility that several may not be disease-causing mutations.
21645498##2011-2-18##Fragmentation of mitochondrial cardiolipin by copper ions in the Atp7b-/- mouse model of Wilson's disease.##Cellular copper overload as found in Wilson's disease may disturb mitochondrial function and integrity. Atp7b(-/-) mice accumulate copper in the liver and serve as an animal model for this inherited disease. The molecular mechanism of copper toxicity in hepatocytes is poorly understood. Total mitochondrial lipids from liver of wild-type mice were subjected to oxidative stress by the Cu(2+)/H(2)O(2)/ascorbate system. Phosphatidic acid (PA) and phosphatidylhydroxyacetone (PHA) were detected as cardiolipin fragmentation products by thin-layer chromatography combined with MALDI-TOF mass spectrometry in oxidized samples, but not in unperturbed ones. The formation of PA and PHA in copper-treated model membrane correlated well with the decrease of cardiolipin. Mitochondrial lipids from Atp7b(-/-) mice of different age were analyzed for the presence of PA. While 32-weeks old wild-type (control) and Atp7b(-/-) mice did not show any PA, there was a steady increase in the amount of this lipid in Atp7b(-/-) mice in contrast to control with increasing age. Hepatocytes from elder Atp7b(-/-)mice contained morphologically changed mitochondria unlike cells from wild-type animals of the same age. We concluded that free-radical fragmentation of cardiolipin with the formation of PA is a likely mechanism that damages mitochondria under conditions of oxidative stress due to copper overload. Our findings are relevant for better understanding of molecular mechanisms for liver damage found in Wilson's disease.
21612960##2011-4-18##Hypokinetic-rigid syndrome in children and inborn errors of metabolism.##Hypokinetic-rigid syndrome (HRS) or "parkinsonism" is rare in children. From a clinical point of view it is characterised by a group of signs in which hypokinesia (decreased number of movements), bradykinesia (slowness of movements), rigidity and rest tremor are the fundamental traits. Nervous system infections, immunomediated encephalitis, hypoxia and some drugs have been described as acquired or secondary causes of HRS in the paediatric age. Inborn errors of metabolism (IEM) comprise and important group regarding genetic causes. Main diseases causing HRS in children are neurotransmitter (biogenic amines) defects, metal storage diseases, energy metabolism disorders and lysosomal diseases. In general, in IEM, the HRS is associated to other neurological signs such as dykinesias, pyramidal signs, and psychomotor delay, is very rare in the neonatal period, tends to be more frequent in advanced stages of progressive diseases, and may respond to specific therapies. In particular, l-dopa + carbidopa can be a very effective treatment in neurotransmitter defects, whereas other disorders such as Wilson disease and some particular lysosomal disorders have different therapeutic possibilities. Furthermore, other genetic conditions in dopa-responsive and non-responsive HRS should be also considered, especially in juvenile parkinsonism. Through this review, a practical orientation for paediatric neurologists concerning clinical clues, diagnostic procedure and treatment of metabolic HRS will be provided.
21710473##2011-6-29##Copper toxicity in Wilson disease explained in a new way.##
21633804##2011-6-3##[Acute Wilson disease].##Wilson disease is an autosomal recessive inherited disorder of human copper metabolism clinically associated with hepatic damage and/or neurological symptoms of varying degree. Copper accumulation and toxicity result in direct injury to hepatocytes followed by inflammation and irreversible impairment of neurons, mainly in the extrapyramidal system. A not insignificant number of cases begin with fulminant liver failure or acute appearance of neurological symptoms. If left untreated or in the case of delayed diagnosis and treatment, both acute manifestations may result in irreversible symptoms or even death. Rapid and exact diagnosis by means of clinical, biochemical and genetic analysis and the immediate initiation of drug therapy with copper chelators or, in the case of fulminant liver failure, orthotopic liver transplantation are essential for a favourable outcome in patients with acute Wilson disease.
21765606##2010-11-18##Administration of PPARβ/δ agonist reduces copper-induced liver damage in mice: possible implications in clinical practice.##In this study we investigated if peroxisome proliferator-activated receptor β/δ activation protects from copper-induced acute liver damage. Mice treated with copper had significant body weight loss, serum alanine aminotransferase increase, modest changes in liver histology, increase of tumor necrosis factor α and macrophage inflammatory protein 2 mRNA and 8-hydroxy-2'-deoxyguanosine. Mice treated with copper and peroxisome proliferator-activated receptor β/δ agonist GW0742 had significantly less body weight loss, less serum alanine aminotransferase increase, less tumor necrosis factor α, macrophage inflammatory protein-2 and 8-hydroxy-2'-deoxyguanosine upregulation than copper treated mice. The opposite effect was observed in mice treated with copper and peroxisome proliferator-activated receptor β/δ antagonist GSK0660. In vitro, copper induced reactive oxygen species, which was lower in cells treated with GW0742 or transfected with peroxisome proliferator-activated receptor β/δ expression vector; together, transfection and GW0742 had an additive reactive oxygen species-reducing effect. Copper also upregulated Fas ligand and Caspase 3/7 activity, effects that were significantly lower in cells also treated with GW0742. In conclusion, peroxisome proliferator-activated receptor β/δ activation reduced copper-induced reactive oxygen species, pro-inflammatory and acute phase reaction cytokines in mice liver. Peroxisome proliferator-activated receptor β/δ agonists could become useful in the management of copper-induced liver damage.
21517843##2011-5-19##Neuroinflammatory and behavioural changes in the Atp7B mutant mouse model of Wilson's disease.##Wilson's disease (WD) is caused by mutations in the copper transporting ATPase 7B (Atp7b). Patients present with liver pathology or behavioural disturbances. Studies on rodent models for WD so far mainly focussed on liver, not brain. The effect of knockout of atp7b on sensori-motor and cognitive behaviour, as well as neuronal number, inflammatory markers, copper and synaptic proteins in brain were studied in so-called toxic milk mice. Copper accumulated in striatum and hippocampus of toxic milk mice, but not in cerebral cortex. Inflammatory markers were increased in striatum and corpus callosum, but not in cerebral cortex and hippocampus, whereas neuronal numbers were unchanged. Toxic milk mice were mildly impaired in the rotarod and cylinder test and unable to acquire spatial memory in the Morris water maze. Despite the latter observation only synaptophysin of a number of synaptic proteins, was altered in the hippocampus of toxic milk mice. In addition to disturbances in neuronal signalling by increased brain copper, inflammation and inflammatory signalling from the periphery to the brain might add to the behavioural disturbances in the toxic milk mice. These mice can be used to evaluate therapeutic strategies to alleviate behavioural disturbances and cerebral pathology observed in WD.
21645214##2011-3-13##Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort.##
21594897##2010-7-29##Quality of life in patients with treated and clinically stable Wilson's disease.##Health-related quality of life (HRQoL) in Wilson's disease (WD) has not been extensively studied. Therefore, the purpose of this cross-sectional study was to identify clinical and demographic factors influencing HRQoL in 60 treated, clinically stable patients with WD using a generic questionnaire, the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36). The level of disability and grading of WD multisystemic manifestations were assessed by the Global Assessment Scale for WD (GAS for WD). The Mini Mental State Examination (MMSE) and the 21-item Hamilton Depression Rating Scale (HDRS) scoring were also applied by the same trained interviewers. Lower scores on the SF-36 domains were found in patients with neurological compared with those with a predominantly hepatic form of WD. The HRQoL of patients with WD and psychiatric symptoms was also lower than that of those without them. Finally, significant inverse correlations were obtained between the various SF-36 domains and all the following: period of latency from the first symptoms/signs appearance and treatment initiation, MMSE and HDRS scores, and different domains of the GAS for WD.
21716286##2010-11-09##Crystal structure of a copper-transporting PIB-type ATPase.##Heavy-metal homeostasis and detoxification is crucial for cell viability. P-type ATPases of the class IB (PIB) are essential in these processes, actively extruding heavy metals from the cytoplasm of cells. Here we present the structure of a PIB-ATPase, a Legionella pneumophila CopA Cu(+)-ATPase, in a copper-free form, as determined by X-ray crystallography at 3.2 Å resolution. The structure indicates a three-stage copper transport pathway involving several conserved residues. A PIB-specific transmembrane helix kinks at a double-glycine motif displaying an amphipathic helix that lines a putative copper entry point at the intracellular interface. Comparisons to Ca(2+)-ATPase suggest an ATPase-coupled copper release mechanism from the binding sites in the membrane via an extracellular exit site. The structure also provides a framework to analyse missense mutations in the human ATP7A and ATP7B proteins associated with Menkes' and Wilson's diseases.
21682854##2011-1-18##Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients.##
21676234##2010-7-17##Early stage transplantation of bone marrow cells markedly ameliorates copper metabolism and restores liver function in a mouse model of Wilson disease.##
21705304##2011-6-28##Work ability assessment in a patient with Wilson's disease.##Wilson's disease (WD) is a rare, progressive autosomal recessive disorder characterised by impaired transport and excessive accumulation of copper in the liver, brain, and other tissues. The disease is diagnosed based on clinical manifestations and screening tests results. Work ability assessment of patients with WD is based on the analysis of liver, kidney, neurological, and cognitive impairments, and takes into account patient's level of education.This article presents a case with a 48-year-old male patient, who was admitted for work ability assessment due to polymorphic symptoms. The patient had been working as a salesman for 28 years. A detailed interview and examination by occupational health and other medical specialists revealed that the patient had been suffering from Wilson's disease from the age of 13, and had now developed hepatic manifestations (compensated liver cirrhosis with portal hypertension), neurological manifestations (dystonia, dysarthria, muscle weakness, vertigo), and psychiatric manifestations (depression, insomnia, cognitive impairment) of the disease, including problems partially caused by long-lasting treatment with copper chelating agents (neurological and haematological manifestations). There were no ocular manifestations of Wilson's disease (Kayser-Fleischer rings or sunflower cataract).The patient was assessed as having drastically diminished general work ability, dominantly due to neurological and psychiatric impairments caused by Wilson's disease.
21380607##2010-12-21##Systems biology approach to Wilson's disease.##Wilson's disease (WD) is a severe disorder of copper misbalance, which manifests with a wide spectrum of liver pathology and/or neurologic and psychiatric symptoms. WD is caused by mutations in a gene encoding a copper-transporting ATPase ATP7B and is accompanied by accumulation of copper in tissues, especially in the liver. Copper-chelation therapy is available for treatment of WD symptoms and is often successful, however, significant challenges remain with respect to timely diagnostics and treatment of the disease. The lack of genotype-phenotype correlation remains unexplained, the causes of fulminant liver failure are not known, and the treatment of neurologic symptoms is only partially successful, underscoring the need for better understanding of WD mechanisms and factors that influence disease manifestations. Recent gene and protein profiling studies in animal models of WD began to uncover cellular processes that are primarily affected by copper accumulation in the liver. The results of such studies, summarized in this review, revealed new molecular players and pathways (cell cycle and cholesterol metabolism, mRNA splicing and nuclear receptor signaling) linked to copper misbalance. A systems biology approach promises to generate a comprehensive view of WD onset and progression, thus helping with a more fine-tune treatment and monitoring of the disorder.
21269263##2009-10-25##Mitochondria in chronic liver disease.##Mitochondria are the main energy source in hepatocytes and play a major role in extensive oxidative metabolism and normal function of the liver. This key role also assigns mitochondria a gateway function in the center of signaling pathways that mediate hepatocyte injury, because impaired mitochondrial functions affect cell survival and contribute to the onset and perpetuation of liver diseases. Altered mitochondrial functions have indeed been documented in a variety of chronic liver diseases including alcohol-induced liver disease, nonalcoholic fatty liver disease, viral hepatitis, primary and secondary cholestasis, hemochromatosis, and Wilson's disease. Major changes include impairment of the electron transport chain and/or oxidative phosphorylation leading to decreased oxidative metabolism of various substrates, decreased ATP synthesis, and reduced hepatocyte tolerance towards stressing insults. Functional impairment of mitochondria is often accompanied by structural changes, resulting in organelle swelling and formation of inclusion in the mitochondrial matrix. Adequate mitochondrial functions in hepatocytes are maintained by mitochondrial proliferation and/or increased activity of critical enzymes. The assessment of mitochondrial functions in vivo can be a useful tool in liver diseases for diagnostic and prognostic purposes, and also for the evaluation of (novel) therapeutic interventions.
21641685##2010-12-26##[Chronic hepatic encephalopathy in a patient with primary biliary cirrhosis].##Chronic or persistent hepatic encephalopathy is a complication that develops in 1% of patients with chronic liver disease. We report a new case of this complication in a patient with primary biliary cirrhosis. A 69-year-old woman with stage IV primary biliary cirrhosis presented with a 6-month history of progressive memory deficits, tremors and somewhat clumsy gait. Examination revealed sub-jaundiced skin tone, short-term memory deficits, fine distal bilateral tremor in the upper extremities and generalized hyperreflexia with spread of the reflexogenic zone. The hemogram showed mild pancytopenia, hypertransaminasemia, cholestatic pattern, lengthened thromboplastin time and hypocholinesterasemia. Wilson's disease was excluded and a cranial magnetic resonance imaging scan showed a bilateral hyperintense globus pallidus on T1-weighted sequences, which, together with the symptoms, were compatible with the diagnosis. Chronic liver diseases may cause chronic hepatic encephalopathy. Gastroenterologists should be familiar with this entity.
21419523##2010-12-30##[Advances in the molecular diagnosis of Wilson's disease].##Wilsońs disease is an autosomal recessive disorder characterized by toxic copper accumulation in the liver and subsequently in the brain and other organs. Clinical diagnosis is based on the detection of low serum ceruloplasmin concentrations, increased urinary copper excretion, Kayser-Fleisher rings in the cornea, and/or high copper levels in hepatic tissue. Diagnosis can be difficult when the typical symptoms of the disease are absent, a situation that can lead to a lack of prophylactic therapy in these patients. Molecular study has improved the diagnosis of this disease, even in doubtful cases. The present article outlines the various techniques applied in the molecular diagnosis of Wilson's disease and the most commonly described mutations. Currently, direct sequencing of the ATP7B gene is the most widely used method to detect mutations. Molecular study and identification of ATP7B gene mutations allow diagnosis of individuals with Wilson's disease and their relatives, as well as the possibility of genetic counselling and prenatal and preimplantation genetic diagnosis.
21484110##2010-2-11##Predictors of outcome in acute-on-chronic liver failure in children.##
21593651##2011-5-20##Is plasma exchange effective in prevention of hepatic transplantation in fulminant Wilson disease with hepatic failure?##
21449011##2010-6-1##Copper deficiency in Wilson's disease: peripheral neuropathy and myelodysplastic syndrome complicating zinc treatment.##
21685853##2011-6-21##Psychiatric aspects of basal ganglia diseases.##This review clarifies the fact that basal ganglia diseases are psychiatric as much as neurological diseases. It illustrates psychiatric aspects in Parkinson's disease and other hereditary basal ganglia diseases such as Wilson's disease, Huntington's chorea and others. In these diseases, psychological disorders can be difficult to diagnose, whether they are concomitant with the primary (neurological) disease, they are its consequence, or they are the result of a specific pharmacotherapy prescribed for these disease, etc. Thus, the choice of appropriate psychopharmacotherapy for these disorders represents a very subtle problem.
21269740##2010-7-5##[Wilson's disease in an adult].##
21595966##2011-4-5##Alterations of lipid metabolism in Wilson disease.##
21546639##2011-5-7##Severe hepatotoxicity and probable hepatorenal syndrome associated with sulfadiazine.##
21555737##2011-5-11##Copper deficiency myeloneuropathy in a patient with Wilson disease.##
21633525##2010-9-11##Mallory-Denk Bodies in chronic hepatitis.##Mallory-Denk Bodies (MDB) are important as investigators, suggesting MDB as an indicator of the histologic severity of chronic hepatitis, causes of which include hepatitis C, primary biliary cirrhosis (PBC), and nonalcoholic fatty liver disease (NAFLD). Matteoni et al scored MDB in patients with NAFLD as none, rare and many, and reported that MDB plays a prominent role in this classification scheme in an earlier classification system. In this study, we evaluated 258 patients with chronic hepatitis due to metabolic, autoimmune and viral etiologies. Liver biopsy samples were evaluated with hematoxylin and eosin, periodic acid-Schiff-diastase, Gordon and Sweet's reticulin, Masson's trichrome, and iron stains. Both staging and grading were performed. Additionally, MDB were evaluated and discussed for each disease. We examined patients with nonalcoholic steatohepatitis (NASH; 50 patients), alcoholic hepatitis (10 patients), PBC (50 patients), Wilson disease (WD; 20 patients), hepatitis B (50 patients), hepatitis C (50 patients) and hepatocellular carcinoma (HCC; 30 patients). Frequency of MDB was as follows; NASH: 10 patients with mild in 60% and moderate in 40% and observed in every stage of the disease and frequently seen in zone 3. PBC: 11 patients with mild in 10%, moderate in 70%, and cirrhosis in 20%, and frequently seen in zone 1. WD: 16 patients with moderate and severe in 60% and cirrhosis in 40% and frequently seen in zone 1. Hep B: 3 patients with mild in 66% and severe in 34%. Hep C: 7 patients with mild in 40% and moderate in 60% and observed in every stage. HCC: 3 patients with hep B in 2 patients. We found that there is no relationship between MDB and any form of chronic hepatitis regarding histologic severity such as alcoholic steatohepatitis and NAFLD and variable zone distribution by etiology.
21398519##2011-3-11##Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B.##Wilson disease (WD) is a disorder of copper metabolism caused by mutations in the Cu-transporting ATPase ATP7B. WD is characterized by significant phenotypic variability, the molecular basis of which is poorly understood. The E1064A mutation in the N-domain of ATP7B was previously shown to disrupt ATP binding. We have now determined, by NMR, the structure of the N-domain containing this mutation and compared properties of E1064A and H1069Q, another mutant with impaired ATP binding. The E1064A mutation does not change the overall fold of the N-domain. However, the position of the α1,α2-helical hairpin (α-HH) that houses Glu(1064) and His(1069) is altered. The α-HH movement produces a more open structure compared with the wild-type ATP-bound form and misaligns ATP coordinating residues, thus explaining complete loss of ATP binding. In the cell, neither the stability nor targeting of ATP7B-E1064A to the trans-Golgi network differs significantly from the wild type. This is in a contrast to the H1069Q mutation within the same α-HH, which greatly destabilizes protein both in vitro and in cells. The difference between two mutants can be linked to a lower stability of the α-HH in the H1069Q variant at the physiological temperature. We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD.
21406212##2010-12-28##Disturbed post-movement beta synchronization in Wilson's disease with neurological manifestation.##We analyzed the changes of post-movement beta synchronization (PMBS) of the electroencephalogram (EEG) in Wilson's disease with neurological manifestation. Our aim was to determine if PMBS in Wilson's disease is altered in a different way than in Parkinson's disease or in essential tremor. Our purpose was to find out whether the analysis of PMBS could help the diagnosis in ambiguous cases. Ten patients with neurological manifestation of Wilson's disease and ten controls performed self-paced movements with the dominant hand during EEG acquisition. Five electrodes above the sensorimotor cortex were selected for evaluation (C3, C1, Cz, C2, C4) as contralateral (C); contralateral medial (CM); medial (M); ipsilateral medial (IM); ipsilateral (I) relative to the dominant hand. Power and latency of PMBS were calculated by time resolved power spectral analysis with multitaper method. PMBS power in the C electrode position was significantly lower in patients than in controls, its contralateral preponderance disappeared in the patient group. In every location, latency of PMBS was significantly longer in the Wilson group compared to controls. More altered PMBS could be measured in patients with both basal ganglia and cerebellar involvements. Since decreased power of PMBS was observed in Parkinson's disease and increased latency in essential tremor, the combined change of PMBS can indicate pathology of different neural circuits and may help the diagnosis in challenging cases.
21518405##2011-4-27##Copper incorporation into ceruloplasmin is regulated by Niemann-Pick C1 protein.##
21654009##2011-6-10##Reversal of severe Wilson arthropathy by liver transplantation.##Wilson disease is associated with multisystem involvement. We describe a patient of Wilson disease with severe arthropathy, which completely reversed following liver transplantation. This is the first case report in literature describing the complete reversal of Wilson disease related arthropathy by liver transplantation.
21532861##2010-10-11##Bacteremia caused by Laribacter hongkongensis misidentified as Acinetobacter lwoffii: report of the first case in Korea.##Laribacter hongkongensis is an emerging pathogen in patients with community-acquired gastroenteritis and traveler's diarrhea. We herein report a case of L. hongkongensis infection in a 24-yr-old male with liver cirrhosis complicated by Wilson's disease. He was admitted to a hospital with only abdominal distension. On day 6 following admission, he complained of abdominal pain and his body temperature reached 38.6℃. The results of peritoneal fluid evaluation revealed a leukocyte count of 1,180/µL (polymorphonuclear leukocyte 74%). Growth on blood culture was identified as a gram-negative bacillus. The isolate was initially identified as Acinetobacter lwoffii by conventional identification methods in the clinical microbiology laboratory, but was later identified as L. hongkongensis on the basis of molecular identification. The patient was successfully treated with cefotaxime. To the best of our knowledge, this case is the first report of hospital-acquired L. hongkongensis bacteremia with neutrophilic ascites.
21516016##2011-4-26##Acute nonimmune hemolytic anemia without fulminant hepatitis in Wilson disease.##Owing to the insidious course and variable presentation, Wilson disease is often diagnosed months to years after the initial symptoms. Although fulminant hepatitis with nonimmune hemolytic anemia is frequently reported, chronic mild hepatitis can occur with bouts of transient hemolytic anemia. We report a 16-year-old female who presented with fatigue, dizziness, and new onset jaundice. She had a hemolytic anemia, although diagnosis of Wilson disease was initially confounded by a family history of autoimmunity with a high erythrocyte sedimentation rate and only mildly elevated bilirubin and aspartate aminotransferase. Macrocytosis, poor liver synthetic function, and low serum alkaline phosphatase led to the diagnosis.
20400112##2009-4-1##Nitric oxide and redox regulation in the liver: part II. Redox biology in pathologic hepatocytes and implications for intervention.##Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in normal hepatocytes and are critical for normal physiologic processes, including oxidative respiration, growth, regeneration, apoptosis, and microsomal defense. When the levels of oxidation products exceed the capacity of normal antioxidant systems, oxidative stress occurs. This type of stress, in the form of ROS and RNS, can be damaging to all liver cells, including hepatocytes, Kupffer cells, stellate cells, and endothelial cells, through induction of inflammation, ischemia, fibrosis, necrosis, apoptosis, or through malignant transformation by damaging lipids, proteins, and/or DNA. In Part I of this review, we will discuss basic redox biology in the liver, including a review of ROS, RNS, and antioxidants, with a focus on nitric oxide as a common source of RNS. We will then review the evidence for oxidative stress as a mechanism of liver injury in hepatitis (alcoholic, viral, nonalcoholic). In Part II of this review, we will review oxidative stress in common pathophysiologic conditions, including ischemia/reperfusion injury, fibrosis, hepatocellular carcinoma, iron overload, Wilson's disease, sepsis, and acetaminophen overdose. Finally, biomarkers, proteomic, and antioxidant therapies will be discussed as areas for future therapeutic interventions.
21491335##2011-4-15##A biopsychosocial approach to liver transplant evaluation in two patients with Wilson's disease.##Wilson's disease (WD) is characterized by hepatic, neurological, and/or psychiatric disturbances. In some cases, liver transplantation is indicated. Because psychologists and other health care workers play an increasing role in the evaluation of individuals presenting for transplant, an understanding of the heterogeneous phenotype of WD is important for mental health professionals working in medical settings. This article reviews two cases of patients with WD (one probable, one confirmed) presenting for liver transplantation and a biopsychosocial assessment approach is demonstrated. Patients are presented in terms of medical, psychiatric, and psychosocial history, neuropsychological examination results, and the subsequent indications for liver transplantation. Both patients exhibited neurocognitive and psychiatric symptoms. One patient was determined to be a marginally suitable candidate for transplantation, whereas the other was considered at high risk for negative outcome post-transplant. This article demonstrates the importance of considering phenotypic presentation, neurocognitive function, psychiatric status, and psychosocial circumstances in assessing transplant readiness in patients with WD. A comprehensive and integrative biopsychosocial assessment approach is appropriate for evaluating patients with WD presenting for liver transplantation.
20444834##2010-5-5##The eye in Wilson disease.##
21839003##2011-8-16##[Wilson disease. A case report and review of the literature].##
21538285##2011-5-2##Genetic modifiers of liver injury in hereditary liver disease.##The genetic background of patients with liver diseases modulates hepatic injury, with some individuals being predisposed to better defenses and regenerative capacity. In this review, we focus our description of this phenomenon on inherited disorders affecting the liver, with a particular emphasis on Wilson disease (WD), genetic hemochromatosis, and α-1 anti-trypsin disease (A1-AT). Wide variations in the clinical phenotype of WD may in part be related to the mutations of the ATP7B genotype, though modifier genes and environmental factors also likely play an important role. There is also a significant variability in the expression of iron overload in patients with genetic hemochromatosis that are homozygous for the C282Y mutation. Homozygosity for the A1-ATZ mutation is generally required for the development of liver disease in A1-AT although there is increasing evidence for modifier effects from a heterozygous genotype in other liver diseases.
21549078##2011-5-10##D-penicillamine elastosis perforans serpiginosa: description of two cases and review of the literature.##Long term D-penicillamine (DPA) therapy to treat Wilson disease can induce elastosis perforans serpiginosa (EPS), a very rare degenerative skin disease characterized by a transepidermal elimination of elastic fiber aggregates. The iatrogenous disease depends on DPA capacity to chelate copper and cause its depletion. Lysyl-oxidase is a copper dependent enzyme crucial to the dermal elastic fiber cross-linking, which is strongly affected by DPA copper depletion. Direct binding of the drug to collagen precursors also affects elastic fiber assemblage and maturation. The abnormal elastin accumulates into the middle dermis and produces a characteristic bramble brush or "lumpy-bumpy" appearance. In this way it acts as a foreign body and is progressively extruded through the epidermis. Clinically, the disease presents with multiple firm keratotic papules and nodules arranged in annular plaques over the neck, axillae, antecubital fossae, and forearms. The rarity of the disease frequently causes misdiagnoses and the process continues unabated causing concerns about systemic elastopathy.
20683594##2010-5-15##Hemolysis in Wilson's disease.##
21455266##2011-4-2##Mechanism of tumor resistance to cisplatin mediated by the copper transporter ATP7B.##The Wilson disease protein (ATP7B) is a copper-transporting ATPase that is responsible for regulating copper homeostasis in human tissues. ATP7B is associated with cancer resistance to cisplatin, one of the most widely used anticancer drugs. This minireview discusses the possible mechanisms of tumor resistance to cisplatin mediated by ATP7B. Cisplatin binds to the N-terminal cytosolic domain of ATP7B, which contains multiple copper-binding sites. Active platinum efflux catalyzed by ATP7B is unlikely to significantly contribute to cisplatin resistance in vivo. Transient platinum sequestration in the metal-binding domain followed by transfer to an acceptor protein or a low molecular weight compound is proposed as an alternative mechanism of cisplatin detoxification in the cell.
22375361##2012-3-2##[Medical aspects of the medical treatment in dystonia].##Dystonias encompass a wide range of movement disorders characterized mainly by abnormal postures or movements. Because of this semiological and etiological heterogeneity, robust clinical trials are rare. Specific etiological treatments are available for only a few forms (e.g. Wilson's disease and dopa-responsive dystonia), which places the emphasis on symptomatic treatment. This is based on the combinations of three complementary approaches: drug therapy (anticholinergics, tetrabenazine and benzodiazepines are first-line drugs, but many others have been tested in small clinical trials), botulinium toxin injections in case of focal dystonia or focal targets in patients with more widespread dystonia, and physiotherapy. This review provides a short overview of available treatments and proposes a basic therapeutic strategy for dystonic patients.
21448835##2011-3-29##[Superficial siderosis of the central nervous system in a patient with hemochromatosis and Wilson's disease].##
21453233##2011-4-2##Leukoencephalopathy syndrome after living-donor liver transplantation.##
21185835##2010-3-7##Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease.##
21772656##2011-7-21##Severe neuropsychiatric presentation of Wilson's disease.##Wilson's disease (WD) is a relatively rare disease of copper metabolism. The diagnosis is often missed initially. The presentation is usually neurologic or hepatic, seen in 40% of patients. Psychiatric presentation of WD is reported in only 15% of patients. We present a 32-year-old patient with severe psychiatric manifestations. On examination, he had mild rest and postural tremors and a KF ring was seen. Serum ceruloplasmin was low and 24-hour urinary copper was elevated. The patient responded to penicillamine, lorazepam and quetiapine, and is being followed up.
24800332##2014-5-8##Aetiological factors of chronic liver disease in children.##
21364284##2010-10-12##Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease.##Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b–/– rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper- dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD.
21415672##2011-3-19##Prognostic scoring indices in Wilson disease: a case series and cautionary tale.##
21452141##2011-4-1##[Inherited disorders of liver metabolism].##Inherited disorders of liver metabolism are in general due to single enzyme defects that result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or lipids. This group of diseases comprises disorders of the amino acid, iron, bilirubin and sphingolipid metabolism as well as disorders of the coagulation cascade, the urea cycle and diverse transport processes. These diseases either lead to structural liver damage or, if the defective enzyme is produced predominantly in the liver, to injury to other organ systems. In this review article, we discuss the pathogenesis, clinical presentation, diagnosis and therapy of hereditary hemochromatosis, Wilson's disease and alpha1-antitrypsin-deficiency which represent the most common hereditary liver diseases.
21406592##2011-3-15##Cellular copper levels determine the phenotype of the Arg875 variant of ATP7B/Wilson disease protein.##In human disorders, the genotype-phenotype relationships are often complex and influenced by genetic and/or environmental factors. Wilson disease (WD) is a monogenic disorder caused by mutations in the copper-transporting P-type ATPase ATP7B. WD shows significant phenotypic diversity even in patients carrying identical mutations; the basis for such diverse manifestations is unknown. We demonstrate that the 2623A/G polymorphism (producing the Gly(875) → Arg substitution in the A-domain of ATP7B) drastically alters the intracellular properties of ATP7B, whereas copper reverses the effects. Under basal conditions, the common Gly(875) variant of ATP7B is targeted to the trans-Golgi network (TGN) and transports copper into the TGN lumen. In contrast, the Arg(875) variant is located in the endoplasmic reticulum (ER) and does not deliver copper to the TGN. Elevated copper corrects the ATP7B-Arg(875) phenotype. Addition of only 0.5-5 μM copper triggers the exit of ATP7B-Arg(875) from the ER and restores copper delivery to the TGN. Analysis of the recombinant A-domains by NMR suggests that the ER retention of ATP7B-Arg(875) is attributable to increased unfolding of the Arg(875)-containing A-domain. Copper is not required for the folding of ATP7B-Arg(875) during biosynthesis, but it stabilizes protein and stimulates its activity. A chemotherapeutical drug, cisplatin, that mimics a copper-bound state of ATP7B also corrects the "disease-like" phenotype of ATP7B-Arg(875) and promotes its TGN targeting and transport function. We conclude that in populations harboring the Arg(875) polymorphism, the levels of bioavailable copper may play a vital role in the manifestations of WD.
21242307##2011-1-17##Clusterin (apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B.##The copper-transporting P(1B)-type ATPases (Cu-ATPases) ATP7A and ATP7B are key regulators of physiological copper levels. They function to maintain intracellular copper homeostasis by delivering copper to secretory compartments and by trafficking toward the cell periphery to export excess copper. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and toxicity disorders, Menkes and Wilson diseases, respectively. This report describes the interaction between the Cu-ATPases and clusterin and demonstrates a chaperone-like role for clusterin in facilitating their degradation. Clusterin interacted with both ATP7A and ATP7B in mammalian cells. This interaction increased under conditions of oxidative stress and with mutations in ATP7B that led to its misfolding and mislocalization. A Wilson disease patient mutation (G85V) led to enhanced ATP7B turnover, which was further exacerbated when cells overexpressed clusterin. We demonstrated that clusterin-facilitated degradation of mutant ATP7B is likely to involve the lysosomal pathway. The knockdown and overexpression of clusterin increased and decreased, respectively, the Cu-ATPase-mediated copper export capacity of cells. These results highlight a new role for intracellular clusterin in mediating Cu-ATPase quality control and hence in the normal maintenance of copper homeostasis, and in promoting cell survival in the context of disease. Based on our findings, it is possible that variations in clusterin expression and function could contribute to the variable clinical expression of Menkes and Wilson diseases.
21323344##2011-2-16##Quantification of oxidative DNA lesions in tissues of Long-Evans Cinnamon rats by capillary high-performance liquid chromatography-tandem mass spectrometry coupled with stable isotope-dilution method.##The purpose of our study was to develop suitable methods to quantify oxidative DNA lesions in the setting of transition metal-related diseases. Transition metal-driven Fenton reactions constitute an important endogenous source of reactive oxygen species (ROS). In genetic diseases with accumulation of transition metal ions, excessive ROS production causes pathophysiological changes, including DNA damage. Wilson's disease is an autosomal recessive disorder with copper toxicosis due to deficiency of ATP7B protein needed for excreting copper into bile. The Long-Evans Cinnamon (LEC) rat bears a deletion in Atp7b gene and serves as an excellent model for hepatic Wilson's disease. We used a sensitive capillary liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS/MS) method in conjunction with the stable isotope-dilution technique to quantify several types of oxidative DNA lesions in the liver and brain of LEC rats. These lesions included 5-formyl-2'-deoxyuridine, 5-hydroxymethyl-2'-deoxyuridine, and the 5'R and 5'S diastereomers of 8,5'-cyclo-2'-deoxyguanosine and 8,5'-cyclo-2'-deoxyadenosine. Moreover, the levels of these DNA lesions in the liver and brain increased with age and correlated with age-dependent regulation of the expression of DNA repair genes in LEC rats. These results provide significant new knowledge for better understanding the implications of oxidative DNA lesions in transition metal-induced diseases, such as Wilson's disease, as well as in aging and aging-related pathological conditions.
21323310##2011-2-16##Copper trafficking mechanism of CXXC-containing domains: insight from the pH-dependence of their Cu(I) affinities.##Copper is trafficked to cellular destinations by homeostatic proteins that also prevent adverse reactivity of the metal. The copper metallochaperone HAH1 (human Atx1) binds Cu(I) via a CXXC motif on loop1/α1 of a βαββαβ ferredoxin-like structure. A similar fold constitutes each of the six metal-binding domains (MBDs) of the two P-type ATPases (Menkes and Wilson disease proteins), the destination for copper bound to HAH1. In this work we have investigated the influence of pH on copper trafficking between HAH1 and the first MBD of the Menkes protein (MNK1). Cu(I) affinities of 5.6 × 10(17) and 3.6 × 10(17) M(-1) have been determined at pH 7.0 for HAH1 and MNK1, respectively, from competition titrations with the chromophoric Cu(I) ligand bathocuproine disulfonate. The mutation of Lys60 on loop5 of HAH1 to Ala (the corresponding residue is Phe67 in MNK1) results in a 3-fold lowering of the affinity for Cu(I) at pH 7.0. The Cu(I) affinity of WT HAH1 exhibits a different pH-dependence compared to MNK1 and Lys60Ala HAH1. This arises because the pK(a) of the second Cys ligand in the CXXC motif of HAH1 is 1.5 pH units lower due to stabilization of the thiolate via a hydrogen-bonding interaction with the side chain of Lys60. The thermodynamic gradient for Cu(I) transfer between HAH1 and MNK1 depends on pH. The decrease in the pK(a) of the Cys ligand in HAH1 can also influence the kinetics of Cu(I) transfer.
21189263##2010-12-27##Involvement of protein kinase D in expression and trafficking of ATP7B (copper ATPase).##ATP7B is a P-type ATPase involved in copper transport and homeostasis. In experiments with microsomes isolated from COS-1 cells or HepG2 hepatocytes sustaining ATP7B heterologous expression, we found that ATP7B utilization of ATP includes autophosphorylation of an aspartyl residue serving as ATPase catalytic intermediate as well as phosphorylation of serine residues by protein kinase D (PKD). The latter was abolished by specific PKD inhibition with CID755673. The presence of PKD protein in the microsomal fraction was demonstrated by Western blotting. PKD is a serine/threonine kinase that associates with the trans-Golgi network, regulating fission of transport carriers destined to the cell surface. Parallel studies on cultured cells showed that nascent WT ATP7B transits to the Golgi complex where it undergoes serine phosphorylation by PKD. Misfolded ATP7B protein (especially if subjected to deletions) underwent proteasome-mediated degradation, which provides effective quality control. Inhibition of proteasome-mediated degradation with MG132 yielded additional, but nonfunctional protein. On the other hand, serine phosphorylation protected WT ATP7B from degradation. Protection was enhanced by PKD activation with phorbol esters and limited by PKD inhibition with CID75673. As a final step, phosphorylated ATP7B was transferred from the Golgi complex to cytosolic trafficking vesicles. Phosphorylation and trafficking were completely prevented by mutations of critical copper binding sites, demonstrating copper dependence of both PKD-assisted phosphorylation and trafficking. ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.
22332042##2011-3-10##Advances in the understanding of mammalian copper transporters.##Copper (Cu) is an essential micronutrient. Its ability to exist in 2 oxidation states (Cu(1+) and Cu(2+)) allows it to function as an enzymatic cofactor in hydrolytic, electron transfer, and oxygen utilization reactions. Cu transporters CTR1, ATP7A, and ATP7B play key roles in ensuring that adequate Cu is available for Cu-requiring processes and the prevention of excess Cu accumulation within cells. Two diseases of Cu metabolism, Menkes disease and Wilson disease, which are caused by mutations in ATP7A and ATP7B, respectively, exemplify the critical importance of regulating Cu balance in humans. Herein, we review recent studies of the biochemical and cell biological characteristics of CTR1, ATP7A, and ATP7B, as well as emerging roles for Cu in new areas of physiology.
21112168##2010-8-23##Pathology, clinical features and treatments of congenital copper metabolic disorders--focus on neurologic aspects.##Genetic disorders of copper metabolism, including Menkes kinky hair disease (MD), occipital horn syndrome (OHS) and Wilson's disease (WD) are reviewed with a focus on the neurological aspects. MD and OHS are X-linked recessive disorders characterized by a copper deficiency. Typical features of MD, such as neurologic disturbances, connective tissue disorders and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care for treatment of MD is parenteral administration of copper-histidine. When the treatment is initiated in newborn babies, neurologic degeneration can be prevented, but delayed treatment is considerably less effective. Moreover, copper-histidine treatment does not improve connective tissue disorders. Novel treatments targeting neurologic and connective tissue disorders need to be developed. OHS is the mildest form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. Although the hepatic and nervous systems are typically most severely affected, initial symptoms are variable, making an early diagnosis difficult. Because early treatments are often critical, especially in patients with neurologic disorders, medical education efforts for an early diagnosis should target primary care physicians. Chelating agents and zinc are effective for the treatment of WD, but neurologic symptoms become temporarily worse just after treatment with chelating agents. Neurologic worsening in patients treated with tetrathiomolybdate has been reported to be lower than rates of neurologic worsening when treating with other chelating agents.
21034864##2010-8-19##Six novel ATP7B mutations in Thai patients with Wilson disease.##WD is an autosomal recessive disorder of copper transport resulting in excessive copper deposition in the liver and brain. It is caused by defects of ATP7B encoding a copper transporting P-type ATPase. To identify the mutations in ATP7B in Thai patients with WD, DHPLC analysis was applied to detect mutations and polymorphisms of the entire ATP7B gene in 19 Thai patients with WD. Mutations in ATP7B were identified in 14 of 19 patients: 2 homozygotes, 8 compound heterozygotes and 4 heterozygotes. Eighteen mutations distributed throughout the entire coding region of ATP7B gene including 11 missense, 3 nonsense, 1 splice-site, 1 deletion and 2 insertions. Of 18 different mutations identified, 6 were found to be novel. Twelve single nucleotide polymorphisms (SNPs) were also identified and two SNPs have not yet previously been reported. Segregation analysis using DHPLC analysis showed mutation transmission patterns within each family of Thai patients with WD. Mutations in ATP7B in Thai patients with WD are worth adding into the public database for genetic epidemiology and population genetics.
21338457##2011-2-23##Moyamoya disease as a possible cause of neurological impairment following liver transplantation for Wilson's disease.##In Wilson's disease, liver transplantation can constitute the only option for patients presenting with fulminant hepatic failure or decompensated liver disease unresponsive to drug therapy. We report the case of a 29-year-old woman receiving a liver transplant for end-stage Wilson's disease who developed neurological complications after transplantation. After an accurate evaluation of possible differential causes of neurological complications developing as the result of liver transplantation, moyamoya disease was diagnosed. Moyamoya disease is a rare cerebrovascular disease of unknown etiology. However, data exist supporting a possible role for some immunosuppressive regimens in determining the peculiar vascular alterations observed in moyamoya disease. To the best of our knowledge, the association with post-transplantation state for Wilson's disease has not been previously described.
21338455##2011-2-23##Late diagnosed Wilson disease with hepatic and neurological manifestations.##A 50-year-old woman was referred to our hospital due to liver dysfunction and progressive neurological symptoms. She had previously been diagnosed with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) had effectively normalized her serum aminotransferase levels, however, she presented with loss of balance, dysarthria and difficulty in handwriting. Autoantibodies and hepatitis virus markers were negative. Serum ceruloplasmin and copper levels were noted to be 9 mg/dL and 32 µg/dL, respectively. The 24-h urinary copper excretion was 331.8 µg/day. Kayser-Fleischer ring was demonstrated. Histological examination of the liver revealed inflammatory infiltrate and fibrosis, and the hepatic copper concentration was 444.4 µg/g dry weight. We diagnosed her as having Wilson disease and started treatment with trientine. Immuohistochemistry for keratin 8 and p62 demonstrated Mallory-Denk bodies. Many of the p62-expressing cells were positive for 4-Hydroxy-2-nonenal (HNE). Few Ki-67-positive hepatocytes were present in the liver. Wilson disease is one of the causes of NASH and UDCA may be a supportive therapeutic agent for Wilson disease. Cell proliferation is suppressed under copper-loaded conditions and this phenomenon may be associated with the clinical course of Wilson disease.
21084060##2010-7-17##Golgi membranes from liver express an ATPase with femtomolar copper affinity, inhibited by cAMP-dependent protein kinase.##Copper-stimulated P-type ATPases are essential in the fine-tuning of intracellular copper. In the present work we characterized a copper-dependent ATPase hydrolysis in a native Golgi-enriched preparation from liver and investigated its modulation by cyclic AMP-dependent protein kinase (PKA). The very high-affinity Atp7b copper pump presented here shows a K(0.5) for free copper of 2.5×10(-17) M in bathocuproine disulfonate/copper buffer and ATP hydrolysis was inhibited 50% upon stimulation of PKA pathway, using forskolin, cAMP or cholera toxin. Incubation with PKA inhibitor (PKAi(5-24) peptide) raises Cu(I)-ATPase activity by 50%. Addition of purified PKA α-catalytic subunit increases K(0.5) for free copper (6.2×10(-17) M) without modification in the affinity for ATP in the low-affinity range of the substrate curve (∼1 mM). The Hill coefficient for free copper activation also remains unchanged if exogenous PKA is added (2.7 and 2.3 in the absence and presence of PKA, respectively). The results demonstrate that this high-affinity copper pump in its natural environment is a target of the liver PKA pathway, being regulatory phosphorylation able to influence both turnover rate and ion affinity.
20535024##2010-6-11##A clinical assessment of Wilson disease in patients with concurrent liver disease.##
20953126##2010-10-13##Radiofrequency radiation at 40 kHz induces hepatic injury in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson disease.##In the present study, we examined effects of radiofrequency (RF) radiation at 40 kHz on hepatic injury in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson disease, which is a heritable disease of copper metabolism in the liver. The activities of ALT and AST in serum of LEC rats exposed to RF radiation for 2 weeks were approximately 3.8-fold and 2-fold higher than those in serum of sham-exposed rats, respectively. Although there were no significant differences in hepatic copper contents between LEC rats exposed to RF radiation for 2 weeks and sham-exposed rats, copper contents in the kidney and serum of exposed LEC rats were approximately 4.2-fold and 12.9-fold higher than those in sham-exposed rats, respectively. Relative O₂⁻-scavenging activities in the S-100 fraction of the liver of LEC rats exposed to RF radiation for 2 weeks were 1.6-fold higher than those in sham-exposed rats. No significant differences were observed in activities of AST and ALT in serum and relative O₂⁻-scavenging activity in the S-100 fraction of the liver of normal control WKAH rats that were sham-exposed and exposed to RF radiation. No significant differences were observed in copper contents in the liver, kidney and serum of WKAH rats that were sham-exposed and exposed to RF radiation for 2 weeks. The results show that RF radiation at 40 kHz induced hepatic injury in LEC rats.
22745856##2011-2-23##A Case of Wilson's Disease in Patient with Mildly Elevated Liver Enzymes.##Wilson's disease is an autosomal recessive disorder affecting copper transport; it results in the accumulation of copper in the liver, brain, and other organs. Wilson's disease is the most common inherited liver disease with more than 500 cases reported in Korea. An impairment in biliary excretion process leads to copper accumulation in the liver, which progressively damages the liver, leading to cirrhosis. Since effective treatment is available for this disease, early and correct diagnosis is very important. Here, we report a case of Wilson's disease with mildly elevated liver enzyme levels in a 29-year-old breast-feeding woman with weight loss.
21537730##2011-5-4##Long-term mood disorder antedating the diagnosis of Wilson's disease.##
21146535##2010-7-24##Elevated copper remodels hepatic RNA processing machinery in the mouse model of Wilson's disease.##Copper is essential to mammalian physiology, and its homeostasis is tightly regulated. In humans, genetic defects in copper excretion result in copper overload and Wilson's disease (WD). Previous studies on the mouse model for WD (Atp7b(-)(/-)) revealed copper accumulation in hepatic nuclei and specific changes in mRNA profile prior to the onset of pathology. To find a molecular link between nuclear copper elevation and changes in hepatic transcriptome, we utilized quantitative ionomic and proteomic approaches. X-ray fluorescence and inductively coupled plasma mass spectrometry analysis indicate that copper in the Atp7b(-/-) nucleus, while highly elevated, does not markedly alter nuclear ion content. Widespread protein oxidation is also not observed, although the glutathione reductase SelH is upregulated, likely to maintain redox balance. We further demonstrate that accumulating copper affects the abundance and/or modification of a distinct subset of nuclear proteins. These proteins populate pathways that are most significantly associated with RNA processing. An alteration in splicing pattern was observed for hnRNP A2/B1, itself the RNA shuttling factor and spliceosome component. Analysis of hnRNP A2/B1 mRNA and protein revealed an increased retention of exon 2 and a selective 2-fold upregulation of a corresponding protein splice variant. Mass spectrometry measurements suggest that the nucleocytoplasmic distribution of RNA binding proteins, including hnRNP A2/B1, is altered in the Atp7b(-/-) liver. We conclude that remodeling of the RNA processing machinery is an important component of cell response to elevated copper that may guide pathology development in the early stages of WD.
20195595##2010-3-3##Unique CT imaging findings of liver in Wilson's disease.##
21350079##2011-2-26##Alois Alzheimer (1864-1915) and the Alzheimer syndrome.##Alois Alzheimer is known for his seminal work in recognizing a form of presenile dementia. His early interests were natural history and botany. He started his medical education in Berlin and attended the universities of Wurzburg and Tübingen. Nissl and Alzheimer worked together on extensive investigation of the pathology of the nervous system, especially the anatomy of the cerebral cortex. In 1902 Emil Kraepelin invited Alzheimer to work with him in the university psychiatric clinic in Heidelberg. In 1903 both moved to work in the university psychiatric clinic in Munich. It was during these years that Alzheimer described the Alzheimer's disease. He also described brain changes in arteriosclerosis, loss of nerve cells in Huntington's disease in the corpus striatum and brain changes in epilepsy. Alzheimer presented a preliminary report of his histological findings in 1906 at Tübingen about a 51-year-old lady who had developed presenile dementia and died within four years of onset of the disease. He published his findings in 1907, reporting the atrophic brain with neurofibrillary deposits and areas in the cerebrum resistant to staining. During the later years of his career Alzheimer concentrated on the study of changes in glial cells. His best-known works from this period were on Westphal-Strümpell pseudo-sclerosis of the brain, now assumed to be the same as Wilson's Disease. His death, at age 51, was the result of cardiac failure following endocarditis.
19691525##2009-8-21##De novo phyllodes tumor in an adolescent female after liver transplantation.##Phyllodes tumor of the breast is a rare disease constituting 0.3-0.9% of all breast neoplasms. Occurring mainly in females aged 35 to 55 yr, the disease is especially rare among adolescent females. There is no published literature about de novo phyllodes tumor after liver transplantation. Here we describe a case of de novo phyllodes tumors in an adolescent female after liver transplantation from a living donor for Wilson disease.
21199858##2011-1-3##Lingual dyskinesia and tics: a novel presentation of copper-metabolism disorder.##Copper is a trace element that is required for cellular respiration, neurotransmitter biosynthesis, pigment formation, antioxidant defense, peptide amidation, and formation of connective tissue. Abnormalities of copper metabolism have been linked with neurologic disorders that affect movement, such as Wilson disease and Menkes disease; however, the diagnosis of non-Wilson, non-Menkes-type copper-metabolism disorders has been more elusive, especially in cases with atypical characteristics. We present here the case of an adolescent with a novel presentation of copper-metabolism disorder who exhibited acute severe hemilingual dyskinesia and prominent tics, with ballismus of the upper limbs, but had normal brain and spinal MRI results and did not show any signs of dysarthria or dysphagia. His serum copper and ceruloplasmin levels were low, but his urinary copper level was elevated after penicillamine challenge. We conclude that copper-metabolism disorders should be included in the differential diagnosis for movement disorders, even in cases with highly unusual presentations, because many of them are treatable. Moreover, a connection between copper-metabolism disorders and tics is presented, to our knowledge, for the first time in humans; further investigation is needed to better establish this connection and understand its underlying pathophysiology.
20860861##2010-9-22##Risk-benefit analysis of mineral intakes: case studies on copper and iron.##Dietary reference values for essential trace elements are designed to meet requirements with minimal risk of deficiency and toxicity. Risk-benefit analysis requires data on habitual dietary intakes, an estimate of variation and effects of deficiency and excess on health. For some nutrients, the range between the upper and lower limits may be extremely narrow and even overlap, which creates difficulties when setting safety margins. A new approach for estimating optimal intakes, taking into account several health biomarkers, has been developed and applied to selenium, but at present there are insufficient data to extend this technique to other micronutrients. The existing methods for deriving reference values for Cu and Fe are described. For Cu, there are no sensitive biomarkers of status or health relating to marginal deficiency or toxicity, despite the well-characterised genetic disorders of Menkes and Wilson's disease which, if untreated, lead to lethal deficiency and overload, respectively. For Fe, the wide variation in bioavailability confounds the relationship between intake and status and complicates risk-benefit analysis. As with Cu, health effects associated with deficiency or toxicity are not easy to quantify, therefore status is the most accessible variable for risk-benefit analysis. Serum ferritin reflects Fe stores but is affected by infection/inflammation, and therefore additional biomarkers are generally employed to measure and assess Fe status. Characterising the relationship between health and dietary intake is problematic for both these trace elements due to the confounding effects of bioavailability, inadequate biomarkers of status and a lack of sensitive and specific biomarkers for health outcomes.
21321834##2011-2-14##Diagnosis and treatment of common forms of tremor.##Tremor is the most common movement disorder presenting to an outpatient neurology practice and is defined as a rhythmical, involuntary oscillatory movement of a body part. The authors review the clinical examination, classification, and diagnosis of tremor. The pathophysiology of the more common forms of tremor is outlined, and treatment options are discussed. Essential tremor is characterized primarily by postural and action tremors, may be a neurodegenerative disorder with pathologic changes in the cerebellum, and can be treated with a wide range of pharmacologic and nonpharmacologic methods. Tremor at rest is typical for Parkinson's disease, but may arise independently of a dopaminergic deficit. Enhanced physiologic tremor, intention tremor, and dystonic tremor are discussed. Further differential diagnoses described in this review include drug- or toxin-induced tremor, neuropathic tremor, psychogenic tremor, orthostatic tremor, palatal tremor, tremor in Wilson's disease, and tremor secondary to cerebral lesions, such as Holmes' tremor (midbrain tremor). An individualized approach to treatment of tremor patients is important, taking into account the degree of disability, including social embarrassment, which the tremor causes in the patient's life.
21298607##2011-2-4##Pantoprazole induces severe acute hepatitis.##A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole.
21155609##2010-12-14##Hepatocyte targeting and intracellular copper chelation by a thiol-containing glycocyclopeptide.##Metal overload plays an important role in several diseases or intoxications, like in Wilson's disease, a major genetic disorder of copper metabolism in humans. To efficiently and selectively decrease copper concentration in the liver that is highly damaged, chelators should be targeted at the hepatocytes. In the present work, we synthesized a molecule able to both lower intracellular copper, namely Cu(I), and target hepatocytes, combining within the same structure a chelating unit and a carbohydrate recognition element. A cyclodecapeptide scaffold displaying a controlled conformation with two independent faces was chosen to introduce both units. One face displays a cluster of carbohydrates to ensure an efficient recognition of the asialoglycoprotein receptors, expressed on the surface of hepatocytes. The second face is devoted to metal ion complexation thanks to the thiolate functions of two cysteine side-chains. To obtain a chelator that is active only once inside the cells, the two thiol functions were oxidized in a disulfide bridge to afford the glycopeptide P(3). Two simple cyclodecapeptides modeling the reduced and complexing form of P(3) in cells proved a high affinity for Cu(I) and a high selectivity with respect to Zn(II). As expected, P(3) becomes an efficient Cu(I) chelator in the presence of glutathione that mimics the intracellular reducing environment. Finally, cellular uptake and ability to lower intracellular copper were demonstrated in hepatic cell lines, in particular in WIF-B9, making P(3) a good candidate to fight copper overload in the liver.
21219664##2010-3-18##Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations.##
22715218##2012-6-21##Complex psychiatric presentation in adolescent onset Wilson's disease.##A previously healthy 15-year-old boy presented with a 2-week history of acute tremor in his hands, fasciculation of his tongue and a sensation that his mind was going blank. Physical examination and investigations confirmed a diagnosis of Wilson's disease and chelating treatment was started. As his neurological symptoms and liver function started to improve he developed tearfulness symptoms of depression and intense doubt about everything he thought and said. He was diagnosed with a moderate depressive episode and obsessive compulsive disorder as a result of Wilson's disease and started on citalopram. After an initial period of improvement with citalopram, his symptoms changed and he appeared irritable, restless, impulsive, disinhibited and was unable to sleep. Bipolar affective disorder was diagnosed and treatment changed to lithium carbonate and olanzepine, which led to a gradual mood stabilisation and successful recovery.
22140659##2011-5-10##Cytokeratin-18 and hyaluronic acid levels predict liver fibrosis in children with non-alcoholic fatty liver disease.##
24733533##2011-2-28##Galactorrhea with menstrual irregularity: something other than a prolactinoma?##
21633612##2010-7-05##Sleep in Wilson's disease: Questionnaire based study.##
22291850##2010-12-01##Resolved Psychosis after Liver Transplantation in a Patient with Wilson's Disease.##A psychiatric involvement is frequently present in Wilson's disease. Psychiatric symptoms are sometimes the first and only manifestation of Wilson's disease. More often a psychiatric involvement is present beside a neurologic or hepatic disease.We describe the case of a 18 years-old male patient who shows a clinic and laboratoristic pattern of cirrhosis and an history of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances with depressed mood. He hadn't familiar history of liver or psychiatric disease. Laboratory and imaging tests confirmed the diagnosis of Wilson's disease with psichiatric involvement. After liver transplantation copper metabolism and liver function normalised and we noticed no recurrency of the psichiatric illness. Very few cases of psychiatric improvement after orthotopic liver transplantation (OLT) has been described until now.
22755415##2012-7-5##More than a quarter of a century of liver transplantation in Kaohsiung Chang Gung Memorial Hospital.##Liver transplantation has been an accepted treatment for end-stage liver disease since the 1980s. The development of living donor liver transplantation (LDLT) was driven by limited deceased donor organ donation and a response to the growing demand for the option of liver replacement. LDLT is now performed with high rates of success due to judicious donor and recipient selection, careful preoperative planning, excellent anesthesia management, and prompt detection and treatment of complications. The first successful liver transplantation in Asia was performed in 1984, in Chang Gung Memorial Hospital in a Taiwanese adolescent with Wilson's disease, complicated by end-stage liver cirrhosis. The longest Asian liver transplant survivor has now been living for 26 years and that patient's transplant was also performed in Chang Gung Memorial Hospital. Through December 31, 2011, a total of 924 (783 living donor, 141 deceased donor) liver transplants have been performed at the Kaohsiung Chang Gung Memorial Hospital, where both graft and patient survivals are excellent. For biliary atresia, hepatitis B virus cirrhosis, and hepatocellular carcinoma recipients, our 5-year LDLT survival rates are 98%, 94%, and 90%, respectively. Our overall (deceased and living donor) actuarial 3-year survival rate is 91%. Innovative techniques in LDLT represent technical refinements in hepatic vein, portal vein, hepatic artery, and biliary reconstruction approaches. Hepatic vein reconstruction is highlighted by venoplasty reconstructions in both graft hepatic vein orifices and recipient hepatic veins, to ensure adequate outflow and decrease ischemia times during implantation. Vascular interposition to reconstruct middle hepatic vein tributaries with either fresh or cryopreserved vessels is used when the middle hepatic vein is not routinely harvested with the graft. We have extended the routine use of microsurgical techniques, initially for hepatic artery reconstruction, to biliary reconstruction where the possibility of duct-to-duct reconstruction is performed with accuracy and precision in pediatric non-biliary atresia and in multiple, small bile ducts. Long-term survival has always been related to the immunosuppression regimen, which influences outcome. Newer drugs do not equate to lesser complications. Rather, improvement in how we can find new uses for old drugs is now the norm. Less immunosuppression, as long as hepatic function is maintained at an acceptable level, decreases the chances of long-term complications related to immunosuppression use.
20946468##2010-10-14##Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.##
21552664##2010-9-28##Wilson's disease in southern Brazil: a 40-year follow-up study.##
21734379##2011-7-05##Nutritional influences in selected gastrointestinal diseases.##Nutritional factors, as sources of luminal antigens, have been thought to be important factors in the immunopathogenesis of numerous gastrointestinal diseases. In some diseases, the role of the nutritional component is causal in the susceptible host. Such diseases include celiac disease, a common heritable chronic inflammatory condition of the small intestine induced by dietary wheat, rye and barley, in susceptible individuals. Specific HLA-DQ2 and HLA-DQ8 risk alleles are necessary, but not sufficient, for disease development. The well-defined role of HLA-DQ heterodimers encoded by these alleles is to present cereal peptides to CD4+ T cells, activating an inflammatory immune response in the intestine. Genome-wide association studies have been performed which identified the IL2-IL21 risk locus and other genes with immune functions and key roles in thymic T-cell selection. Another example for this group is Wilson's disease, an autosomal recessive disorder of copper metabolism caused by mutation of the ATP7B gene, resulting in a defect of biliary copper excretion and toxic accumulation in the body, especially in the liver, brain and cornea, resulting in hepatic and/or neurological symptoms. In other diseases, however, the association is less well established. In such endeavor, epidemiological observations may become a valuable part of the overall investigations aimed at identifying dietary factors, which are involved in the initiation and perpetuation of the specific disease. As an example, relationships between nutrition and colorectal cancer have been hypothesized early on (e.g. folate, calcium, vitamin D, red meat). Similarly, intake of certain diet constituents like fat, refined sugar, fruits, vegetables and fiber was reported to be associated with the expression of inflammatory bowel diseases. In addition, in children with active Crohn's disease, enteral nutrition was found to be equally effective as corticosteroids in induction of remission, with mucosal healing induced by downregulation of mucosal pro-inflammatory cytokine profiles in both the ileum and the colon after enteral nutrition. However, the particular effect of the consumption of each type of food remains questionable in most cases, at least in part because of insufficient data and serious methodological limitations (e.g. recall bias, heterogeneity between collected data, lack of correction for covariates, difficulties in double blinding).
20928916##2010-10-8##Extraordinary stability of copper(I)-tetrathiomolybdate complexes: possible implications for aquatic ecosystems.##An extraordinary affinity of MoS₄²⁻ for Cu accounts for Mo-induced Cu deficiency in ruminants (molybdenosis) and offers an approach to treating Wilson's disease in humans. Evidence of thiomolybdates in sulfidic natural waters, and possibly even as metastable traces in oxic natural waters, raises the question of how Cu-Mo affinity might affect Cu availability or toxicity in aquatic ecosystems. Stabilities of inorganic Cu-MoS₄²⁻ complexes are characterized and quantified here for the first time. Two remarkably stable Cu(I) dissolved complexes are identified (T = 23°C ± 2°C): Cu₂(HS)₂MoS₄²⁻ and Cu₂S₂MoS₄⁴⁻. In addition, the solubility constant for a precipitate (NH₄CuMoS₄) was measured. Under the extremely reducing conditions in rumen fluids, these complexes will greatly suppress Cu(+) activity, supporting prior conclusions about the mechanism of molybdenosis. In sulfidic natural waters, they help to prevent complete Cu impoverishment, as might otherwise occur by sulfide mineral precipitation. On the other hand, the complexes discovered here are HS⁻-dependent and could not be important in oxic natural waters (with HS⁻ concentrations < 10⁻⁹ M) even if metastable, biogenic MoS₄²⁻ indeed were present as previously conjectured.
20550561##2010-6-17##Sleep disorders in Wilson's disease.##
21865760##2010-11-12##Reduced serum caeruloplasmin levels in non-wilsonian movement disorders.##Reduction in caeruloplasmin (Cp) levels is sometimes found in other sporadic movement disorders, not limited to Wilson's disease (WD). Serum levels of Cp, copper, iron and gamma-glutamyl transpeptidase were measured in 71 patients with various diagnoses of movement disorders, including Parkinson's disease (PD), atypical parkinsonian disorders, tardive dyskinesia, essential tremor, and idiopathic focal dystonia, and compared with those of 26 healthy age- and gender-matched controls. The mean Cp level in the patient group was 20.5 ± 4.2 mg/dl , lower than in controls (23.5 ± 7.2 mg/dl; p = 0.005). In subgroup analysis, mean Cp level of PD patients (19.6 ± 3.0 mg/dl) was lower than that of controls (p = 0.045). In a group analysis as neurodegenerative movement disorders (NDD), their mean Cp level was 19.9 ± 3.0 mg/dl, lower than that of controls (p = 0.019). Linear regression analysis indicated that the presence of NDD was the main factor associated with lower Cp levels. The finding of reduced serum Cp level in non-Wilsonian movement disorders and selective reduction in the neurodegenerative subgroup supports the notion that Cp might be associated with the cascade of neurotoxicity in NDD. The variation in Cp level in other non-WD conditions highlights the fact that Cp level is a poor screening test for WD in the absence of clear clinical suspicion.
21496616##2011-4-19##Wilson's disease.##In the almost 100 years since Wilson's description of the illness that now bears his name, tremendous advances have been made in our understanding of this disorder. The genetic basis for Wilson's disease - mutation within the ATP7B gene - has been identified. The pathophysiologic basis for the damage resulting from the inability to excrete copper via the biliary system with its consequent gradual accumulation, first in the liver and ultimately in the brain and other organs and tissues, is now known. This has led to the development of effective diagnostic and treatment modalities that, although they may not eliminate the disorder, do provide the means for efficient diagnosis and effective amelioration if carried out in a dedicated and persistent fashion. Nevertheless, Wilson's disease remains both a diagnostic and treatment challenge for physician and patient. Its protean clinical manifestations make diagnosis difficult. Appropriate diagnostic evaluations to confirm the diagnosis and institute treatment can be confusing. In this chapter, the clinical manifestations, diagnostic evaluation, and treatment approaches for Wilson's disease are discussed.
21220881##2011-1-12##Penicillamine-induced elastosis perforans serpiginosa with abnormal "lumpy-bumpy" elastic fibers in lesional and non-lesional skin.##Four types of elastosis perforans serpiginosa (EPS) have been described in literature: 1) idiopathic EPS, 2) reactive perforating elastosis associated with connective tissue disorders, 3) in some instances of pseudoxanthoma elasticum (PXE), disease-specific calcified elastic tissue is extruded, producing a clinical picture indistinguishable from other types, may also be seen in patients undergoing hemodialysis and 4) EPS induced by long-term treatment with D-penicillamine is observed in patients suffering from Wilson's disease. Long term D-penicillamine therapy causes an alteration in the dermal elastic tissue. D-penicillamine induced EPS has a distinctive histopathologic feature - serrated appearance of elastic fibers due to perpendicular budding from their surface giving a "lumpy-bumpy" look. D-penicillamine induced elastic fiber alteration may not always manifest clinically as EPS. We report a case of D-penicillamine induced widespread alteration in skin elastic tissue with distinct histopathologic features.
21949909##2011-5-9##Paradigm shift in treatment of Alzheimer's disease: zinc therapy now a conscientious choice for care of individual patients.##Breakthrough in treatment of Alzheimer's disease with a shift from irrational dangerous chelation therapy to rational safe evidence based oral zinc therapy. Evidence based medicine: After synthesizing the best available clinical evidence I conclude that oral zinc therapy is a conscientious choice for treatment of free copper toxicosis in individual patients with Alzheimer's disease. Hypothesis 1: Age related free copper toxicosis is a causal factor in pathogenesis of Alzheimer's disease. There are 2 neurodegenerative diseases with abnormalities in copper metabolism: (a) the juvenile form with degeneration in the basal ganglia (Wilson's disease) and (b) the age related form with cortical neurodegeneration (Alzheimer's disease). Initially the hypothesis has been that neurodegeneration was caused by accumulation of copper in the brain but later experiences with treatment of Wilson's disease led to the conviction that free plasma copper is the toxic form of copper: it catalyzes amyloid formation thereby generating oxidative stress, free radicals and degeneration of cortical neurons. Hypothesis 2: Oral zinc therapy is an effective and safe treatment of free copper toxicosis in Alzheimer's disease. Proposed dosage: 50 mg elementary zinc/day. Warning: Chelation therapy is irrational and dangerous in treatment of copper toxicosis in Alzheimer's disease.
21760992##2010-12-30##Association between the c. 2495 A>G ATP7B Polymorphism and Sporadic Alzheimer's Disease.##Nonceruloplasmin-bound copper ("free") is reported to be elevated in Alzheimer's disease (AD). In Wilson's disease (WD) Cu-ATPase 7B protein tightly controls free copper body levels. To explore whether the ATP7B gene harbours susceptibility loci for AD, we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most of the Mediterranean WD-causing mutations lie. No WD mutation, but sequence changes corresponding to c.1216 T>G Single-Nucleotide Polymorphism (SNP) and c.2495 A>G SNP were found. Thereafter, we genotyped 190 AD patients and 164 controls for these SNPs frequencies estimation. Logistic regression analyses revealed either a trend for the c.1216 SNP (P = .074) or a higher frequency for c.2495 SNP of the GG genotype in patients, increasing the probability of AD by 74% (P = .028). Presence of the GG genotype in ATP7B c.2495 could account for copper dysfunction in AD which has been shown to raise the probability of the disease.
21496412##2011-4-19##An 18-year follow-up of a case of D-penicillamine-induced Elastosis perforans serpiginosa.##Elastosis perforans serpiginosa (EPS) is a rare complication of chronic therapy with a high-dose of D-penicillamine (1 g daily for more than 5 years), characterized by the elimination of abnormal elastic fibers from the upper dermis through the epidermis. D-penicillamine (DPA) is a heavy metal chelator primarily used for disorders such as cystinuria and Wilson disease. This therapy can lead to induction of EPS through a still unknown mechanism. We report the follow-up of a D-penicillamine-induced EPS in patient with Wilson disease, which prompted us to switch the therapy with trientine (another metal chelator). After 14 years the cutaneous lesions are still visible; therefore, we conclude that the DPA-induced cutaneous damage is irreversible.
20942594##2010-10-13##Influence of IL-1RN intron 2 variable number of tandem repeats (VNTR) polymorphism on the age at onset of neuropsychiatric symptoms in Wilson's disease.##ABSTRACT Wilson's disease (WND) is an autosomal recessive copper storage disease characterized with diverse clinical pictures with the hepatic and/or neuropsychiatric symptoms manifesting at variable age. On the basis of the existing knowledge on possible copper-proinflammatory cytokines interactions, we hypothesized that in WND hereditary, over-/underexpression of PC or anti-inflammatory cytokines may have an impact on the course of the disease. We analyzed the clinical manifestations of WND in relationship to polymorphisms within genes for interleukin-1 receptor antagonist (IL1RN intron 2 VNTR polymorphism), interleukin-1α (IL1A G4845T), IL-1β (IL1B C-511T), IL-6 (IL6 G-174C), and tumor necrosis factor (TNF G-308A) in a total sample of 332 patients. The IL1B C-511T and IL1RN VNTR polymorphisms had an impact on copper metabolism parameters. None of the studied gene polymorphisms had effect on the mode of WND manifestation (neuropsychiatric vs. hepatic). Carriership of the IL1RN *2 allele was related to earlier WND onset, especially among patients with neuropsychiatric form of the disease (median 27.5 vs. 32.0 years, p = .003). Because of the crucial modulatory role of IL1ra on IL-1α and IL-1β proinflammatory functions, IL1ra and its interactions may play a role in the pathogenesis of the neurodegenerative process in WND; our results need to be replicated, possibly in different ethnic groups.
21757830##2011-7-15##Excess copper chelating therapy for Wilson disease induces anemia and liver dysfunction.##A 37-year-old man was diagnosed with Wilson disease at the age of 14. His first manifestations were neurological. He was treated with trientine for more than 10 years and suffered from anemia and liver dysfunction. Wilson disease is a genetic disorder characterized by accumulation of copper in the body. Excess copper is toxic, but copper is an essential trace element. Copper-binding ceruloplasmin is important for iron metabolism. Excess copper chelating treatment-induced anemia and iron deposition in the liver was suspected. Proper monitoring of copper status is important for the management of Wilson disease.
21720066##2011-7-1##Hepatocellular carcinoma in a case of Wilson's disease treated with radiofrequency ablation therapy.##A 37-year-old Japanese man was diagnosed with liver cirrhosis due to Wilson's disease in 2001 and treated with D-penicillamine. Thereafter, he was admitted to our hospital for further examination of a space occupying lesion in the liver. The patient was diagnosed with hepatocellular carcinoma (HCC) (7th segment, 2.5 cm in diameter) in May 2010 and treated with radiofrequency ablation therapy. Biopsy findings from a non-cancerous area revealed a fatty liver, though cirrhotic nodules were not found. Long-term treatment for Wilson's disease may improve hepatic fibrosis, and careful screening for HCC by abdominal imaging is needed in such cases.
22389819##2011-3-16##Penicillamine neurotoxicity: an hypothesis.##Penicillamine, dimethyl cysteine, thiovaline, remains the drug of choice for the treatment of patience with Wilson disease. It is also of value in the treatment of cysteinuria and rheumatoid arthritis, it has also been suggested that it has value in the management of other rare diseases. It also has multiple toxicities. The majority of these can be explained as chemical toxicity, for instance its weak antipyridoxine action and its ability to interfere with lysyloxidea resulting in skin lesions. More important are its ability to induce immune reactions such as SLE, immune complex nephritis, the Ehlers Danlos syndrome and Goodpasture's syndrome. However the sudden increase in neurological signs which may occur in a small number of patients remains unexplained. The theory is proposed that this is due to lethal synthesis. In susceptible patients the-SH radical is liberated from penicillamine and will inhibit-SH dependent enzymes in the Krebs cycle leading to death in neurones. Other toxic metabolites may also be produced such as methyl mercaptan and ethyl mercaptan either of which could produce a similar metabolic block.
21648288##2011-6-9##Neurological Wilson's disease with refractory rickets.##Wilson's disease rarely presents with isolated neurological complaints without any hepatic involvement. Refractory rickets with Wilson's disease has been infrequently reported in literature. We are reporting a case of isolated neurological Wilson's disease associated with refractory rickets which on complete evaluation was diagnosed as familial hypophosphatemic rickets.
21977083##2011-10-7##Wilson's disease: MRI features.##A 15-year-old boy presented with coarse tremors of right hand and dysarthric speech. Neurologic examination demonstrated Kayser-Fleischer rings and dystonic tremor of the right hand. Serum ceruloplasmin and urine copper studies established the diagnosis of Wilson's disease. Brain MRI showed bilateral T2 hyperintensity involving putamen, thalami, and brainstem. Involvement of brainstem revealed the characteristic "double panda sign."
21773030##2011-3-18##A case of isolated elevated copper levels during pregnancy.##
21342755##2010-5-7##Risks and benefits of copper in light of new insights of copper homeostasis.##Copper is an essential micronutrient involved in a variety of biological processes indispensable to sustain life. At the same time, it can be toxic when present in excess, the most noticeable chronic effect being liver damage. Potent, efficient regulatory mechanisms control copper absorption in the digestive tract and copper biliary excretion; absorption ranges between 12 and 60% in humans, depending on Cu intake, presence of other factors in the diet that may promote or inhibit its absorption and on the copper status of the individual. Current evidence suggests that copper deficiency may be more prevalent than previously thought, while copper toxicity is uncommon under customary daily life conditions. Menkes syndrome and Wilson disease are genetic conditions associated with severe copper deficiency and severe copper toxicity, respectively. Effects of milder degrees of copper deficiency and excess copper exposure are not well described, mainly due to lack of sensitive and specific indicators; serum copper concentration and ceruloplasmin are the most frequently used indicators, but they only detect rather intense changes of copper status. Of the many proteins assessed as potential markers of copper status the chaperone of Zn-Cu superoxide dismutase (CCS1) has yielded promising results; data on its performance under different conditions are needed to confirm its use as an indicator of early copper deficiency. Defining copper requirements and upper safe limits of consumption (UL) is a complex process since there are adverse health consequences from both copper deficiency and copper excess (U shape curve). The regulatory framework for risk assessment of essential trace elements introduced by the International Programme on Chemical Safety (IPCS) has proposed a homeostatic model to determine the Adequate Range of Oral Intake (AROI) of essential trace elements; the nadir of the resulting U shape curve serves to define the AROI. At this range of intake physiological mechanisms allow for normal homeostasis and basically, there are no detectable adverse effects. At present, Recommended Dietary Intakes (DRIs) and Adequate Intakes (AIs) are used to recommend copper intakes at different ages and life situations. Evidence obtained in humans and non-human primates presented here suggest that current copper UL should be re evaluated. Developing the scientific basis for a copper UL and evaluating the relevance of copper deficiency globally are future key challenges for copper researchers.
21242075##2010-1-11##The biogenic methanobactin is an effective chelator for copper in a rat model for Wilson disease.##Copper is an essential redox-active metal ion which in excess becomes toxic due to the formation of reactive oxygen species. In Wilson disease the elevated copper level in liver leads to chronic oxidative stress and subsequent hepatitis. This study was designed to evaluate the copper chelating efficiency of the bacterial methanobactin (MB) in a rat model for Wilson disease. Methanobactin is a small peptide produced by the methanotrophic bacterium Methylosinus trichosporium OB3b and has an extremely high affinity for copper. Methanobactin treatment of the rats was started at high liver copper and serum aspartate aminotransferase (AST) levels. Two dosing schedules with either 6 or 13 intraperitoneal doses of 200mg methanobactin per kg body weight were applied. Methanobactin treatment led to a return of serum AST values to basal levels and a normalization of liver histopathology. Concomitantly, copper levels declined to 45% and 24% of untreated animals after 6 and 13 doses, respectively. Intravenous application of methanobactin led to a prompt release of copper from liver into bile and the copper was shown to be associated with methanobactin. In vitro experiments with liver cytosol high in copper metallothionein demonstrated that methanobactin removes copper from metallothionein confirming the potent copper chelating activity of methanobactin.
20958917##2010-10-20##Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation.##
21275100##2011-1-29##The puzzle posed by COMMD1, a newly discovered protein binding Cu(II).##Copper is critically important for cellular metabolism. It plays essential roles in developmental processes, including angiogenesis. The liver is central to mammalian copper homeostasis: biliary excretion is the major route of excretion for ingested copper and serves to regulate the total amount of copper in the organism. An extensive network of proteins manipulates copper disposition in hepatocytes, but comparatively little is known about this protein system. Copper exists in two oxidation states: most extracellular copper is Cu(II) and most, if not all, intracellular copper is Cu(I). Typical intracellular copper-binding proteins, such as the Cu-transporting P-type ATPases ATP7B (Wilson ATPase) and ATP7A (Menkes ATPase), bind copper as Cu(I). Accordingly, the recent discovery that the ubiquitous protein COMMD1 binds Cu(II) exclusively raises the question as to what role Cu(II) may play in intracellular processes. This issue is particularly important in the liver and brain. In humans, Wilson’s disease, due to mutations in ATP7B, exhibits progressive liver damage from copper accumulation; in some Bedlington terriers, mutations in COMMD1 are associated with chronic copper-overloaded liver disease, clinically distinct from Wilson’s disease. It seems unlikely that Cu(II), which generates reactive oxygen species through the Fenton reaction, has a physiological role intracellularly; however, Cu(II) might be the preferred state of copper for elimination from the cell, such as by biliary excretion. We argue that COMMD1 participates in the normal disposition of copper within the hepatocyte and we speculate about that role. COMMD1 may contribute to the mechanism of biliary excretion of copper by virtue of binding Cu(II). Additionally, or alternatively, COMMD1 may be an important component of an intracellular system for utilizing Cu(II), or for detecting and detoxifying it.
22008159##2011-10-20##[Acute liver failure in a young adult].##Acute liver failure is a rare but mostly severe disorder in previously healthy patients. Viral infections and drugs are the most common causes in the Western world. A small percentage of acute liver failure is caused by Wilson's disease. We describe a previously healthy 23-year-old female with acute haemolytic anemia and liver failure as the first manifestations of Wilson's disease. There was rapid deterioration to multi-organ failure and the patient died less than 24 hours after initial presentation. Relatively simple laboratory tests can be used for initial screening of acute liver failure due to Wilson's disease. Liver transplantation is the only way to ensure survival of the patient. Rapid transfer to a specialised centre is, therefore, of the utmost concern.
21176821##2010-5-25##Dental considerations in the patient with Wilson's disease.##Wilson's disease was described by Wilson in 1912. It is an autosomal recessive disorder caused by mutations in the ATP7B gene, a membrane-bound copper transporting ATPase. The deficiency of ATP7B protein impairs the biliary copper excretion, resulting in positive copper balance, hepatic copper accumulation, and copper toxicity from oxidant damage. The disease is a form of copper poisoning caused by a defect in the transport of copper that renders the patient unable to handle trace amounts of copper normally present in the diet and hence the clinical manifestations are those typically caused by copper toxicity and primarily involve the liver and the brain. Because effective treatment is available, it is important to make an early diagnosis. In this article, a review of clinical aspects of Wilson's disease, and its impact on dental management and dental considerations are discussed.
21115196##2010-7-29##Differential intracellular localisation of the Menkes and Wilson copper transporting ATPases in the third trimester human placenta.##Copper is an essential trace element necessary for normal growth and development. During pregnancy, copper is transported from the maternal circulation to the fetus by mechanisms which have not been clearly elucidated. Two copper transporting ATPases, Menkes (ATP7A; MNK) and Wilson (ATP7B; WND) are known to be expressed in the placenta and are thought to have a role in copper transport to the fetus. In this study, the intracellular localisation of the MNK and WND proteins in the third trimester human placental tissue was investigated in detail using double-label immunohistochemistry and immuno-electron microscopy. MNK and WND were differentially localised within the placenta. MNK was present at the basal side of the syncytiotrophoblast layer and also within the fetal vascular endothelial cells, whereas WND was localised at the microvillous membrane of the syncytiotrophoblast. These data offer some insights into possible differential roles for MNK and WND within the placenta.
22216203##2011-9-20##Liver-specific Commd1 knockout mice are susceptible to hepatic copper accumulation.##Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver-specific Commd1 knockout mice (Commd1(Δhep)) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1(Δhep) mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1(Δhep) mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1(Δhep) mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1(Δhep) mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1(Δhep) mice could be detected. Despite the absence of hepatocellular toxicity in Commd1(Δhep) mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis.
22046264##2011-1-9##Elucidation of the ATP7B N-domain Mg2+-ATP coordination site and its allosteric regulation.##The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg(2+)-ATP coordination site and answer to the controversial role of the Mg(2+) ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg(2+)-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process.
21751523##2011-7-15##[Rapidly progressive ANCA-negative glomerulonephritis in the course of pauci immune microscopic vasculitis with hemolytic anemia probable in the course of Wilson's disease].##Pauci-immune glomerulonephritis, i.e., with no evidence of immune deposits in the blood vessel, is the most prevalent form of rapidly progressive glomerulonephritis (RPGN). In the pathogenesis of pauci-immune renal disease inflammation of blood vessels in the presence of circulating anti-neutrophil cytoplasm antibodies (ANCA) takes place. However the lack of ANCA (about 5-30% of patients) does not exclude pauci-immune vasculitis. The patients without circulating ANCA might have fewer extrarenal symptoms than those who are ANCA-positive. We describe a case of a 40-year old women with ANCA-negative renal limited pauci-immune small-vessel vasculitis with rapidly decreasing kidney function. She was ineffectively treated with plasmapheresis combined with a puls of cyclophosphamide (i.v.) and 3 pulses of methyloprednisolone (i.v.). The patient progressed to end-stage renal disease and should be treated with renal replacement therapy. In differential diagnosis we excluded other causes of pauci-immune vasculitis (Churg-Strauss syndrome, Wegener's granulomatosis), vasculitis with immune complexes deposition (systemic lupus erythematosus, Schoenlein-Henoch purpura, post-infection RPGN), Goodpasture disease, haemolytic-uremic syndrome (HUS), disseminated intravascular coagulation (DIC) and Wilson's disease.
21682185##2011-6-21##Wilson's disease: a challenging diagnosis. Clinical manifestations and diagnostic procedures in 12 patients.##
21977043##2011-3-17##Hepatic differentiation of murine disease-specific induced pluripotent stem cells allows disease modelling in vitro.##Direct reprogramming of somatic cells into pluripotent cells by retrovirus-mediated expression of OCT4, SOX2, KLF4, and C-MYC is a promising approach to derive disease-specific induced pluripotent stem cells (iPSCs). In this study, we focused on three murine models for metabolic liver disorders: the copper storage disorder Wilson's disease (toxic-milk mice), tyrosinemia type 1 (fumarylacetoacetate-hydrolase deficiency, FAH(-/-) mice), and alpha1-antitrypsin deficiency (PiZ mice). Colonies of iPSCs emerged 2-3 weeks after transduction of fibroblasts, prepared from each mouse strain, and were maintained as individual iPSC lines. RT-PCR and immunofluorescence analyses demonstrated the expression of endogenous pluripotency markers. Hepatic precursor cells could be derived from these disease-specific iPSCs applying an in vitro differentiation protocol and could be visualized after transduction of a lentiviral albumin-GFP reporter construct. Functional characterization of these cells allowed the recapitulation of the disease phenotype for further studies of underlying molecular mechanisms of the respective disease.
21120788##2010-11-30##[Metabolic disorders of the liver. Part 1: Hemochromatosis, Wilson's disease, α(1)-antitrypsin-deficiency, Gaucher's disease].##
21040274##2010-10-7##Clinical features of Wilson disease: Analysis of 10 cases.##
21105104##2010-11-25##Mining for a diagnosis of Wilson's disease in children: genetics, score, and ore.##
20967755##2010-2-11##Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease.##
21273697##2011-1-29##Middle-aged heterozygous carriers of Wilson's disease do not present with significant phenotypic deviations related to copper metabolism.##
20832891##2010-5-7##Molecular pathology of Wilson's disease: a brief.##
20517649##2009-10-21##Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease.##Wilson disease (WD) is an autosomal-recessive copper overload disorder caused by mutations in the copper-transporting adenosine triphosphatase (ATPase) ATP7B. It presents with a highly variable clinical phenotype ranging from asymptomatic to fulminant hepatic failure or progressive neurological involvement. No clear genotype-phenotype correlation has been established. Thus, variants in modifier genes could have an impact on WD manifestation and severity. Recently, the antiapoptotic protein baculoviral IAP repeat-containing protein 4 BIRC4/XIAP has been suggested as a regulator of copper-induced cell death. With the aim of investigating a putative role of BIRC4/XIAP as modifier gene in individuals with copper overload, we analyzed a WD patient cohort (n = 98) for sequence variants at the BIRC4/XIAP locus. When compared with clinical data, the previously described coding single nucleotide polymorphisms (SNPs) at the BRIC4/XIAP locus (rs28382721, rs28382722, rs28382723, rs5956583, rs28382740, rs12838858, rs28382741) did not correlate with age of onset or clinical presentation in our collective. However, three previously unreported variants in the BIRC4/XIAP gene were identified (c.1-26 T > G; c.1408A > T; p.T470S; c.1019A > G; p.N340S). The two patients with variants leading to amino acid exchanges in the BIRC4/XIAP protein showed a remarkably early disease onset at the age of 5 years. Furthermore, one of these patients was only heterozygous for disease-causing mutations in the ATP7B gene. In summary, these data emphasize the need to further elucidate a role of BIRC4/XIAP variants as putative pathogenetic factors in copper overload disorders.
20921535##2010-10-4##Zinc-induced copper deficiency in Wilson disease.##
20708958##2010-3-1##Genetics of Wilsons disease.##Wilson's disease is a rare autosomal recessive disorder of copper transport due to mutations in the ATP7B gene, responsible for transport of copper into bile from hepatocytes and its incorporation into apoceruloplasmin to form ceruloplasmin resulting in excessive accumulation of copper in the liver and extrahepatic tissues. Clinical features of WD result from toxic accumulation of copper in liver, brain and kidney. Early diagnosis is mandatory to initiate early treatment to prevent morbidity and mortality. More than 400 mutations have been reported, some of which are rather characteristic of geographical regions and ethnic population. Genetic testing is not useful as a routine procedure, but has its role in at risk individuals such as siblings and children of probands and in individuals with suggestive symptoms but where other tests are contradictory.
21078496##2010-1-4##Effects of long-term zinc treatment in Japanese patients with Wilson disease: efficacy, stability, and copper metabolism.##Wilson disease is an autosomal recessive disorder with copper metabolism. In Japan, the standard treatment is the administration of copper chelating agents, such as D-penicillamine and trientine. In this study, the authors used zinc acetate to treat Japanese patients with Wilson disease and investigated its efficacy. The 37 patients that comprise this study were found to have Wilson disease using clinical and biochemical tests and were administrated zinc acetate for 48 weeks. The authors followed the clinical symptoms and laboratory findings of the patients by assessing their complete blood counts, biochemical findings, as well as the results of urinalysis and special laboratory tests for copper and zinc metabolism. We also examined side effects of the treatment. Zinc acetate did not aggravate the hepatic or neurological symptoms of any of the patients. Blood biochemical analysis also did not reveal elevation of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltranspeptidase levels. Zinc treatment did not aggravate the patients' clinical signs and/or laboratory findings. However, it did improve some clinical symptoms of the Wilson disease patients. Although this agent had some side effects, none of them were severe. The authors measured spot urinary copper excretion, which gave an indication of the efficacy of treatment and of the sufficient dosage of zinc. We recommend maintaining a spot urinary copper excretion less than 0.075-μg/mg creatinine. The authors conclude that zinc acetate is an effective and safe treatment for Japanese patients with Wilson disease.
21331995##2011-2-19##Gallstones associated with nonalcoholic steatohepatitis (NASH) and metabolic syndrome.##
20964302##2010-10-27##Comparative features of copper ATPases ATP7A and ATP7B heterologously expressed in COS-1 cells.##ATP7A and ATP7B are P-type ATPases required for copper homeostasis and involved in the etiology of Menkes and Wilson diseases. We used heterologous expression of ATP7A or ATP7B in COS-1 cells infected with adenovirus vectors to characterize differential features pertinent to each protein expressed in the same mammalian cell type, rather than to extrinsic factors related to different cells sustaining expression. Electrophoretic analysis of the expressed protein, before and after purification, prior or subsequent to treatment with endoglycosidase, and evidenced by protein or glycoprotein staining as well as Western blotting, indicates that the ATP7A protein is glycosylated while ATP7B is not. This is consistent with the prevalence of glycosylation motifs in the ATP7A sequence, and not in ATP7B. ATP7A and ATP7B undergo copper-dependent phosphorylation by utilization of ATP, forming equal levels of an "alkali labile" phosphoenzyme intermediate that undergoes similar catalytic (P-type ATPase) turnover in both enzymes. In addition, incubation with ATP yields an "alkali stable" phosphoprotein fraction, attributed to phosphorylation of serines. Alkali stable phosphorylation occurs at lower levels in ATP7A, consistent with a different distribution of serines in the amino acid sequence. Immunostaining of COS-1 cells sustaining heterologous expression shows initial association of both ATP7A and ATP7B with Golgi and the trans-Golgi network. However, in the presence of added copper, ATP7A undergoes prevalent association with the plasma membrane while ATP7B exhibits intense trafficking with cytosolic vesicles. Glycosylation of ATP7A and phosphorylation of ATP7B apparently contribute to their different trafficking and membrane association when expressed in the same cell type.
20965182##2010-9-27##ATP dependent charge movement in ATP7B Cu+-ATPase is demonstrated by pre-steady state electrical measurements.##ATP7B is a copper dependent P-type ATPase, required for copper homeostasis. Taking advantage of high yield heterologous expression of recombinant protein, we investigated charge transfer in ATP7B. We detected charge displacement within a single catalytic cycle upon ATP addition and formation of phosphoenzyme intermediate. We attribute this charge displacement to movement of bound copper within ATP7B. Based on specific mutations, we demonstrate that enzyme activation by copper requires occupancy of a site in the N-terminus extension which is not present in other transport ATPases, as well as of a transmembrane site corresponding to the cation binding site of other ATPases.
21061148##2010-4-30##Brain proton magnetic spectroscopy in long-term treatment of Wilson's disease patients.##We reported the brain proton magnetic resonance spectroscopy (MRS) findings in 27 Wilson's disease (WD) patients treated more than 6 years in neurological (nWD) and hepatic (hWD) subgroups. We investigated 4 hWD patients, with no improvement and 8 with marked improvement; and 8 nWD patients with marked improvement and 7 with no improvement of clinical status. In nWD patients with improvement the MRS showed significantly higher Cho/Cr, Glx/Cr ratios levels. In hWD patients with no improvement the lower Cho/Cr and in nWD significantly lower NAA/Cr and higher Cho/Cr and Lip/Cr ratios were detected. In nWD patients with improvement the spectroscopic pattern, can be related to gliosis. In patients with no neurological improvement a persistent neuronal dysfunction can occur, perhaps as a result of copper or iron deposition.
21165224##2009-10-08##Penicillamine-induced Elastosis Perforans Serpiginosa and Cutis Laxa in a Patient with Wilson's Disease.##Elastosis perforans serpiginosa (EPS) is a rare reactive perforating dermatosis that is characterized by the transepidermal elimination of abnormal elastic fibers. Penicillamine, which is one of the clear triggers for EPS, is a heavy metal chelator that is primarily used for disorders such as cystinuria and Wilson's disease. It may cause alterations in the dermal elastic tissue such as pseudo-pseudoxanthoma elasticum, acquired cutis laxa, EPS and anetoderma. Herein we present a case of cutis laxa and EPS in a 34-year-old man who was previously on a long-term, high-dose of penicillamine for Wilson's disease. The combination of EPS and cutis laxa induced by penicillamine has rarely been reported and we report the first such case in Korea.
20694531##2010-8-10##Rare causes of dystonia parkinsonism.##The list of genetic causes of syndromes of dystonia parkinsonism grows constantly. As a consequence, the diagnosis becomes more and more challenging for the clinician. Here, we summarize the important causes of dystonia parkinsonism including autosomal-dominant, recessive, and x-linked forms. We cover dopa-responsive dystonia, Wilson's disease, Parkin-, PINK1-, and DJ-1-associated parkinsonism (PARK2, 6, and 7), x-linked dystonia-parkinsonism/Lubag (DYT3), rapid-onset dystonia-parkinsonism (DYT12) and DYT16 dystonia, the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) including pantothenate kinase (PANK2)- and PLA2G6 (PARK14)-associated neurodegeneration, neuroferritinopathy, Kufor-Rakeb disease (PARK9) and the recently described SENDA syndrome; FBXO7-associated neurodegeneration (PARK15), autosomal-recessive spastic paraplegia with a thin corpus callosum (SPG11), and dystonia parkinsonism due to mutations in the SLC6A3 gene encoding the dopamine transporter. They have in common that in all these syndromes there may be a combination of dystonic and parkinsonian features, which may be complicated by pyramidal tract involvement. The aim of this review is to familiarize the clinician with the phenotypes of these disorders.
20931554##2010-10-9##Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B.##
21113750##2010-5-19##Structural and neurochemical evaluation of the brain and pons in patients with Wilson's disease.##
21076593##2010-1-22##Clinical application of liver MR imaging in Wilson's disease.##
21150062##2010-12-15##Sleep in Wilson's disease: a polysomnography-based study.##Wilson's disease (WD) has neuro-anatomical, pathophysiological and neurochemical basis for sleep disturbances. The aim of the study was objective evaluation of the frequency and nature of sleep abnormalities using polysomnography (PSG) in patients with WD. The study included 25 subjects with WD (males, 18; age , 24.4 ± 9.25 years) and 25 healthy controls (all males; age, 33.1 ± 9.7 years). After phenotypic assessment and magnetic resonance imaging (MRI), sleep-related questionnaires were administered, and PSG was performed. Patients had significantly reduced total sleep-time (P=.001), sleep-efficiency (P=.001), percentage of deep sleep (P=.01), and REM-sleep (P=.04) with prolonged sleep-onset latency (P=.05) and latency to stage 2 (P=.02). Subgroup analyses of patients based on demographic and clinical parameters were done. Men had significantly more bradycardia both during awake (P=.002) and sleep (P=.03) states. Younger patients (<20 years) had frequent tachycardia (P=.01), higher Periodic Limb Movement (PLM) Index (P=.01) and lesser REM% sleep (P=.05). Patients on de-coppering therapy had prolonged REM-sleep-onset latency (P=.03) and mixed apnea events (P=.04). The isolated limb movements were more in the severe form of disease (P=.05) and in patients taking anticonvulsants (P=.03). This study, the first of its kind in literature, revealed significant sleep disturbances in patients with Wilson's disease.
20174787##2009-10-28##Wilson's disease: (31)P and (1)H MR spectroscopy and clinical correlation.##
20554092##2009-5-7##[Abnormal copper metabolism in adult].##Copper is essential for many enzymatic reactions and in neurotransmitter biosynthesis. Its deficiency or its excess has consequences on many organs, especially the liver and the brain. The biochemical tests performed in case of suspicion of copper metabolism disorder are difficult to analyse. They include the measurement of serum ceruloplasmin, serum copper and 24h urinary copper excretion. The interpretation must take into account the clinical features. We distinguish mainly: (1) copper deficiency, acquired in malabsorption or in copper diet deficiency, or related to a genetic disease (Menkes disease); (2) copper overload, acquired or from a genetic origin (Wilson disease); (3) aceruloplasminemia, reducing ferroxidase activity leading to iron overload. It is important to diagnose these diseases as some of them have an effective treatment if it is started early enough.
20732822##2009-12-27##Partial status epilepticus induced by hypocupremia in a patient with Wilson's disease.##Although seizures are rarely encountered in Wilson's disease (WD), seizures related to hypocupremia have not been reported before. We report a patient presenting with partial status epilepticus who was on strict low-copper diet and chelating therapy for WD. Despite other rare causes of seizures in WD including penicillamine-induced pyridoxine deficiency, cerebral copper deposition and metabolic encephalopathy, the most probable cause of resistant status epilepticus in this patient was found as hypocupremia from overzealous treatment. This case exemplifies that hypocupremic states should be kept in mind as a risk factor for resistant seizures.
21043007##2010-11-1##Giant cell hepatitis: an unusual cause of fulminant liver failure.##Giant cell hepatitis is a very rare disease of unknown origin. It has been hypothesized that drugs, viral infections, or autoimmune reactions may play a pathogenetic role. Here, we describe a 33 year old patient with bacterial bronchitis who was treated with doxycycline (100 mg/d) for one week. Furthermore the patient complained of malaise and a distinct jaundice. Liver parameters increased dramatically (AST 4670 U/l, ALT 5350 U/l, bilirubin 226 µmol/l) and liver function was impaired (INR = 1,45). The ultrasound scan showed a hepatomegaly with no signs of cirrhosis, normal spleen size and normal bile ducts; liver perfusion was normal. No evidence of Wilson's disease, hemochromatosis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis A, B, C and E, HIV, CMV, VZV, adenoviral infections, or paracetamol intoxication was found. Subsequently, the patient developed acute liver failure (AST 2134 U/l, ALT 2820 U/l, bilirubin 380 µmol/l, INR 3.0) and a beginning renal failure. Therefore, he was transferred to our transplant center. Due to increasing confusion and somnolence due to cerebral edema mechanical ventilation was needed. Because of an acute renal failure and severe hepatic encephalopathia MARS-hemodialysis was performed. Three weeks after the appearance of the jaundice he underwent liver transplantation (MELD 40). Surprisingly, in the explanted liver the diagnosis of giant cell hepatitis was made. Today--2 years after successful liver transplantation--the patient is in very good condition with normal liver function. In conclusion, giant cell hepatitis is a rare cause of acute liver failure that is often recognized only histologically.
20818655##2010-9-7##Predominant ataxia, low ceruloplasmin, and absent K-F rings: hypoceruloplasminemia or Wilson's disease.##
20799727##2010-9-10##NMR characterization of copper-binding domains 4-6 of ATP7B .##The Wilson disease protein (ATP7B) is a copper-transporting member of the P-type ATPase superfamily, which plays a central role in copper homeostasis and interacts with the copper chaperone Atox1. The N-terminus of ATP7B is comprised of six copper-binding domains (WCBDs), each capable of binding one copper atom in the +1 oxidation state. To better understand the regulatory effect of copper binding to these domains, we have performed NMR characterization of WCBD4-6 (domains 4-6 of ATP7B). (15)N relaxation measurements on the apo and Cu(I)-bound WCBD4-6 show that there is no dramatic change in the dynamic properties of this three-domain construct; the linker between domains 4 and 5 remains flexible, domains 5 and 6 do not form a completely rigid dimer but rather have some flexibility with respect to each other, and there is minimal change in the relative orientation of the domains in the two states. We also show that, contrary to previous reports, the protein-protein interaction between Atox1 and the copper-binding domains takes place even in the absence of copper. Comparison of apo and Cu(I)-bound spectra of WCBD1-6 shows that binding of Cu(I) does not induce the formation of a unit that tumbles as a single entity, consistent with our results for WCBD4-6. We propose that copper transfer to and between the N-terminal domains of the Wilson Cu-ATPase occurs via protein interactions that are facilitated by the flexibility of the linkers and the motional freedom of the domains with respect to each other.
21049186##2010-1-05##Acoustic analysis of prosody in Sydenham's chorea.##There are few studies of language and speech in patients with Sydenham's chorea (SC). We have done an acoustic analysis of fundamental frequency (F0), duration and intensity of declarative and interrogative sentences made by 20 SC patients, 20 patients with rheumatic fever (RF) without chorea, and compared them with 20 healthy age-matched controls (CO). Each group included 12 females. We found that there is no difference between the RF and CO groups in all studied parameters. Patients with SC, however, presented with a speech characterized by decreased F0 range (difference between minimum and maximum F0), shorter duration of sentences, and higher intensity of the first syllable of sentences. The findings were not influenced by the nature of the sentences (i.e. , declarative or interrogative), but for all variables they were significantly more severe in males than females. In conclusion, we have demonstrated that patients with acute SC have an impairment of modulation of F0 and longer duration of emission of sentences, resulting in a monotone and slow speech. This pattern is similar to what has been described in other basal ganglia illnesses, such as Parkinson's disease, Huntington's disease and Wilson's disease.
20955957##2010-4-11##Wilson disease.##Wilson disease is an inherited autosomal recessive disorder of copper balance leading to hepatic damage and neurological disturbance of variable degree. The defective gene, ATP7B, encodes a hepatic copper-transporting protein, which plays a key role in human copper metabolism. Our knowledge of the genetic basis of Wilson disease has increased dramatically; however, understanding of genotype-phenotype correlation and multifarious effects of copper toxicity as basis for targeted and individualised therapy strategies is still insufficient. Clinical manifestations are related to copper accumulation predominantly in the liver and brain and include hepatic disease ranging from mild hepatitis to acute liver failure or cirrhosis and/or neurological symptoms such as dystonia, tremor, dysarthria, psychiatric disturbances. Mixed presentations occur frequently. Early recognition by means of clinical, biochemical or genetic examination and initiation of therapy with copper chelators, zinc salts or even liver transplantation in cases of acute and chronic liver failure are essential for favourable outcome.
20812166##2010-9-1##[The role of ceruloplasmin in the differential diagnosis of neuropsychiatric disorders].##The blue copper protein ceruloplasmin has been of interest to psychiatrists for decades following Heilmeyer's observation of elevated serum copper levels in schizophrenic patients. Immunoturbidimetry, however, does not yield elevated serum ceruloplasmin concentrations in schizophrenia while ceruloplasmin-related oxidase activity appears to be elevated in patients with schizophrenia and reduced in patients with Alzheimer's disease. Low serum concentrations of immuno-turbidimetrically measured ceruloplasmin, and of oxidase activity, are typical of Wilson's disease, Menkes' disease, and aceruloplasminemia, three familial neurodegenerative disorders of pronounced variability, with regard to both genotype and phenotype. Especially patients with Wilson's disease may exhibit behavioural symptoms only over a long period. Heterozygous carriers of Wilson's disease and aceruloplasminaemia may have low serum ceruloplasmin concentrations; they will not develop somatic symptoms, but the significance of these carrier states, or of "hypoceruloplasminaemia", with regard to mental disorders is unknown.
20647314##2010-7-20##Wilson disease at a single cell level: intracellular copper trafficking activates compartment-specific responses in hepatocytes.##Wilson disease (WD) is a severe hepato-neurologic disorder that affects primarily children and young adults. WD is caused by mutations in ATP7B and subsequent copper overload. However, copper levels alone do not predict severity of the disease. We demonstrate that temporal and spatial distribution of copper in hepatocytes may play an important role in WD pathology. High resolution synchrotron-based x-ray fluorescence imaging in situ indicates that copper does not continuously accumulate in Atp7b(-/-) hepatocytes, but reaches a limit at 90-300 fmol. The lack of further accumulation is associated with the loss of copper transporter Ctr1 from the plasma membrane and the appearance of copper-loaded lymphocytes and extracellular copper deposits. The WD progression is characterized by changes in subcellular copper localization and transcriptome remodeling. The synchrotron-based x-ray fluorescence imaging and mRNA profiling both point to the key role of nucleus in the initial response to copper overload and suggest time-dependent sequestration of copper in deposits as a protective mechanism. The metabolic pathways, up-regulated in response to copper, show compartmentalization that parallels changes in subcellular copper concentration. In contrast, significant down-regulation of lipid metabolism is observed at all stages of WD irrespective of copper distribution. These observations suggest new stage-specific as well as general biomarkers for WD. The model for the dynamic role of copper in WD is proposed.
20491539##2010-5-25##High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease.##
20886423##2010-9-30##[Wilson disease--evaluation of disease-related topics through the eyes of patients by patient-generated paintings--a cooperative study with the German patient organisation Verein morbus Wilson e. V].##
20465995##2010-3-6##Development of a high-resolution melting method for the screening of Wilson disease-related ATP7B gene mutations.##
20877768##2010-9-30##The eyes have it - A diagnostic challenge.##
20695873##2010-8-11##Unexpected combination of inherited chorea-acanthocytosis with MDR3 (ABCB4) defect mimicking Wilson's disease.##
21886393##2008-6-29##Hemolytic Anemia as a Presenting Feature of Wilson's Disease: A Case Report.##Wilson's disease is a rare inherited disorder of copper metabolism causing severe damage to vital organs. Liver and brain disorders are the main manifestations. Severe hemolytic anemia is an unusual complication of Wilson's disease. We present a case who developed spherocytic acute hemolytic anemia (Coomb's negative) as the initial manifestation of Wilson's disease. On examination Kayser- Fleischer ring was found. Laboratory data supported a diagnosis of Wilson's disease.
20562412##2010-6-18##Transplantation of a fetal liver cell-loaded hyaluronic acid sponge onto the mesentery recovers a Wilson's disease model rat.##An auxiliary liver represents a promising alternative for liver transplantation. The use of a large amount of mature hepatocytes, however, despite their high function, is limited in a clinical setting. Here, we propose a novel transplantation system that dramatically improved a diseased animal by incorporating fetal liver cells (FLCs) as a cell source, the mesentery as a transplantation site and a hyaluronic acid (HA) sponge as a cell scaffold. We transplanted wild-type Long Evans Agouti rat FLCs embedded in HA sponges onto the mesentery of Long Evans Cinnamon (LEC) rats, an animal model for Wilson's disease. The FLC-loaded HA sponges successfully grafted and consequently prevented jaundice. Accordingly, the treated animals showed a significant reduction in blood copper concentration, which consequently led to significant decreases in serum total bilirubin and direct bilirubin, and to a significant increase in albumin productivity. Furthermore, haematoxylin and eosin staining of the host livers demonstrated that fibrosis at the periportal area was moderated in the treated animals. In conclusion, we transplanted FLC-loaded HA sponges onto the mesenteric blood vessels, leading to thick, liver-like tissue possessing blood vessels, and the liver tissue engineered thus exhibited a remarkable therapeutic effect on the copper metabolism deficiency of LEC rats.
20818742##2010-9-7##Recurrent liver failure in a 25-year-old female.##Acute liver failure (ALF) is defined as severe and sudden liver dysfunction leading to coagulopathy and encephalopathy in a previously healthy person without preexisting liver disease. Almost half of adult cases of ALF are due to acetaminophen toxicity, with 21% labeled indeterminate or other. We present a patient with a second episode of ALF, both episodes being initiated by catabolic stress. Elevated aminotransferases, jaundice, an elevated international normalized ratio, and confusion were typical of idiopathic ALF, and a low serum ceruloplasmin level initially led to a misdiagnosis of acute Wilson disease. Citrullinemia type I, a urea cycle defect caused by a deficiency of argininosuccinate synthetase, was diagnosed on the basis of plasma amino acids and was confirmed by molecular testing. Urea cycle defects are not generally considered causes of ALF in adults and are described rarely in children beyond the neonatal period. Our case illustrates the importance of screening patients with idiopathic ALF for a metabolic disorder. A prompt diagnosis and timely treatment enabled her to recover fully without the need for liver transplantation.
20838861##2010-4-30##Brain proton magnetic spectroscopy in long-term treatment of Wilson's disease patients.##We reported the brain proton magnetic resonance spectroscopy (MRS) findings in 27 Wilson's disease (WD) patients treated more than 6 years in neurological (nWD) and hepatic (hWD) subgroups. We investigated four hWD patients, with no improvement and eight with marked improvement; and eight nWD patients with marked improvement and seven with no improvement of clinical status. In nWD patients with improvement the MRS showed significantly higher Cho/Cr, Glx/Cr ratios levels. In hWD patients with no improvement the lower Cho/Cr and in nWD significantly lower NAA/Cr and higher Cho/Cr and Lip/Cr ratios were detected. In nWD patients with improvement the spectroscopic pattern, can be related to gliosis. In patients with no neurological improvement a persistent neuronal dysfunction can occur, perhaps as a result of copper or iron deposition.
20660601##2010-7-26##Triethylenetetramine pharmacology and its clinical applications.##Triethylenetetramine (TETA), a Cu(II)-selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs.
21045506##2010-11-4##Gabapentin as a rescue drug in D-penicillamine-induced status dystonicus in patients with Wilson disease.##D-penicillamine induced status dystonicus is a unique but serious drug related complication in a subset of patients with Wilson disease. Patho-physiological basis of its occurrence is not known. It often responds poorly to anti dystonia medications. We present three patients with Wilson disease who developed severe paroxysmal dystonic spells after receiving D-penicillamine treatment. All three patients responded well to gabapentin after failing to respond to other anti dystonia drugs.
21045492##2010-11-4##Cognitive profile and structural findings in Wilson's disease: a neuropsychological and MRI-based study.##
20943091##2010-10-15##[4 cases of fulminant Wilson's disease: the clinical features and treatments].##
20566629##2010-6-21##Role of glutaredoxin1 and glutathione in regulating the activity of the copper-transporting P-type ATPases, ATP7A and ATP7B.##The copper-transporting P-type ATPases (Cu-ATPases), ATP7A and ATP7B, are essential for the regulation of intracellular copper homeostasis. In this report we describe new roles for glutathione (GSH) and glutaredoxin1 (GRX1) in Cu homeostasis through their regulation of Cu-ATPase activity. GRX1 is a thiol oxidoreductase that catalyzes the reversible reduction of GSH-mixed disulfides to their respective sulfhydryls (deglutathionylation). Here, we demonstrated that glutathionylation of the Cu-ATPases and their interaction with GRX1 were affected by alterations in Cu levels. The data support our hypothesis that the Cu-ATPases serve as substrates for Cu-dependent GRX1-mediated deglutathionylation. This in turn liberates the Cu-ATPase cysteinyl thiol groups for Cu binding and transport. GSH depletion experiments led to reversible inhibition of the Cu-ATPases that correlated with effects on intracellular Cu levels and GRX1 activity. Finally, knockdown of GRX1 expression resulted in an increase in intracellular Cu accumulation. Together, these data directly implicate GSH and GRX1 with important new roles in redox regulation of the Cu-ATPases, through modulation of Cu binding by the Cu-ATPase cysteine motifs.
20704379##2010-8-14##Human plasma copper proteins speciation by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry. Solutions for columns calibration by sulfur detection.##Among the hyphenated techniques used to probe and identify metalloproteins, size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS) has shown to have a central place. However, the calibration of SEC columns reveals to be tedious and always involves UV detection prior to ICP-MS. The presence of sulfur in 98% of proteins allows their detection by quadrupole ICP-MS, despite the isobaric interference ((16)O(16)O) on S, by monitoring (32)S(16)O at mass to charge ratio (m/z) 48. The formation of SO occurs spontaneously in the argon plasma but can be optimized by the introduction of oxygen gas into a reaction cell (RC) to achieve nM levels. In this article, sulfur detection was discussed upon instrumental conditions and S detection was then optimized by applying O(2) as a reaction gas. SO formation was used to calibrate SEC columns without UV detection. This simple SEC-ICP-MS method was used for plasma copper proteins in plasma healthy subjects (HS) and an untreated Wilson disease (WD) patient. Copper proteins identified in healthy subjects were transcuprein, ceruloplasmin (Cp) and albumin. The method led to results in good agreement with other methods of determination. Copper bound to Cp in the WD patient was lowered with regard to the HS, and the exchangeable Cu was highly increased.
20684609##2010-8-6##Synthesis and biological characterization of novel charge-deficient spermine analogues.##Biogenic polyamines, spermidine and spermine, are positively charged at physiological pH. They are present in all cells and essential for their growth and viability. Here we synthesized three novel derivatives of the isosteric charge-deficient spermine analogue 1,12-diamino-3,6,9-triazadodecane (SpmTrien, 5a) that are N(1)-Ac-SpmTrien (5c), N(12)-Ac-SpmTrien (5b), and N(1),N(12)-diethyl-1,12-diamino-3,6,9-triazadodecane (N(1),N(12)-Et(2)-SpmTrien, 5d). 5a and 5d readily accumulated in DU145 cells at the same concentration range as natural polyamines and moderately competed for the uptake with putrescine (1) but not with spermine (4a) or spermidine (2). 5a efficiently down-regulated ornithine decarboxylase and decreased polyamine levels, while 5d proved to be inefficient, compared with N(1),N(11)-diethylnorspermine (6). None of the tested analogues were substrates for human recombinant spermine oxidase, but those having free aminoterminus, including 1,8-diamino-3,6-diazaoctane (Trien, 3a), were acetylated by mouse recombinant spermidine/spermine N(1)-acetyltransferase. 5a was acetylated to 5c and 5b, and the latter was further metabolized by acetylpolyamine oxidase to 3a, a drug used to treat Wilson's disease. Thus, 5a is a bioactive precursor of 3a with enhanced bioavailability.
20698945##2010-2-9##Leptospirosis presenting in a woman with fulminant hepatic failure from Wilson's disease: a case report.##
20637709##2010-6-11##Encopresis and epilepsy: an unusual presentation of Wilson's disease.##
20427090##2010-2-1##Effect of glutathione depletion on removal of copper from LEC rat livers by tetrathiomolybdate.##Tetrathiomolybdate (TTM) is a powerful and selective copper (Cu) chelator that is used as a therapeutic agent for Wilson disease. TTM is the sole agent that can remove Cu bound to metallothionein (MT) in the livers of Long-Evans rats with a cinnamon-like coat color (LEC rats). However, the administration of excess TTM causes the deposition of Cu and molybdenum (Mo) in the liver. In the present study, the effect of hepatic glutathione (GSH) depletion on the removal of Cu from the livers of LEC rats was evaluated to establish an effective therapy by TTM. Pretreatment with l-buthionine sulfoximine (BSO), a depletor of GSH in vivo, reduced the amounts of Cu and Mo excreted into both the bile and the bloodstream, and increased the amounts of Cu and Mo deposited in the livers of LEC rats in the form of an insoluble complex 4h after the TTM injection. The results suggest that GSH depletion creates an oxidative environment in the livers of LEC rats, and the oxidative environment facilitates the insolubilization of Cu and Mo in the livers of LEC rats after the TTM injection. Therefore, the effect of TTM on the removal of Cu from the liver was reduced in the oxidized condition. Wilson disease patients and LEC rats develop liver injury caused by oxidative damage. From a clinical viewpoint, increasing in the GSH concentration is expected to enhance the effect of TTM.
20384464##2010-4-14##Oral complications associated with D-penicillamine treatment for Wilson disease: a clinicopathologic report.##
20138984##2009-11-4##Development of TaqMan allelic specific discrimination assay for detection of the most common Sardinian Wilson's disease mutations. Implications for genetic screening.##Wilson's disease (WD) is an autosomal recessive disorder caused by a defective function of the copper transporting ATP7B protein. Analysis of ATP7B gene in the Sardinian population revealed the presence of six common mutations that together account for 85% of WD chromosomes. We have developed an automated approach for the detection of these 6 common Sardinian mutations based on TaqMan technology. Ten DNA samples of WD patients carrying different combinations of the six most common Sardinian mutations and normal controls previously analysed were used in triplicate to set up the allelic discrimination assays. The system was validated in 96 samples obtained from WD patients carrying different combinations of the most common mutations under investigation. The results showed that allelic discrimination is a valid method that could be used for efficient diagnosis of single cases but also for a mass screening.
20942273##2010-10-15##Preliminary study of spontaneous hepatitis in Long-Evans Cinnamon rats: a blood exchange may improve fetal hepatitis.##Long-Evans Cinnamon rats are a Wilson disease model highly susceptible to fulminant hepatitis around the age of 20 weeks, and hepatoma over the age of one year. Although prophylaxis has been established for the otherwise fatal hepatitis, effective treatment remains unknown. A blood exchange was tested to determine whether the prognosis of spontaneous hepatitis could be modified in icteric female rats. When bilirubinuria appeared, the rats immediately underwent surgery. Rats under anesthesia were first cannulated into the right atrium via the carotid vein, followed by 2.5 mL of blood exchange with heparinized fresh blood from Long-Evans agouti rats. Treated rats and controls were then observed for 2 months. Compared to the 50% mortality of untreated rats, all icteric rats that received a blood exchange survived the acute episode. We confirmed that Wilson disease animals are highly susceptible to acute hepatitis and show a poor prognosis. However, a single blood exchange improved spontaneous hepatitis in this animal model. This would serve as a first step for establishing a treatment for fatal hepatitis in animals. A blood exchange may improve fulminant hepatitis of Wilson disease model rats.
20557474##2010-6-15##The current status of pediatric liver transplantation in Mainland China.##The aim of this article is to study the current status of pediatric liver transplantation in Mainland China. A total of 337 cases of pediatric liver transplantation enrolled in CLTR between 1993 and May 2009 were analyzed retrospectively. The median transplant age was 8.7 yr (64 day-17.8 yr), and Wilson's disease was the most common indication (35.4%). Liver transplantation for biliary atresia accounted for 49.3% and 54.2% in 2008 and 2009 and had become the most common indication nowadays. One- and three-yr survival rates of children transplanted at age<1 yr were 69.2% and 59.3%, respectively, and were significantly worse than those transplanted at age > or =1 yr (83.9% and 76.6%, p < 0.05).In 63.8% (208/326) of the patients, LDLT was used with an overall one- and three-yr survival rates of 87.5% and 84.4%, respectively. The one- and three-yr survival for DDLT was significantly lower (66.7% and 52.2%, p < 0.05). The one- and three-yr survival rates for those transplanted in era 1993-2000 were 63.6% and 36.4%, respectively, and the one- and two-yr survival rates in the latest era (2007-2009) were markedly improved (81.9% and 79.0%, p < 0.05). Cox's analysis identified DDLT (HR = 2.90, CI 95% 1.5-5.6), being transplanted in era 1993-2000(HR = 3.4, CI 95% 1.1-10.2), fulminant liver failure (HR = 6.0, CI 95% 2.0-17.5), and malignancy (HR = 3.8, CI 95% 1.4-10.3) as predictors of increased mortality, and children transplanted at age 8-17 yr have an better survival (HR = 0.2, CI 95% 0.1-0.6). We concluded that pediatric liver transplantation is gradually developing and would probably be a promising therapy for pediatric end-stage liver diseases in Mainland China.
20842827##2010-9-17##[Wilson's disease].##Wilson's disease is caused by a P-type ATP-ase gene mutations with reduced biliary copper excretion and accumulation copper in the liver and other tissues. Clinical symptoms can be heterogeneous but in many cases on the first stage the only abnormalities is elevation of aminotransferase activity. In some cases the first fatal symptom of disease is acute liver failure, therefore early diagnosis and treatment is essential. We present an actual recommendations for diagnosis and treatment of patients with Wilson's disease.
20629153##2010-7-15##Pallidopyramidal disease: a misnomer?##The combination of recessive early-onset parkinsonism and pyramidal tract signs caused by pallidopyramidal degeneration is known as pallidopyramidal disease or syndrome (PPD/S). We investigated whether patients diagnosed as Davison's PPD/S showed any definite proof of pyramidal and pallidal involvement, without findings suggestive of other nosological entities. Since Davison's original description, 15 other PPD/S cases have been reported, yet all lack proof of pyramidal or pallidal degeneration. Because of the dopa-responsiveness in all patients subsequent to Davison's report, we argue that these patients probably suffered from early-onset nigral parkinsonism or dopa-responsive dsystonia, rather than pallidal parkinsonism; in such cases, the presumed pyramidal Babinski could be a pseudobabinski ("striatal toe"). Secondary pallidopyramidal syndromes do occur, for example, in multiple system atrophy or Wilson's disease, but in these patients additional findings indicate diseases other than Davison's PPD/S. We conclude that the existence of PPD/S as a distinct clinico-pathological nosological entity, as proposed by Davison, is doubtful. In cases reported as Davison's PPD/S, the description "pallidopyramidal" seems to be a misnomer.
20430895##2010-4-29##Role of external loops of human ceruloplasmin in copper loading by ATP7B and Ccc2p.##Ceruloplasmin is a multicopper oxidase required for correct iron homeostasis.Previously, we have identified a ceruloplasmin mutant associated with the iron overload disease aceruloplasminemia, which was unable to acquire copper from the mammalian pump ATP7B but could be produced in an enzymatically active form in yeast. Here, we report the expression of recombinant ceruloplasmin in the yeast Pichia pastoris and the study of the role of five surface-exposed loops in copper incorporation by comparing the efficiencies of mammalian ATP7B and yeast Ccc2p. The possibility to "mix and match" mammalian and yeast multicopper oxidases and copper ATPases can provide clues on the molecular features underlying the process of copper loading in multicopper oxidases.
20877260##2010-9-30##Preemptive administration of recombinant factor VII (rVIIa) in patients transplanted due to fulminant Wilson's disease.##
20381321##2009-12-1##Preparation of polyamine-functionalized copper specific adsorbents for selective adsorption of copper.##The level of serum free copper is greatly elevated in Wilson's disease. For patients with acute Wilson's disease, liver transplantation is the only lifesaving treatment. Plasma exchange or albumin dialysis is often used as a bridge to liver transplantation to maintain a stable clinical status for patients. Hemoperfusion is another effective therapy in removing toxins from the plasma. However, hemoperfusion has not been reported to remove copper due to lack of copper specific adsorbent. In this work, copper chelating agents, triethylenetetramine and tetraethylenepentamine, were covalently immobilized onto macroporous poly(glycidyl methacrylate-co-trimethylolpropane trimethacrylate) microspheres to prepare copper specific adsorbents. The resulting adsorbents demonstrated good adsorption capacities of 63.44 and 58.48 mg/g, respectively, for Cu2+ ion. Additionally, with the interference of other metal ions such as Fe2+, Mg2+, Zn2+ and Ca2+, the prepared copper adsorbents still demonstrated good specificity toward Cu2+ ion. These results indicate that the adsorbents are promising adsorbents in hemoperfusion therapy for selective removal of copper for patients with severe Wilson's disease.
20590811##2010-7-2##The role of genes in causing dystonia.##
20485189##2010-5-21##Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease.##
20421802##2010-4-28##Genotype-phenotype correlation in Wilson disease.##
20444470##2009-4-1##Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis.##Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in normal hepatocytes and are critical for normal physiologic processes, including oxidative respiration, growth, regeneration, apoptosis, and microsomal defense. When the levels of oxidation products exceed the capacity of normal antioxidant systems, oxidative stress occurs. This type of stress, in the form of ROS and RNS, can be damaging to all liver cells, including hepatocytes, Kupffer cells, stellate cells, and endothelial cells, through induction of inflammation, ischemia, fibrosis, necrosis, apoptosis, or through malignant transformation by damaging lipids, proteins, and/or DNA. In Part I of this review, we will discuss basic redox biology in the liver, including a review of ROS, RNS, and antioxidants, with a focus on nitric oxide as a common source of RNS. We will then review the evidence for oxidative stress as a mechanism of liver injury in hepatitis (alcoholic, viral, nonalcoholic). In Part II of this review, we will review oxidative stress in common pathophysiologic conditions, including ischemia/reperfusion injury, fibrosis, hepatocellular carcinoma, iron overload, Wilson's disease, sepsis, and acetaminophen overdose. Finally, biomarkers, proteomic, and antioxidant therapies will be discussed as areas for future therapeutic interventions.
20587439##2010-7-1##Transcranial sonographic findings in Wilson disease.##
19626597##2009-7-24##Copper in diseases and treatments, and copper-based anticancer strategies.##Copper is found in all living organisms and is a crucial trace element in redox chemistry, growth and development. It is important for the function of several enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biological molecules involve oxidation-reduction reactions in which they react directly with molecular oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is associated, respectively, with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at molecular levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, respectively. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic molecules. More recently, mixtures of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compounds in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.
20613699##2010-7-9##Swine-origin influenza a (H1N1) infection with acute respiratory distress syndrome in a child with Wilson disease.##
20739831##2010-8-27##"Split thalamus": internal medullary involvement in Wilson's disease.##
20739809##2010-8-27##R778L, H1069Q, and I1102T mutation study in neurologic Wilson disease.##There is paucity of the studies on mutations in neurologic Wilson disease (WD) in India. We studied H1069Q, R778L, I1102T mutations in 26 patients with neurologic WD from 25 families in north India. The basis of diagnosis of neurologic WD was clinical, Kayser-Fleischer (KF) ring, and ceruloplasmin. Data collected included: family history, clinical characteristics, laboratory data, ultrasound findings, magnetic resonance imaging (MRI) findings, and severity of the disease. DNA was isolated from venous blood and subjected to H1069Q, R778L, and I1102T mutation study. The age range was 5-41 years. Family history was present in 8 patients. The H1069Q, R778L, and I1102T mutations were absent in all the patients and in 16 parents and siblings. Severity of the illness was related to the extent of MRI changes but not with age of onset and hepatic involvement. H1069Q, R778L, and I1102T mutations were absent in our patients, which may be due to genetic and ethnic heterogeneity and further studies are required.
20369313##2009-11-20##Metal toxicity, liver disease and neurodegeneration.##Hepatocerebral disorders are serious neuropsychiatric conditions that result from liver failure. These disorders are characterized neuropathologically by varying degrees of neuronal cell death in basal ganglia, cerebellum, and spinal cord, and include clinical entities such as Wilson's Disease, post-shunt myelopathy, hepatic encephalopathy, and acquired non-Wilsonian hepatocerebral degeneration. Morphologic changes to astrocytes (Alzheimer type II astrocytosis) are a major feature of hepatocerebral disorders. Neurological symptoms include Parkinsonism, cognitive dysfunction, and ataxia. Pathophysiologic mechanisms responsible for cerebral dysfunction and neuronal cell death in hepatocerebral disorders include ammonia toxicity and neurotoxic effects of metals such as copper, manganese, and iron. Molecular mechanisms of neurotoxicity include oxidative/nitrosative stress, glutamate (NMDA)-receptor-mediated excitotoxicity, and neuroinflammatory mechanisms. However, neuronal cell death in hepatocerebral disorders is limited by adaptive mechanisms that may include NMDA-receptor down-regulation, the synthesis of neuroprotective steroids and hypothermia. Management and treatment of hepatocerebral disorders include chelation therapy (Wilson's Disease), the use of ammonia-lowering agents (lactulose, antibiotics, ornithine aspartate) and liver transplantation.
20363758##2010-4-2##CtpA, a copper-translocating P-type ATPase involved in the biogenesis of multiple copper-requiring enzymes.##The ctpA (ccoI) gene product, a putative inner membrane copper-translocating P1B-type ATPase present in many bacteria, has been shown to be involved only in the cbb(3) assembly in Rhodobacter capsulatus and Bradyrhizobium japonicum. ctpA was disrupted in Rubrivivax gelatinosus, and the mutants showed a drastic decrease in both cbb(3) and caa(3) oxidase activities. Inactivation of ctpA results also in a decrease in the amount of the nitrous oxide reductase, NosZ. This pleiotropic phenotype could be partially rescued by excess copper in the medium, indicating that CtpA is likely a copper transporter that supplies copper-requiring proteins in the membrane with this metal. Although CtpA shares significant sequence homologies with the homeostasis copper efflux P1B-type ATPases including the bacterial CopA and the human ATP7A and ATP7B, disruption of ctpA did not result in any sensitivity to excess copper. This indicates that the CtpA is not crucial for copper tolerance but is involved in the assembly of membrane and periplasmic copper enzymes in this bacterium. The potential roles of CtpA in bacteria in comparison with CopA are discussed.
20550661##2009-11-11##A novel COMMD1 mutation Thr174Met associated with elevated urinary copper and signs of enhanced apoptotic cell death in a Wilson Disease patient.##Wilson disease (WD) results from accumulation of copper and caused due to mutations in ATP7B, a copper transporting ATPase. Besides regular hepatic and neurological symptoms, WD patients occasionally manifest atypical symptoms due to unknown cause. To understand the molecular etiology of atypical WD manifestations, we screened COMMD1, a gene implicated in canine copper toxicosis, in 109 WD patients including those with atypical symptoms. In a patient showing apoptotic symptoms and high urinary copper surpassing normal WD levels, we identified a novel, putative mutation in COMMD1. Two other changes were also identified in the gene. We have examined genotype-phenotype correlation between the detected changes and the atypical presentation of the WD patient.
20494888##2010-5-25##[Hepatocellular carcinoma: occurrence, risk factors, biomarkers].##Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Primary hepatocellular carcinoma can be found most frequently (80-90 %) in patients with liver cirrhosis. The most frequent causes of liver cirrhosis are chronic hepatitis B and C virus infections and chronic alcohol consumption. The occurrence of hepatocellular carcinoma is about 3-15 % in patients with alcoholic liver disease. Other predisposing causes can be: non-alcoholic steatohepatitis (NASH), obesity, diabetes mellitus, autoimmune hepatitis, intrahepatic biliary inflammations (primary biliary cirrhosis, primary sclerosing cholangitis), copper and iron metabolic diseases (Wilson-disease, haemochromatosis), congenital alpha-1-antitripsin deficiency. The causative role of hepatitis B és C viruses have been well established in the pathogenesis of liver cancer. Other pathogenic factors are smoking, and different chemical agents. Treatment options for these patients have previously been limited to best supportive care and palliative therapy. Beside surgical treatment (resection, liver transplantation) the invasive radiologic therapy also has been widely used. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In year 2007, sorafenib, a multitargeted kinase inhibitor was introduced to clinical practice and found to prolong survival significantly for patients with advanced HCC.
20489626##2010-5-22##Liver transplantation for inherited metabolic disorders of the liver.##
20100230##2010-1-20##Population-based epidemiologic study of Wilson's disease in Taiwan.##
20513009##2010-6-1##Potential of curcumin as a multifunctional agent to combat Wilson disease.##
20642964##2009-1-31##Correlation of thrombocytopenia with grading of esophageal varices in chronic liver disease patients.##
20594231##2010-7-3##Evidence for a critical role of ceruloplasmin oxidase activity in iron metabolism of Wilson disease gene knockout mice.##
20232210##2009-6-29##Copper deficiency myelopathy.##Acquired copper deficiency has been recognised as a rare cause of anaemia and neutropenia for over half a century. Copper deficiency myelopathy (CDM) was only described within the last decade, and represents a treatable cause of non-compressive myelopathy which closely mimics subacute combined degeneration due to vitamin B12 deficiency. Here, 55 case reports from the literature are reviewed regarding their demographics, aetiology, haematological and biochemical parameters, spinal imaging, treatment and outcome. The pathophysiology of disorders of copper metabolism is discussed. CDM most frequently presented in the fifth and sixth decades and was more common in women (F:M = 3.6:1). Risk factors included previous upper gastrointestinal surgery, zinc overload and malabsorption syndromes, all of which impair copper absorption in the upper gastrointestinal tract. No aetiology was established in 20% of cases. High zinc levels were detected in some cases not considered to have primary zinc overload, and in this situation the contribution of zinc to the copper deficiency state remained unclear. Cytopenias were found in 78%, particularly anaemia, and a myelodysplastic syndrome may have been falsely diagnosed in the past. Spinal MRI was abnormal in 47% and usually showed high T2 signal in the posterior cervical and thoracic cord. In a clinically compatible case, CDM may be suggested by the presence of one or more risk factors and/or cytopenias. Low serum copper and caeruloplasmin levels confirmed the diagnosis and, in contrast to Wilson's disease, urinary copper levels were typically low. Treatment comprised copper supplementation and modification of any risk factors, and led to haematological normalisation and neurological improvement or stabilisation. Since any neurological recovery was partial and case numbers of CDM will continue to rise with the growing use of bariatric gastrointestinal surgery, clinical vigilance will remain the key to minimising neurological sequelae. Recommendations for treatment and prevention are made.
20383712##2009-11-19##Comparative analysis of MTF-1 binding sites between human and mouse.##MTF-1 is a crucial transcription factor involved in the cellular response to heavy-metal load and other stresses by specifically binding to metal response elements (MREs). Thus far only a handful of direct target genes are known for this transcription factor, limiting our understanding of the biological network it governs. In this article we try to employ a computational strategy based on the generation of literature-based positional weight matrices (PWM) and log-likelihood scoring of the candidate binding sites (BSs) for identification of direct targets of the transcription factor MTF-1 in human and mouse. Through comparisons, we explore the conservation and unique characteristics between two species. Our results show that the numbers of MREs differ dramatically between species and their positions relative to their cognate promoter is also flexible. Importantly, we identify a set of target genes generally well conserved between human and mouse. Finally, by combining expression analysis we provide two putative targets (HMGCR and CYP51A), which regulate lipid metabolism conserved in human and mouse. Overall, interspecies comparison from our study may provide some valuable information for further studying human Wilson disease (WD) using mouse model systems.
20227147##2008-5-8##[Liver malignancy in a patient with Wilson's disease].##Hepatocellular carcinoma and other tumours of the liver are extremely rare in Wilson's disease. We report a patient who presented with a cholangiocarcinoma associated with Wilson's disease. The literature review underlines that patients with Wilson's disease should be considered at risk of hepatocellular carcinoma, cholangiocarcinoma and undifferentiated carcinoma in the liver. Risk factors seem to be long disease duration and probably a poor observance to therapy. A liver imaging should be included in the follow-up of patients with Wilson's disease.
20362556##2010-3-11##Overexpressed ATP7B protects mesenchymal stem cells from toxic copper.##Wilson's disease (WD) is characterized by accumulation of high levels of copper in liver due to malfunction of copper transporter ATP7B which is central for copper homeostasis. Here we report for the first time that mesenchymal stem cells (MSC) derived from bone marrow express detectable levels of ATP7B. The role of ATP7B overexpression for MSC survival and selection in high copper was investigated. Hepatoma cell line HepG2 that has a high intrinsic expression of ATP7B served as a control. Using retroviral vector a significant higher expression level of ATP7B could be achieved in MSCs. Whereas copper treatment resulted in cell death in untransduced MSCs, viability assays demonstrated a unique copper resistance of ATP7B overexpressing MSCs that outcompeted HepG2. In long-term cell culture stable transgene expression for up to 9weeks was shown for ATP7B overexpressing MSCs which rapidly overgrew untransduced cells. Our findings suggest that ATP7B overexpression provides an important selection advantage to MSCs in high copper microenvironments, and may represent novel cell transplants for therapy of WD.
20346064##2010-3-19##Fulminant Wilson's disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation.##Acute decompensated Wilson's disease (WD) that presents as fulminant hepatic failure carries significant mortality without hepatic replacement. The abnormal gene implicated in WD, ATP7B, has been mapped to chromosome 13, and leads to decreased passage of copper from hepatocytes to bile. Excess copper accumulation exceeds hepatocyte storage capacity resulting in intracellular necrosis, apoptosis and cell death in various organs of the body. The hepatic injury induced by the abnormal accumulation of copper in WD has variable presentation such as acute hepatitis, rapid hepatic deterioration resembling fulminant hepatic failure, or as progressive chronic liver disease in the form of chronic active hepatitis or cirrhosis. There are reports in the literature describing monozygotic (identical) twins with similar hepatic progression requiring liver transplantation, however, with different neurological outcome after transplant. We report a case of one monozygotic twin presenting with acute liver failure requiring emergent liver transplantation while the other twin presented with mild liver disease, when both shared an identical genetic mutation.
20042865##2010-1-1##Wilson's disease: long-term follow-up of a cohort of 24 patients treated with D-penicillamine.##
20432273##2010-5-1##Adjunctive vitamin E treatment in Wilson disease and suggestions for future trials.##
20333758##2010-3-25##Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B.##Wilson disease (WND) is an autosomal recessive disorder resulting from mutation of ATP7B. Transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body. Although copper is an essential nutrient, homeostasis must be carefully maintained. If homeostasis is disrupted, copper can accumulate within the liver, kidney, cornea, and/or brain. The range of organs affected leads to clinical heterogeneity and difficulty in WND diagnosis. Sequencing of ATP7B is an important adjunct for diagnosis but has led to the discovery of many novel missense variants. Although prediction programs are available, functional characterization is essential for determining the consequence of novel variants. We have tested 12 missense variants localized to the ATP loop of ATP7B and compared three predictive programs (SIFT, PolyPhen, and Align-GVGD). We found p.L1043P, p.G1000R, p.G1101R, p.I1102T, p.V1239G, and p.D1267V deleterious; p.G1176E and p.G1287S intermediate; p.E1173G temperature sensitive; p.T991M and p.I1148T mild; and p.R1228T functioning as wild type. We found that SIFT most often agreed with functional data (92%), compared with PolyPhen (83%) and Align-GVGD (67%). We conclude that variants found to negatively affect function likely contribute to the WND phenotype in patients.
20033472##2009-9-25##Suppression of tumor suppressor Tsc2 and DNA repair glycosylase Nth1 during spontaneous liver tumorigenesis in Long-Evans Cinnamon rats.##Chronic inflammation and oxidative stress are arguably associated with an increased risk of cancer. Certain diseases that are characterized by oxyradical overload, such as Wilson's disease (WD), have also been associated with a higher risk of liver cancer. The Long-Evans Cinnamon (LEC) rat, an animal model for WD, is genetically predisposed to the spontaneous development of liver cancer and has been shown to be very useful for studying the mechanisms of inflammation-mediated spontaneous carcinogenesis. Endonuclease III (Nth1) plays a significant role in the removal of oxidative DNA damage. Nth1 and a tumor suppressor gene Tuberous sclerosis 2 (Tsc2) are bi-directionally regulated in humans, mice, and rats by a common minimal promoter containing two Ets-binding sites (EBSs). In this study, we examined the expression of Nth1 and Tsc2 genes during disease progression in the LEC rat liver. During the period of acute hepatitis (16-17 weeks), we observed decreased Nth1 and Tsc2 mRNA levels and a continued decrease of the Tsc2 gene in 24 weeks in LEC rats, while the effect was minimal in Long-Evans Agouti (LEA) rats. This reduction in the mRNA levels was due to the reduced binding of EBSs in the Nth1/Tsc2 promoter. Increase in protein oxidation (carbonyl content) during the same time period (16-24 weeks) may have an effect on the promoter binding of regulatory proteins and consequent decrease in Nth1 and Tsc2 gene expressions during tumorigenesis.
20442963##2010-3-5##Tackling metal regulation and transport at the single-molecule level.##To maintain normal metal metabolism, organisms utilize dynamic cooperation of many biomacromolecules for regulating metal ion concentrations and bioavailability. How these biomacromolecules work together to achieve their functions is largely unclear. For example, how do metalloregulators and DNA interact dynamically to control gene expression to maintain healthy cellular metal level? And how do metal transporters collaborate dynamically to deliver metal ions? Here we review recent advances in studying the dynamic interactions of macromolecular machineries for metal regulation and transport at the single-molecule level: (1) The development of engineered DNA Holliday junctions as single-molecule reporters for metalloregulator-DNA interactions, focusing onMerR-family regulators. And (2) The development of nanovesicle trapping coupled with single molecule fluorescence resonance energy transfer (smFRET) for studying weak, transient interactions between the copper chaperone Hah1 and the Wilson disease protein. We describe the methodologies,the information content of the single-molecule results, and the insights into the biological functions of the involved biomacromolecules for metal regulation and transport. We also discuss remaining challenges from our perspective.
20625962##2010-7-14##Persistence with treatment in patients with Wilson disease.##
20036408##2009-6-6##[A novel mutation in ATP7B gene associated with severe neurological impairment in Wilson's disease].##
20422502##2010-4-26##A patient with persistent pruritus.##We present a patient with an initial and acute presentation of jaundice and marked persistent pruritus. Laboratory and radiology test results eliminated the possibility of acute hepatitis A/B/C viral infections, primary biliary cirrhosis, autoimmune hepatitis, Wilson disease, paraneoplastic cholestasis, and obstructive biliary disease. Centrilobular cholestasis was prominent in a liver biopsy specimen. Benign recurrent intrahepatic cholestasis (BRIC) was diagnosed through a review of the clinical history, available data, and the subsequent exclusion of other possible etiologies. The patient's clinical features resolved within 3 months of medical treatment.
20127216##2008-7-3##Urinary copper/zinc ratio: a promising parameter for replacement of 24-hour urinary copper excretion for diagnosis of Wilson's disease in children.##
20464657##2010-5-14##[Schizophreniform symptoms in Chorea Minor--case report and literature review].##Sydenham's chorea is the most frequently acquired movement disorder in childhood and is characterized by involuntary and abrupt movement patterns. Some patients also show neuropsychiatric dysfunctions and psychiatric disorders, including anxiety, obsessive-compulsive disorders and tic disorders. In contrast, the association with psychotic symptoms has been reported very rarely up to now (n=4, two case reports, one prospective and one retrospective study). We report on a 12-year-old girl with acute paranoid hallucinatory symptoms and choreiform movements. Whereas her paranoid-hallucinatory symptoms responded to antipsychotic therapy, the negative symptoms and choreiform movement patterns only disappeared during additional prednisolone treatment. After tapering prednisolone, her negative symptoms and the choreiform movements reappeared. Dysfunctions of the corpus striatum have been linked to the pathogenesis of schizophrenia. This striatal dysfunction may secondarily affect working memory and the prefrontal cortex, resulting in impaired cognitive flexibility. Choreiform movements in chorea minor are attributed to dysfunction of the basal ganglia based on post-streptococcal autoimmune-mediated mechanisms. Huntington's disease and Wilson's disease are movement disorders caused by basal-ganglia dysfunction and are also associated with psychotic symptoms. In the present case, the association of psychotic and choreiform symptoms might be caused by dysfunction of the basal ganglia. The negative symptoms may result from disturbances of the prefrontal cortex impaired by basal-ganglia dysfunction.
20497654##2010-5-26##[Follow-up study on the therapeutic efficacy in 80 children with Wilson disease].##
20437536##2010-5-4##Do MRI features distinguish Wilson's disease from other early onset extrapyramidal disorders? An analysis of 100 cases.##Magnetic resonance imaging (MRI) is frequently used in the evaluation of various extrapyramidal disorders. Among the plethora of MRI features in Wilson's disease (WD), only "face of the giant panda" sign has been recognized to distinguish WD from other early onset extrapyramidal disorders (EOEPD). To ascertain the value of various MRI features in differentiating neuropsychiatric form of WD from other EOEPD. This retrospective analysis included 100 patients (M:F = 56:44) of EOEPD (5-40 years), who had undergone MRI during Jan'03 to Nov'08. Their clinical features were recorded and the following MR sequences were analyzed: T1WI, T2WI, FLAIR. Fifty-six patients had WD (M:F = 28:30, age at onset: 14 +/- 6.8 years) and 44 had other EOEPD (M:F = 27:17, age at onset: 19 +/- 9.8 years) that included Huntington's disease--4, young-onset Parkinson's disease--7, mitochondrial disorders--2, Hallervorden-Spatz disease--8, non-Wilsonian hepatolenticular degeneration--2, toxic/metabolic disorder--1, and others--20. The duration of illness at the time of MRI was comparable (WD: 3.1 +/- 4.9 years; Other EOEPD: 2.8 +/- 2.4 years). MR signal characteristics varied in topography and severity in both the groups. All the patients of WD had signal abnormalities in MRI, as against 16/44 of the other EOEPD group. The following MR observations were noted exclusively in WD: "Face of giant panda" sign (14.3%), tectal plate hyperintensity (75%), central pontine myelinolysis (CPM)-like abnormalities (62.5%), and concurrent signal changes in basal ganglia, thalamus, and brainstem (55.3%). Besides "Face of giant panda" sign, hyperintensities in tectal-plate and central pons (CPM-like), and simultaneous involvement of basal ganglia, thalamus, and brainstem are virtually pathognomonic of WD.
20421574##2010-4-28##Teaching NeuroImages: MRI reversal in Wilson disease with trientine treatment.##
20116809##2009-11-20##Spectrum of epilepsy in Wilson's disease with electroencephalographic, MR imaging and pathological correlates.##
20417464##2009-6-3##Clinical features and therapeutic response in Taiwanese children with Wilson's disease: 12 years of experience in a single center.##
20862985##2010-9-25##Clinical profile of chronic hepatobiliary disorders in children: experience from tertiary referral centre in Western India.##
20333789##2010-3-25##Wilson disease: histopathological correlations with treatment on follow-up liver biopsies.##
21811529##2010-4-6##Anesthetic management of a pediatric patient with wilsons disease.##
20166696##2010-2-20##Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of Wilson disease protein.##The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metal-binding domains (MBDs) of P(1B)-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4's Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1's Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (DeltaE = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data.
20005242##2009-9-29##ATP7B detoxifies silver in ciliated airway epithelial cells.##Silver is a centuries-old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increased cell death in ATP7B shRNA-treated HepG2 cells. In addition, mTEC from ATP7B(-/-) mice showed enhanced loss of ciliated cells compared to wild type. These studies are the first to demonstrate a cell type-specific expression of the Ag+/Cu+ transporters ATP7A, ATP7B, and CTR1 in airway epithelial cells and a role for ATP7B in detoxification of these metals in the lung.
20224790##2009-12-15##Category and perceptual learning in subjects with treated Wilson's disease.##To explore the relationship between category and perceptual learning, we examined both category and perceptual learning in patients with treated Wilson's disease (WD), whose basal ganglia, known to be important in category learning, were damaged by the disease. We measured their learning rate and accuracy in rule-based and information-integration category learning, and magnitudes of perceptual learning in a wide range of external noise conditions, and compared the results with those of normal controls. The WD subjects exhibited deficits in both forms of category learning and in perceptual learning in high external noise. However, their perceptual learning in low external noise was relatively spared. There was no significant correlation between the two forms of category learning, nor between perceptual learning in low external noise and either form of category learning. Perceptual learning in high external noise was, however, significantly correlated with information-integration but not with rule-based category learning. The results suggest that there may be a strong link between information-integration category learning and perceptual learning in high external noise. Damage to brain structures that are important for information-integration category learning may lead to poor perceptual learning in high external noise, yet spare perceptual learning in low external noise. Perceptual learning in high and low external noise conditions may involve separate neural substrates.
19562272##2009-5-22##Copper and zinc in the serum, urine, and hair of patients with Wilson's disease treated with penicillamine and zinc.##The purpose of this study was to determine the different levels of copper and zinc in the serum, urine, and scalp hair of patients with Wilson's disease receiving different, currently accepted methods of treatment to reduce the copper load (penicillamine-group 1, n = 8; zinc-group 2, n = 8; penicillamine+zinc-group 3, n = 8). Blood, urine, and hair samples were collected from the patients. All three treatments resulted in a significant decrease of the serum copper levels. Significantly increased levels of zinc in the serum were detected in the patients in groups 2 and 3 (19.1 and 18.8 micromol/l, respectively; p < 0.05). Copper excretion in the urine significantly increased during its administration to groups 1 and 3 (11.5 and 7.94 micromol/24 h respectively; p < 0.001) due to the effect of penicillamine. The administration of zinc as monotherapy (group 2) or in combination with penicillamine (group 3) led to an increase of its excretion (25.3 and 22.4 micromol/24 h, respectively; p < 0.01). Only an insignificant rise of the copper content in the hair was found in all three groups of patients. The content of zinc in the hair did not differ significantly in any of the groups in comparison with the control group.
20437931##2010-5-5##Neuronal Intranuclear Inclusion Disease presenting as juvenile Parkinsonism.##
19640812##2009-1-20##HFE gene mutations and Wilson's disease in Sardinia.##
20199365##2010-3-5##Neuromuscular complication after liver transplant in children: a single-center experience.##
20479926##2009-7-01##Appendiceal Orifice Inflammation in an 8-Year-Old Girl with Ulcerative Colitis Complicating Wilson's Disease.##Appendiceal orifice inflammation (AOI) may occur as a skipped lesion in ulcerative colitis (UC). Cases of ulcerative colitis complicated by Wilson's disease have also been reported. We report herein a case of AOI that occurred as a missed lesion in an 8-year-old girl with UC complicating Wilson's disease, which is rare in children.
20147789##2010-2-12##Evaluation of Cuprimine and Syprine for decorporation of (60)Co and (210)Po.##The acknowledged risk of deliberate release of radionuclides into local environments by terrorist activities has prompted a drive to improve novel materials and methods for removing internally deposited radionuclides. These decorporation treatments will also benefit workers in the nuclear industry, should an exposure occur. Cuprimine and Syprine are oral therapeutics based on the active ingredients D-penicillamine and N,N'-bis-(2-aminoethyl)-1,2-ethanediamine dihydrochloride, respectively. These therapeutic drugs have been used for several decades to treat Wilson's disease, a genetic defect leading to copper overload, by chelation and accelerated excretion of internally deposited copper. Studies were undertaken to evaluate these FDA-approved drugs for the in vivo decorporation of radioactive cobalt (Co) and polonium (Po) using male Wistar-Han rats. In these studies, Co or Po was administered to animals by IV injection, followed by oral gavage doses of either Cuprimine or Syprine. Control animals received the radionuclide alone. For Co studies, animals received a single dose of Cuprimine or Syprine, while for Po studies animals were repeatedly dosed at 24-h intervals for a total of 5 doses. Results show that Syprine significantly increased urinary elimination and skeletal concentrations of Co compared to controls. While Cuprimine had little effect on total excretion of Co, the skeletal, kidney, liver, muscle, and stomach tissues had significantly lower radioactivity compared to control animals. The low overall excretion of Po made it difficult to reliably measure urinary or fecal radioactivity and draw a definitive conclusion on the effect of Cuprimine or Syprine treatment on excretion. However, Cuprimine treatment was effective at reducing spleen levels of Po compared to controls. Similarly, Syprine treatment produced statistically significant reductions of Po in the spleen and skeletal tissues compared to control animals. Based on these promising findings, further studies to evaluate the dose-response pharmacokinetic profiles for decorporation are warranted.
20225771##2010-3-16##Risk factors for fulminant hepatic failure and their relation with outcome in children.##
19156444##2008-4-2##Nephrolithiasis related to inborn metabolic diseases.##Nephrolithiasis associated with inborn metabolic diseases is a very rare condition with some common characteristics: early onset of symptoms, family history, associated tubular impairment, bilateral, multiple and recurrent stones, and association with nephrocalcinosis. The prognosis of such diseases may lead to life threatening conditions, not only because of unabated kidney damage but also because of progressive extra-renal involvement, either in a systemic form (e.g. primary hyperoxaluria type 1, requiring combined liver and kidney transplantation), or in a neurological form (Lesch-Nyhan syndrome leading to auto-mutilation and disability, phosphoribosyl pyrophosphate synthetase superactivity, which is associated with mental retardation). Patients with other inborn metabolic diseases present only with recurrent stone formation, such as cystinuria, adenine phosphoribosyl-transferase deficiency, xanthine deficiency. Finally, nephrolithiasis may be secondarily part of some other metabolic diseases, such as glycogen storage disease type 1 or inborn errors of metabolism leading to Fanconi syndrome (nephropathic cystinosis, tyrosinaemia type 1, fructose intolerance, Wilson disease, respiratory chain disorders, etc.). The diagnosis is based on highly specific investigations, including crystal identification, biochemical analyses and DNA study. The treatment of nephrolithiasis requires hydration as well as specific measures. Compliance is a major issue regarding the progression of renal damage, but the overall outcome mainly depends on extra-renal involvement in relation to the metabolic defect.
20032459##2009-12-23##Interactions between copper-binding sites determine the redox status and conformation of the regulatory N-terminal domain of ATP7B.##Copper-transporting ATPase ATP7B is essential for human copper homeostasis and normal liver function. ATP7B has six N-terminal metal-binding domains (MBDs) that sense cytosolic copper levels and regulate ATP7B. The mechanism of copper sensing and signal integration from multiple MBDs is poorly understood. We show that MBDs communicate and that this communication determines the oxidation state and conformation of the entire N-terminal domain of ATP7B (N-ATP7B). Mutations of copper-coordinating Cys to Ala in any MBD (2, 3, 4, or 6) change the N-ATP7B conformation and have distinct functional consequences. Mutating MBD2 or MBD3 causes Cys oxidation in other MBDs and loss of copper binding. In contrast, mutation of MBD4 and MBD6 does not alter the redox status and function of other sites. Our results suggest that MBD2 and MBD3 work together to regulate access to other metal-binding sites, whereas MBD4 and MBD6 receive copper independently, downstream of MBD2 and MBD3. Unlike Ala substitutions, the Cys-to-Ser mutation in MBD2 preserves the conformation and reduced state of N-ATP7B, suggesting that hydrogen bonds contribute to interdomain communications. Tight coupling between MBDs suggests a mechanism by which small changes in individual sites (induced by copper binding or mutation) result in stabilization of distinct conformations of the entire N-ATP7B and altered exposure of sites for interactions with regulatory proteins.
19968254##2009-12-9##Risks of copper and iron toxicity during aging in humans.##Copper and iron are essential but also toxic metals. Their essentiality is known, but their toxicity, except for the genetic overload diseases, Wilson's disease and hemochromatosis, is not so well known. Yet, their toxicities are so general in the population that they are a looming public health problem in diseases of aging and in the aging process itself. Both metals are transition elements, and their resulting redox properties have been used during evolution in the development of oxidative energy generation. But both contribute to the production of excess damaging oxidant radicals. Evolution has kept stores of copper and iron in excess during the reproductive years because they are so vital to life. But the oxidant damage from these excess stores of metals builds up as we age, and natural selection ceases to act after about age 50 since diseases after that do not contribute to reproductive fitness. Diseases of aging such as Alzheimer's disease, other neurodegenerative diseases, arteriosclerosis, diabetes mellitus, and others may all be contributed to by excess copper and iron. A very disturbing study has found that in the general population those in the highest fifth of copper intake, if they are also eating a relatively high fat diet, lose cognition at over three times the normal rate. Inorganic copper in drinking water and in supplements is handled differently than food copper and is therefore more toxic. Trace amounts of copper in drinking water, less than one-tenth of that allowed in human drinking water by the Environmental Protection Agency, greatly enhanced an Alzheimer's-like disease in an animal model. In the last part of this review, I will provide advice on how to lower risks from copper and iron toxicity.
20078131##2010-1-19##Interdomain interactions modulate collective dynamics of the metal-binding domains in the Wilson disease protein.##Wilson disease protein or ATP7B is a key player in human copper (Cu) homeostasis. Belonging to the P(1B) type subfamily of ATPases, its N-terminal region contains six soluble domains (WD1-WD6) connected by linkers that vary in length. These domains share a similar fold and bind Cu(I) in the conserved motif MCXXC. It is unclear why there are six similar domains in the human protein (whereas bacteria and yeast contain only one or two) and why the human metallochaperone Atox1 delivers Cu(I) to only a subset of them. It has been speculated that the extra domains in humans regulate the ATPase in response to different Cu levels, suggesting that, although usually separated by long linkers, the domains can communicate with each other. Here, we performed extensive molecular dynamics simulations on three two-domain constructs in the apo- (WD12, WD34, WD56) and holo- (Cu(I) added to the most C-terminal domain of each construct: WD12c, WD34c and WD56c) forms to investigate how covalent linkage between domains and Cu(I) binding regulate their conformational dynamics. Our results suggest that when linked together the domains do not act as individual units but instead exhibit a distinct pattern of correlated motions, which are domain dependent and modulated by the presence of Cu. Conformational plasticity and degree of reorientation did not correlate with linker length, suggesting strong interdomain communication regardless of the linker length. Our computational findings suggest that cooperativity and long-range communication between domains may be important for the function and regulation of the ATPase.
20127637##2010-2-4##[Wilson's Disease].##Wilson's disease is a rare inherited disorder of copper metabolism. If left untreated, the disorder has a fatal course within a few years after symptom onset. If discovered early, effective treatment is available, preventing further clinical deterioration and leading to a normal life expectancy. Accumulation of copper in liver and brain can lead to a variety of unspecific hepatic, neurologic and psychiatric symptoms such as jaundice, tremor, ataxia or depression. In patients under the age of 40 with unexplained hepatic, neurologic or psychiatric symptoms, Wilson's disease must be considered. Diagnosis can be made by measurement of urinary copper excretion and other tests as required. Lifelong decoppering treatment must be maintained. For the detection of deterioration of the disease or adverse effects of the medication as well as for the assessment of therapeutic compliance, regular clinical controls are necessary.
20425485##2010-4-29##Genetic testing for Wilson disease: availability and utility.##Wilson disease, a genetic disorder of copper metabolism, presents typically in the second and third decades of life with hepatic or neuropsychiatric disease. Clinical presentations often vary depending on age and degree of onset; although clinical and biochemical testing can usually establish a diagnosis, the data are difficult to interpret in some patients. Correctly identifying patients from nonaffected carriers is important because treatment is lifelong. Genetic testing has greatly improved the ability to diagnose Wilson disease in affected patients and in their siblings even without clear-cut clinical and biochemical data. Direct sequencing of ATP7B for disease-specific mutations is now the standard for molecular diagnosis. However, haplotype analysis is useful when only a single mutation can be found. In specific populations with a higher frequency of a specific mutation, direct testing for these mutations can simplify and expedite molecular diagnosis. The molecular genetic test is now available commercially and in specific research laboratories; however, barriers to its use include cost, understanding when to perform it, and interpretation. This test eventually will be incorporated into the diagnostic armamentarium, allowing timely diagnosis and perhaps reversal or even prevention of further copper-induced injury.
19851743##2009-10-24##[Wilson's disease and multiple sclerosis. Co-occurrence].##Wilson's disease is a rare autosomal recessive disorder of hepatic copper transport leading to hepatic but also to highly variable neurological symptoms with basal ganglia and cerebellar manifestation. Symptoms, signs and results of investigations can overlap with those of other central nervous system disorders such as multiple sclerosis and sometimes delay diagnosis.We report on a 38-year-old male patient who was diagnosed with a hepatic form of Wilson's disease at age 12 and with multiple sclerosis at age 38. Intravenous radio copper test confirmed the diagnosis of Wilson's disease. Multiple sclerosis was diagnosed after occurrence of transient sensory disturbances in both legs, based on typical changes on MRI over the course of 2 years, in the cerebrospinal fluid and in multimodal evoked potentials.Although Wilson's disease and multiple sclerosis are known as distinct diseases with a completely different pathophysiology, symptoms and results of evoked potentials overlap, and they share a common historic background. Similarities and differences of both disorders are discussed.
20082719##2009-10-7##Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease.##
20020678##2009-12-22##Identifying health impacts of exposure to copper using transcriptomics and metabolomics in a fish model.##Copper (Cu) is a micronutrient essential for the biochemical functioning of numerous processes in vertebrates but is also often present in the aquatic environment at concentrations able to cause adverse health effects in aquatic organisms. This study investigated the signaling pathways mediating the effects of exposure to Cu using a toxicogenomic approach in a fish model, the stickleback ( Gasterosteus aculeatus ). Freshwater-acclimated male fish were exposed via the water to Cu, including at environmentally relevant concentrations (3.2-128 microg of Cu/L for 4 days), and the biological responses explored through analyses of the hepatic transcriptome and metabolome and phenotypic end points, including assessment of DNA damage in blood cells. The Cu exposures resulted in DNA strand breaks in blood cells at all exposure concentrations and alterations in hepatic gene expression and metabolite concentrations in a concentration-dependent manner (from 10 microg of Cu/L). Genes associated with the cholesterol biosynthesis pathway were significantly over-represented and consistently down-regulated (at 128 microg of Cu/L), similar to that occurring in a mouse model for Wilson's disease. Additionally, inductions in metallothionein and catalase were also observed. The concentrations of NAD(+) and lactate increased significantly with the Cu exposure, consistent with a shift toward anaerobic metabolism, and these aligned closely with changes observed in gene expression. The pathways of Cu toxicity identified in our study support the conserved mechanisms of Cu toxicity from lower vertebrates to mammals, provide novel insights into the deleterious effects of Cu in fish, and further demonstrate the utility of fish as environmental sentinels for chemical impacts on both environmental and human health.
19965379##2009-11-26##Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation.##Tetrathiomolybdate (TM) is an orally active agent for treatment of disorders of copper metabolism. Here we describe how TM inhibits proteins that regulate copper physiology. Crystallographic results reveal that the surprising stability of the drug complex with the metallochaperone Atx1 arises from formation of a sulfur-bridged copper-molybdenum cluster reminiscent of those found in molybdenum and iron sulfur proteins. Spectroscopic studies indicate that this cluster is stable in solution and corresponds to physiological clusters isolated from TM-treated Wilson's disease animal models. Finally, mechanistic studies show that the drug-metallochaperone inhibits metal transfer functions between copper-trafficking proteins. The results are consistent with a model wherein TM can directly and reversibly down-regulate copper delivery to secreted metalloenzymes and suggest that proteins involved in metal regulation might be fruitful drug targets.
20521445##2010-6-5##Monitoring copper in Wilson's disease.##Monitoring copper metabolism in patients with Wilson's disease is not an exact science. At present, there are no simple methods of estimating the total body load of this metal. Indirect methods must therefore be used. A survey of the current literature shows that most approaches rely on the determination of blood and urine copper concentration. Both these should decrease with treatment. In parallel with decreased copper concentration, there should be subsequent improvement in more routine laboratory tests including liver and renal function, blood count parameters, and clotting factors. Lack of compliance is revealed by a reversal of this trend. This chapter critically reviews current testing methods and describes other approaches that may be helpful.
20023268##2009-12-22##Non-viral-related pathologic findings in liver needle biopsy specimens from patients with chronic viral hepatitis.##Liver biopsy is a vital part of chronic viral hepatitis management. Pathologists should view these biopsies as screening tools for other liver diseases. We describe our experience in a 6-year period and discuss the pathologist's role. Liver biopsies of 1,842 patients with hepatitis B or C, for the 2001-2007 period at the University Health Network, Toronto, Canada, were reviewed; 410 other diagnoses were documented in 377 patients (20.5%; mean age, 25.4 years; range, 15-80 years). These diagnoses included 58 hepatocellular carcinomas and 16 dysplastic nodules, which are recognized complications of chronic viral hepatitis. The remaining findings included the following: steatosis/steatohepatitis, 251; hemosiderosis, 62; granulomatous disease, 7; drug-induced hepatitis, 4; primary biliary cirrhosis, 3; Wilson disease, 2; metastases, 2; and cholangiocarcinoma, atypical lymphoid proliferation, alpha(1)-antitrypsin deficiency, cystic fibrosis, and schistosomiasis, 1 each. Liver biopsies in patients with viral hepatitis revealed other processes with the potential to modify disease progression and/or the management strategy in 20.5% of patients.
20124325##2010-2-4##Association of ATP7B mutation detection rate with biochemical characteristics in Korean patients with Wilson disease.##Wilson disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, yet many patients have either one mutation, or no mutation. We investigated whether the mutation detection rate is associated with any biochemical characteristics of WD. In a study of 71 patients, we used PCR-sequencing to screen for ATP7B mutations in 7 exons (exons 8, 10, 11, 14, 15, 16, and 18) covering 95% of known mutations in Korean patients with WD. We also investigated serum concentrations of various biochemical analytes. Data were analyzed by linear association test and one-way ANOVA. Based on the number of detected ATP7B mutations, a significant difference in serum ceruloplasmin concentration was found among the 3 groups (p <0.001). Serum ceruloplasmin concentration averaged 3.32 +/- 1.74, 10.8 +/- 5.50, and 14.9 +/- 3.88 mg/dl (mean +/- SD) in the 25, 20, and 26 patients with two, one, and no ATP7B mutations, respectively. We observed 82.9% and 16.7% of mutant allele frequency in WD patients with ceruloplasmin concentration <10 mg/dl and 10-20 mg/dl, respectively (p <0.001). Thus serum ceruloplasmin concentrations among WD patients differed according to the number of ATP7B mutations detected.
20146697##2010-2-12##Neurologic Wilson's disease.##Despite a long history, Wilson's disease, an autosomal recessive disease caused by mutations in the ATP7B gene, remains a commonly misdiagnosed import disease. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. Clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. Among neurodegenerative diseases, it is unusual in that misdiagnosis and delay in treatment are clinically relevant because treatments can prevent and cure Wilson's disease, if they are given appropriately. If left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability and death, while those adequately treated have normal life spans. This review focuses on the neurologic features of Wilson's disease, its diagnosis, and treatment options.
19381668##2009-1-13##Clinical features of hemolysis, elevated liver enzymes, and low platelet count syndrome in undiagnosed Wilson disease: report of two cases.##
20502001##2010-1-25##Ceramide in suicidal death of erythrocytes.##The suicidal death of erythrocytes or eryptosis is characterized by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling resulting in phosphatidylserine exposure at the cell surface. Eryptosis is stimulated in a wide variety of diseases including sepsis, haemolytic uremic syndrome, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency and Wilson's disease. Moreover, eryptosis is elicited by osmotic shock, oxidative stress, energy depletion as well as a wide variety of endogenous mediators and xenobiotics. Excessive eryptosis is observed in erythrocytes lacking the cGMP-dependent protein kinase type I (cGKI) or the AMP-activated protein kinase AMPK. Inhibitors of eryptosis include erythropoietin, nitric oxide NO, catecholamines and high concentrations of urea. Eryptosis-triggering diseases and chemicals are partially effective by stimulating the formation of ceramide, which in turn fosters cell membrane scrambling. Accordingly, ceramide-induced eryptosis participates in the pathophysiology of several diseases and contributes to the effects of a large number of xenobiotics. The mechanisms underlying ceramide formation in erythrocytes are, however, still ill defined. In case of osmotic cell shrinkage, ceramide formation is apparently due to activation of phospholipase 2, leading to formation of platelet activating factor PAF and PAF-dependent stimulation of ceramide formation, which possibly involves acid sphingomyelinase. Additional experiments are needed to conclusively define the ceramide-generating enzyme and the ceramide-dependent cellular events eventually leading to suicidal erythrocyte death.
20597314##2010-7-6##[Wilson's disease].##Wilson's disease is a disorder of the liver's copper metabolism. Accumulation of copper causes liver and central nervous system damage. Wilson's disease should always be suspected, when a liver disease is detected in a child or an adolescent. The disease may also manifest itself as severe neurological or neuropsychiatric disorders. The diagnosis is often delayed despite the fact that the accumulation of copper in the body can be shown by various means. Early started medication will stop the accumulation of copper into the body. If the treatment is delayed or ineffective, liver transplantation is required.
21071947##2010-5-03##Neurology in the People's Republic of China--an update.##The present note provides an overview of the historical development of neurology and its current status in the People's Republic of China, against the backdrop of the current massive transformation of Chinese society. We trace the origins of neurology in China to missionary medicine during the Republican period (1911-1949), and describe how the discipline grows with difficulty throughout the subsequent decades (1950-1976). We then introduce an influential legacy of the post-revolutionary period, the ideal of integrating traditional Chinese medicine (TCM) and Western medicine, and briefly describe recent efforts to modernize medical education and training. Finally, we provide a brief overview of topics in neurology and neuropsychiatry that have a 'Chinese face', last but not least the successful integration of TCM and Western medicine in the treatment of hepatolenticular degeneration/Wilson's disease.
20606453##2010-2-26##Evaluation of the symptomatic treatment of residual neurological symptoms in Wilson disease.##The intention of this analysis was to identify patients with treated Wilson disease (WD) and residual neurological symptoms in order to determine whether or not they were undergoing any treatment in addition to the common decoppering medication. Moreover, the effects of any symptomatic medication were analyzed. Two samples of WD patients were investigated either by a mailed questionnaire survey (n = 135) or by a retrospective analysis (n = 75). A considerable proportion of patients still suffered from neurological symptoms (n = 106, 50.5%), of whom a relatively small proportion was treated symptomatically (n = 33, 31.1%). The documented effects varied substantially, with anticholinergics and botulinum toxin (against dystonia) and primidone (against tremor) apparently being the most promising compounds. Further studies are required to analyze the symptomatic treatment of WD patients with residual neurological symptoms in more detail.
19892144##2009-11-7##Chapter 41: the history of neurology in Scandinavia.##Neurology is well developed in Scandinavia (Denmark, Finland, Iceland, Norway, and Sweden) with a large number of clinical departments and specialists. The care for neurological patients is fairly equally organized even if neurology has evolved from different sources, from psychiatry in Denmark and Finland, internal medicine in Sweden and electrotherapy in Norway. Evidence of diagnostic activity and treatment of neurological diseases can be found in Scandinavia for more than 5000 years. The oldest are trepanned skulls. Written documentation exists from the Viking era, describing treatment of seizures and possibly also the effect of ergotamine. The methods were in concordance with medical practice in the rest of Europe. Scandinavian neurobiologists have produced important contributions to neuroscience during the last 300 or 400 years. Their names can be recognized as eponyms and Nobel prize laureates. Examples are Niels Stensen (Nicolaus Stenoni), the Bartholin family and Knud Krabbe of Denmark, Ragnar Granit of Finland, Bjørn Sigurdsson (the concept of slow virus infections) of Iceland, Asbjørn Følling and Sigvald Refsum of Norway and Gunnar Wohlfart, Eric Kugelberg, Lisa Welander and Arvid Carlsson of Sweden. In addition, well known neurological diseases were described in Scandinavia long before those neuroscientists that today have their names attached to them: Otto Christian Stengel, Norway (1826: Batten-Spielmayer-Vogt's disease), Johan Christian Lund, Norway (1860: Huntington's chorea) and Ernst Alexander Homén, Finland (1889: Wilson's disease).
19892136##2009-11-7##Chapter 33: the history of movement disorders.##
20174521##2010-2-23##Psychiatric manifestations of Wilson's disease and treatment with electroconvulsive therapy.##Wilson's disease is a rare genetic disorder involving the liver and brain, with onset frequently in adolescence. Psychiatric symptoms are often the first manifestation of the disease and can obscure the diagnosis. Although such patients are more commonly seen in neurological and hepatological settings, mental health professionals must keep in mind a high level of suspicion, once first presentations may be of psychiatric nature. We present the case of a 20-year-old female patient who initially presented with psychiatric symptoms. The neuropsychiatric manifestations and treatment of this patient with electroconvulsive therapy is presented.
20465616##2010-5-15##Rippled hyperpigmentation in Wilson's disease.##
20692507##2010-8-10##Transcranial sonography in depression.##Transcranial sonography, which displays tissue echogenicity of the brain through the intact skull, reveals reduced echogenicity of the brainstem raphe (BR) as a characteristic finding in unipolar depression and in depression associated with Parkinson's or Wilson's disease, but in general not in healthy adults, bipolar affective disorders, schizophrenia, multiple sclerosis with depression, or Parkinson's disease without concomitant depression. The reason for the reduced echogenicity of the BR is not entirely clear. Magnetic resonance imaging investigations, however, provide evidence that the signal alteration may be caused by a modification of tissue cell density, the interstitial matrix composition, or an alteration of fiber tracts integrity. An involvement of the basal limbic system in the pathogenesis of unipolar depression and depression associated with certain neurodegenerative diseases is assumed.
20692501##2010-8-10##Transcranial sonography in brain disorders with trace metal accumulation.##Transcranial sonography (TCS) can detect trace metal accumulation in deep brain structures with higher sensitivity than conventional MRI. Especially, increased iron content in the substantia nigra in Parkinson's disease, increased copper content in the lenticular nucleus (LN) in Wilson's disease and idiopathic dystonia, and increased manganese content in the LN in manganese-induced Parkinsonism were detected with TCS, even in subjects with normal MRI. TCS, therefore, might be useful to detect an increased risk of developing neurological symptoms in relatives of patients with Parkinson's or Wilson's disease. The exact mechanism of how an elevated trace metal content leads to an increased echogenicity needs to be further elucidated.
20692495##2010-8-10##Early diagnosis of Parkinson's disease.##The accuracy of the clinical diagnosis of Parkinson's disease (PD) is still limited. Especially in the early stages, when cardinal symptoms are not conclusive, diagnosis can be delayed as structural neuroimaging methods such as CCT or MRI do not provide characteristic features that allow the diagnosis of this chronic neurodegenerative disorder. Functional neuroimaging using PET and SPECT techniques is helpful in patients with first signs of parkinsonism, but expensive and not broadly available. In this scenario, transcranial sonography (TCS) has proven to be helpful. Up to 90% of PD patients show hyperechogenicity of the substantia nigra (SN) on TCS. Already in the early stages of PD this echofeature is visible, allowing the differentiation of very mildly affected patients with idiopathic PD from healthy persons and from patients with atypical parkinsonism with high sensitivity and specificity. Additionally, specific ultrasound features for some forms of secondary parkinsonism can be detected by TCS, helping in the early identification, for example, of patients with Wilson's disease. Therefore, especially in the early diagnosis, TCS can be recommended as a supplementary tool to facilitate the diagnostic classification of patients with first signs of parkinsonism.
20453399##2010-4-30##Current state of Wilson disease patients in central Japan.##
20453398##2010-4-30##Wilson disease and its current problems.##
21117320##2010-12-2##[Structure and function of ATP7A and ATP7B proteins--Cu-transporting ATPases].##Living organisms have developed refined and geneticaly controlled mechanisms of the copper metabolism and transport. ATP7A and ATP7B proteins play the key role in copper homeostasis in the organism. Both proteins are P-type Cu-transporting ATPases and use the energy of ATP hydrolysis to transfer the copper ions across the cellular membranes. Both proteins are localised in Golgi aparatus and involved in regulation of overall copper status in the body and their function is the export of excess copper from the cells and delivery of copper ions to Cu-dependent enzymes. Moreover in organism Cu-transporting ATPases are involved in absorption of dietary copper, Cu removal with the bile, placental copper transport and its secretion to the milk during lactation. Moreover it is known that Cu-transporting ATPases play a role in generation of anti-cancer drug resistance. Disturbances of ATP7A and ATP7B function caused by mutations lead to severe metabolic diseases Menkes and Wilson diseases, respectively.
19901085##2009-11-9##The hypointense liver lesion on T2-weighted MR images and what it means.##The vast majority of focal liver lesions are hyperintense on T2-weighted magnetic resonance (MR) images. Rarely, however, hepatic nodules may appear totally or partially hypointense on those images. Causes for this uncommon appearance include deposition of iron, calcium, or copper and are related to the presence of blood degradation products, macromolecules, coagulative necrosis, and other conditions. Although rare, low signal intensity relative to surrounding liver on T2-weighted images may be seen in a wide spectrum of lesions. Examples include cases of focal nodular hyperplasia, hepatocellular adenoma, hepatocellular carcinoma, metastases, leiomyoma, siderotic or dysplastic nodules, nodules in Wilson disease, granuloma, and hydatid cyst. On fat-suppressed T2-weighted images, nodules with a lipomatous component, such as lipoma, angiomyolipoma, hepatocellular adenoma, and hepatocellular carcinoma may also appear partially or totally hypointense. The conjunction of other MR imaging findings and their integration in the clinical setting may allow a correct diagnosis in a considerable proportion of cases. The cause for T2-weighted hypointensity may not be, however, always recognized, and only pathologic correlation may provide the answer. The aims of this work are to discuss the causes and mechanisms of hypointensity of liver lesions on T2-weighted images and proposing an algorithm for classification that may be useful as a quick reminder for the interested reader.
20422781##2010-4-29##[Wilson's disease].##
20128970##2010-2-5##[The reassessment of the diagnostic value of 24-hour urinary copper excretion in children with Wilson's disease].##
19665943##2008-4-16##Cardiovascular and sudomotor autonomic dysfunction in Wilson's disease--limited correlation with clinical severity.##
20069234##2009-6-07##Neuropareidolia: diagnostic clues apropos of visual illusions.##Diagnosis in neuroimaging involves the recognition of specific patterns indicative of particular diseases. Pareidolia, the misperception of vague or obscure stimuli being perceived as something clear and distinct, is somewhat beneficial for the physician in the pursuit of diagnostic strategies. Animals may be pareidolically recognized in neuroimages according to the presence of specific diseases. By associating a given radiological aspect with an animal, doctors improve their diagnostic skills and reinforce mnemonic strategies in radiology practice. The most important pareidolical perceptions of animals in neuroimaging are the hummingbird sign in progressive supranuclear palsy, the panda sign in Wilson's disease, the panda sign in sarcoidosis, the butterfly sign in glioblastomas, the butterfly sign in progressive scoliosis and horizontal gaze palsy, the elephant sign in Alzheimer's disease and the eye-of-the-tiger sign in pantothenate kinase-associated neurodegenerative disease.
19533206##2009-2-10##Self-injury behavior in an adolescent with Wilson's disease.##
19840131##2009-10-14##What, if anything, is specific about having a rare disorder? Patients' judgements on being ill and being rare.##
19937698##2009-11-26##Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin.##
20013564##2009-12-10##Wilson's disease: monocentric experiences over a period of 10 years [corrected].##
19581055##2009-5-14##Potential of vitamin E as an antioxidant adjunct in Wilson's disease.##Wilson's disease is a rare genetic illness of copper metabolism, which leads to copper-overload in mitochondria and organ damage, especially to the liver. Oxidative stress is central to the pathogenesis and a case is briefly made for rigorous trials of vitamin E as an antioxidant adjunct based on earlier corollary studies of its levels in the blood and liver of Wilson's disease patients and its effects in animal models of the illness.
20082972##2010-1-20##Wilson's disease.##
19559640##2008-11-2##Neuropsychiatric aspects of treated Wilson's disease.##The objective of the current cross-sectional study was to use standardized psychiatric interviews (the Structured Clinical Interview for DSM-IV Axis I Disorders and the Neuropsychiatric Inventory; NPI) in order to better characterize psychiatric symptoms in 50 consecutive, treated and clinically stable patients with Wilson's disease (WD). Nine patients (18%) had one, 7 patients (14%) had two, and 20 (40%) had >or= 3 neuropsychiatric symptoms present. The most often endosed symptoms were anxiety (62%), depression (36%), irritability (26%), as well as disinhibition and apathy (24% each). Twenty two patients (44%) had a score >or= 4 on at least one of the NPI items: again, most frequently anxiety (17 patients; 34%), depression (13 patients; 26%) and apathy (9 patients; 18%). Therefore, even among stable, long-term treated patients with WD approximately 70% experienced psychiatric symptoms.
19441067##2009-5-15##Interactions of Valeriana officinalis L. and Passiflora incarnata L. in a patient treated with lorazepam.##There is an increasing interest in the health risks related to the use of herbal remedies. Although most consumers think that phytomedicines are safe and without side effects, interactions between complementary alternative and conventional medicines are being described. The aim of this clinical case report is to highlight the importance of the safe use of herbal remedies by providing a clinical interaction study between pharmaceutical medicines and herbal medicinal products. The case of a patient self-medicated with Valeriana officinalis L. and Passiflora incarnata L. while he was on lorazepam treatment is described. Handshaking, dizziness, throbbing and muscular fatigue were reported within the 32 h before clinical diagnosis. The analysis of family medical history ruled out essential tremor, Parkinson's disease, Wilson's disease and other symptom-related pathologies. His medical history revealed a generalized anxiety disorder and medicinal plant consumption but no neurological disorder. Appropriate physical examination was carried out. An additive or synergistic effect is suspected to have produced these symptoms. The active principles of Valerian and passionflower might increase the inhibitory activity of benzodiazepines binding to the GABA receptors, causing severe secondary effects. Due to the increase in herbal product self-medication, the use of herbal remedies should be registered while taking the personal clinical history. Multidisciplinary teams should be created to raise studies on medicinal plants with impact on medical praxis.
19929173##2009-11-26##Is it possible to diagnose Wilson disease with a piece of skin?##Renal, skeletal, cardiac, and ophthalmic involvement in Wilson disease (WD) is well known. In this case report, high copper content and ultrastructural findings of skin of a patient with WD accompanied by xerosis are presented.
19863064##2009-10-30##Lysine-60 in copper chaperone Atox1 plays an essential role in adduct formation with a target Wilson disease domain.##The mechanism by which the human copper (Cu) chaperone Atox1 delivers Cu to metal-binding domains of Wilson disease (WD) protein for insertion into cuproenzymes is unclear. Using near-UV circular dichroism as a new tool to probe chaperone-target interactions, in combination with gel filtration and molecular dynamics simulations, we here demonstrate that Atox1 forms a stable Cu-dependent adduct with the fourth metal-binding domain of WD (WD4). Using point-mutated Atox1 variants, we show that the adduct forms in the absence of conserved residues M10 or T11 but K60 is essential for heterocomplex formation and Cu transfer. Dissection of heterocomplex energetic components reveals a crucial role for K60-mediated electrostatic interaction.
18771870##2008-5-5##Fulminant hepatic failure in children: etiology, histopathology and MDCT findings.##
19877301##2009-10-31##Zinc treatment for symptomatic Wilson disease: moving forward by looking back.##
19731238##2009-9-5##Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients.##
20329449##2010-3-25##Wilson's disease presenting as haemolytic anaemia.##
19720421##2009-2-7##Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson's disease.##
19917413##2008-12-21##Successful living donor left liver transplantation by using liver graft with multiple large cysts: a case report.##There are few reports regarding the use of liver grafts with multiple large cysts in living donor liver transplantation. A 40-year-old woman who was diagnosed with Wilson's disease underwent living donor left liver transplantation; the donor was her 67-year-old mother. The liver graft had multiple large cysts, with a maximum diameter of 9 cm. At donor hepatectomy, the largest cyst and one small cyst were fenestrated, because they were located in the left paramedian sector; the other cysts were left intact. After transplantation, the liver graft exhibited good function with no cyst-related complications, such as hemorrhage, infection, or rupture, despite slight enlargement of the cysts. Thus, a liver graft with multiple large cysts is transplantable. However, the necessity of treating large cysts remains debatable.
19805724##2009-10-7##Teaching video neuroimages: excessive grinning in Wilson disease.##
20087277##2010-1-21##Arthritis due to Wilson disease, penicillamine, psoriasis or hepatocellular carcinoma? Blurred focus, sharp boundaries.##
19725132##2009-9-3##Multiple genomic aberrations in a patient with mental retardation and hypogonadism: 45,X/46,X,psu dic(Y) karyotype, thyroid hormone receptor beta (THRB) mutation and heterozygosity for Wilson disease.##We report on multiple genomic aberrations in a patient with mental retardation. In addition, he had hypogonadism, elevated thyroid hormone levels, hearing loss, delayed speech development and mild dysmorphic features. First, we identified a mosaic karyotype, 45,X/46,X,psu dic(Y). The pseudo-dicentric Y chromosome has three short arm segments. Second, we found a germline mutation (Pro453Thr) of the thyroid hormone receptor beta (THRB) which is associated with resistance to thyroid hormone. Third, he was found to be a carrier of a heterozygous ATP7B mutation (c.2575 + 5G > C), the Wilson disease gene. Even though an array-CGH (with a density of approximately 1 Mb) did not reveal any further genomic gains or losses, we cannot exclude that all contributing factors have been identified. However, this case report shows that with increasing technological possibilities we can find more than one cause for developmental problems in a single patient. The identification of multiple causes in a single patient may complicate explaining the disorder and genetic counseling.
20009144##2009-12-17##Late acute celiac and hepatic artery thrombosis with portal vein thrombosis resulting in hepatic infarction 12 years post orthotopic liver transplantation.##Hepatic artery thrombosis (HAT) is relatively infrequent, but possibly a devastating complication of orthotopic liver transplantation (OLT). It often requires urgent retransplantation. Two main forms of HAT are recognized as early and late HAT (diagnosis within or after 30 days following LT). Early HAT typically results in graft failure. Late HAT features biliary obstruction, cholangitis, and hepatic abscess formation. We report here the case of a patient of Wilson's disease who presented twelve years post-liver transplant symptoms typical of acute HAT and hepatic infarction. On diagnostic imaging, celiac axis and hepatic artery were thrombosed, resulting in ischemic necrosis of the left hepatic lobe. The resulting sepsis and transient hepatic insufficiency were managed conservatively, and repeat OLT was avoided. The patient remains stable more than one year later. To the best of our knowledge this case report is unique in the literature for the unusually long interval between OLT and late acute HAT, as well as celiac and portal vein occlusion. The acute presentation of sub massive hepatic necrosis is also uncharacteristic of late HAT and more typical of acute HAT. This report describes our experience in managing this and a literature review of the topic.
19647032##2009-3-23##Wilson disease: current status and the future.##The focus of this minireview is on the current status and new advances in diagnosis and treatment of Wilson disease, an autosomal recessive disorder of copper metabolism. Molecular diagnostics have improved and complements current biochemical and clinical methods for screening for Wilson disease. Screening for Wilson disease in newborns is feasible and has been tested in limited populations, but is not yet widely performed. Identification of patients with Wilson disease as the cause of acute liver failure is possible using standard biochemical tests. Treatments for Wilson disease include chelating agents and zinc salts and liver transplantation. Future therapies may include hepatocyte transplantation and gene therapy, both of which have been tested and shown to work in animal models of Wilson disease. Future human studies await advances in these areas.
19540904##2009-2-18##A minigene approach for analysis of ATP7B splice variants in patients with Wilson disease.##Wilson disease (WND) is an autosomal recessive condition that results in accumulation of copper in the liver and brain when a membrane bound copper transporter, ATP7B, is defective. ATP7B is expressed in hepatic, brain and kidney cells, and a defect can lead to liver, neurological and renal damage in WND patients. Presentation is variable with a broad range of age of onset and symptoms, and not all biochemical signs used in diagnosis are found in every patient. Therefore, diagnosis by mutation analysis is particularly important. To date, there are approximately 380 probable disease-causing variants in ATP7B, 33 of which are splice site variants that are predicted to affect splicing, based on their location. Few of these splice site variants have been analyzed in vivo. Some exonic variations also have the potential to affect splicing. The aim of this project was to use minigenes for transcript analysis. We have chosen exon 8 as our focus and have cloned a wild-type three-exon minigene into a mammalian expression vector. After transfection, extracted RNA was analyzed by reverse transcription PCR and accurate splicing was detected. This minigene will facilitate the analysis of the numerous potential splice variants identified in exon 8 of ATP7B, with the advantage that patient cell lines are not required for each variant.
19787150##2009-2-20##Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?##Non-alcoholic steatohepatitis (NASH) has been associated with hepatocellular carcinoma (HCC) often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis). Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC) criteria, we identified 7 cases (1.7%) with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 +/- 13 years) were either overweight (4) or obese (3); 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1) based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.
19572946##2009-6-30##Hypoceruloplasminemia-related movement disorder without Kayser-Fleischer rings is different from Wilson disease and not involved in ATP7B mutation.##
19753579##2009-9-16##Laser secondary neutral mass spectrometry for copper detection in micro-scale biopsies.##Disease progression and clinical diagnostics of a number of hereditable metabolic diseases are determined by organ involvement in disturbed deposition of certain molecules. Current clinical imaging is unable to visualize this maldistribution with sufficient specificity and sensitivity, such as in Wilson's disease. The quest for understanding cellular Cu distribution in these patients requires element- and molecule-specific images with nanometer-scale spatial resolution. We have used a new cryo-mass spectrometric instrument with an integrated cryosectioning chamber for preparation and analysis of frozen hydrated samples of Wilson's disease tissue. With laser post-ionization secondary neutral mass spectrometry (laser-SNMS), we were able to image Cu and other intrinsic elements and molecules in less than 1 mg of frozen hydrated liver tissue from a murine model of Wilson's disease. A 40-50 times higher Cu concentration was measured in the disease tissue as compared to the control mouse. Furthermore, major histomorphological changes were observed using this advanced nano-science tool. The results showed that the combination of in-vacuum cryosectioning and cryo-laser-SNMS technologies is particularly well suited for identifying specific cell structures and imaging trace element concentrations with subcellular resolution and upper-parts-per-billion sensitivity in biological samples. This technology can provide a novel diagnostic tool for clinical applications in various diseases involving trace elements.
19479249##2009-1-28##Wilson's disease: two treatment modalities. Correlations to pretreatment and posttreatment brain MRI.##
20556197##2008-2-23##Proteomic analysis of sera of asymptomatic, early-stage patients with Wilson's disease.##Wilson's disease (WD) is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues, leading to significant oxidative stress and tissue damage. To date, several diagnostic biomarkers for WD such as serum ceruloplasmin, serum or urine copper levels and copper content in liver have been identified. However, these biomarkers may not be convincing for the diagnosis in some WD patients. To identify additional novel diagnostic biomarkers, we compared the serum protein profiles of asymptomatic childhood WD patients (n=20), without neurologic manifestation or liver cirrhosis, with normal controls (n=13). Fourteen spots, five up-regulated and nine down-regulated (>2-fold), were differentially expressed in WD patients in comparison to normal control on 2-DE. Among them, three spots were down-regulated in both male and female WD. MS/MS analysis revealed that the three spots were complement component C3, complement factor B and alpha-2 macroglobulin. By comparative proteome analysis, complement component C3, complement factor B and alpha-2 macroglobulin, which are related to oxidative stress and inflammation, turned out to be good candidates for novel diagnostic biomarkers for early stages of WD.
19857681##2009-10-28##Results of treatment of acute liver failure patients with use of the prometheus FPSA system.##
19066958##2008-10-7##Triethylene tetramine dihydrochloride (trientine) in children with Wilson disease: experience at King's College Hospital and review of the literature.##Our aim was to review our experience of trientine as chelation therapy in children with Wilson disease (WD) and compare to that reported in the literature. We made a retrospective review of the medical notes of 16 of 96 (17%) children diagnosed with WD between 1981 and 2006. Children were 6.6 to 15 years old. Only three received trientine as initial therapy [parental choice (two), allergic reactions to penicillamine (one) during the penicillamine challenge], 13 of 16 were converted from penicillamine to trientine because of reactions to penicillamine: haematuria in four, bone marrow suppression in three, neutropenia in three. Trientine was discontinued in three due to allergic rash, low copper excretion and one with compliance problems requiring transplantation. Seventy-five per cent of children presented with chronic liver disease. Kayser-Fleischer rings were noticed in eight of 16, Wilson Ferenci score range was between 4 and 10 (nl < 4). Laboratory indices remained relatively stable. In line with previous reports, trientine was used mainly as secondary treatment when there were severe side effects with penicillamine. Whilst the current evidence is low quality, it appears that trientine is as efficacious as penicillamine and small population studies show a lower side effect profile.
19596473##2009-1-5##Hepatocyte GP73 expression in Wilson disease.##
19783880##2009-9-29##[Haplotype analysis and possible founder effect at the R778L mutation of the ATP7B gene in Korean patients with Wilson's disease].##
19783878##2009-9-29##[Haplotype analysis at R778L mutation of ATP7B gene in Korean patients with Wilson disease].##
19707862##2009-4-29##Heterozygous carriers for Wilson's disease--magnetic spectroscopy changes in the brain.##Wilson's disease (WD) is an autosomal recessive disorder and the WD heterozygote carriers (Hzc) should not exhibit symptoms of the disease. The aim of this study was to assess 12 WD Hzc by brain Proton MR Spectroscopy. In three cases, the levels of caeruloplasmin, and in one case, serum copper, were below our normal range. In two Hzc the aspartate and alanine aminotransferase levels in the blood were slightly increased, however, no ultrasonographic liver changes were detected. The brain metabolite analysis showed a statistically significant higher mean ratio of Glx/Cr and Lip/Cr in MRS in Hzc in both the pallidum and thalami compared to control subjects. Our results suggest that WD Hzc may accumulate free copper in the basal ganglia.
19934550##2009-11-26##Wilson's disease: An Indian perspective.##Wilson's disease (WD) is an autosomal recessive disease involving a defect of copper transport by the hepatic lysosomes. It leads to excess copper deposition in the liver, the brain, the kidneys and the skeletal system, affecting most commonly children or young adults and running an invariably fatal course if not adequately treated by de-coppering therapy. The last century has witnessed several changes, notable among these are: Increased awareness, improved diagnostic facilities leading to earlier recognition even in the pre-symptomatic phase, clear distinction from its mimics, aggressive therapeutic approaches owing to availability of effective treatment and an overall reduction in the morbidity and mortality. It is widely acknowledged that the disease is not as rare as once believed. Sir SAK Wilson published his landmark article in 1912, but it was only in 1968 that the first patient of WD was reported from our country. Publications from India on WD have focused on phenotypic characterization, documentations of lesser recognized aspects of the disease e.g. seizures, behavior abnormality, speech and cognitive impairment, sub-clinical affection of visual pathway, heart and autonomic function and pre-symptomatic detection. Attempts have been made to understand the clinical heterogeneity of the disease through identification of biochemical and immunological markers, magnetic resonance imaging, neuropathological study and genetic analysis for novel and/or known mutations. Assessment of impairment and severity and effect of various therapeutic interventions namely zinc sulphate on the long-term outcome and quality of life have also been studied. Nevertheless, clinicians often face difficulties in long-term care of these patients. Diagnostic errors leading to delay in diagnosis and initiation of treatment are common, even in patients with positive family history. There is no consensus regarding therapeutic protocols since the use of penicillamine, once a 'gold standard' for treatment, has been debated by experts. Mortality and morbidity of this potentially treatable disease and nonavailability of medications to the poor patients remain a major area of concern.
19346156##2008-7-31##Metabolic changes in 37 newly diagnosed Wilson's disease patients assessed by magnetic resonance spectroscopy.##Wilson's Disease (WD) is a rare autosomal recessive disorder. The literature about proton MR spectroscopy (MRS) in WD is based mostly on data derived from patients undergoing treatment. The aim of this study was to identify brain metabolic changes in newly diagnosed WD patients using MRS to elucidate the pathomechanism of the cerebral pathology of WD. The globus pallidus and thalamus of 37 patients with WD were examined bilaterally with MRS. The calculations were performed for: myoinositol (mI), choline (Cho), creatine (Cr), N-acetyl-aspartate (NAA), lipid (Lip), glutamine, and glutamate (Glx). In all WD patients a significantly decreased mI/Cr and NAA/Cr ratio levels and an increased Lip/Cr ratio in the pallidum were observed. Analysis revealed a significantly increased Glx/Cr and Lip/Cr ratio in the thalamus. In the pallidum of neurologically impaired patients, Cho/Cr, Glx/Cr and Lip/Cr ratios were higher than in control subjects, and the NAA/Cr was significantly lower. In hepatic patients, the mI/Cr, Cho/Cr and NAA/Cr ratio levels were lower than in controls. The Cho/Cr and Lip/Cr ratios were higher in the thalami of neurologically impaired patients, and Lip/Cr ratios were higher than controls' in hepatic patients. Both findings were statistically significant. Compared to the thalamus, the basal ganglia are more sensitive to ongoing degenerative changes and portal-systemic encephalopathy in WD. The NAA/Cr reduction in hepatic and neurologically impaired patients could indicate that neurodegeneration is associated with all presentations of WD. In hepatic patients a mI and Cho decrease and in neurological Glx increase can be caused by porto-systemic shunting.
19873855##2009-10-31##Non-motor symptoms may herald Parkinson's disease.##Parkinson's disease is the second most common neurodegenerative disorder, after Alzheimer's disease. It predominantly affects the elderly. Age is the most clearly established risk factor and there is a male:female ratio of 1.5:1. Current incidence in the general population is 8.4-19 per 100,000 population per year with an approximate prevalence of 120 per 100,000 population. NICE recommends that patients with suspected Parkinson's disease should be referred untreated to a specialist with expertise in parkinsonian disorders. The diagnosis is primarily clinical. Parkinson's disease should be suspected in all patients presenting with bradykinesia (which is essential for the diagnosis of any form of parkinsonism, including Parkinson's disease), muscular rigidity, resting tremor (4-6 Hz) and postural instability not caused by a primary visual, vestibular, cerebellar, or proprioceptive dysfunction. At present, there are no specific biochemical, imaging or genetic tests to assist in the diagnosis of Parkinson's disease. Structural brain imaging (MRI or CT) has no role in the diagnosis of Parkinson's disease but may be useful to exclude cerebrovascular disease, hydrocephalus and Wilson's disease in selected cases. Parkinson's disease is a condition that results in both motor and non-motor symptoms. Morbidity associated with non-motor symptoms in Parkinson's disease is becoming increasingly recognised and some non-motor symptoms such as hyposmia, apathy, depression and REM sleep behaviour disorder may precede the onset of motor symptoms.
19574022##2009-4-23##[Fulminant and subfulminant hepatitis: causes and treatment].##Fulminant hepatitis is an emergency because within a few hours, the physician must find the cause of the hepatitis (not identified in 15 to 20% of cases), rule out any contraindication to liver transplantation, verify that it is indicated, and prevent and/or treat the complications associated with liver failure. Viruses (especially hepatitis viruses A and B), drugs, and toxic agents are the most common causes of fulminant hepatitis, with the proportions varying between countries. Hepatitis viruses, the leading cause through 1995-1996, have fallen behind drugs and in particular paracetamol, which is now the leading cause of this disease in Europe and in the United States. There are also other rarer causes: other viruses (e.g., herpes virus HSV1 or 2, hepatitis virus E, parvovirus B19, and chickenpox-herpes zoster), Wilson Disease, acute Budd-Chiari and Reyes syndromes, autoimmune hepatitis, neoplastic infiltration of the liver, hypoxic hepatitis, heatstroke, acute pregnancy-related steatosis, and the HELLP syndrome. Prognosis is essentially determined by neurological status, but is also affected very rapidly by damage to other organs. Liver transplantation has revolutionized the prognosis of fulminant hepatitis, causing survival to increase from 10-20% (all causes combined) to 75-80% at 1 year and 70% at 5 years. These patients can be treated only in specialized centers with access to liver transplantation and to different modern means of liver resuscitation (hypothermia, artificial liver support, albumin dialysis, monitoring intracranial pressure and cerebral perfusion, etc.) -all from the onset of the disease.
19765460##2009-9-22##Split liver transplantation in Shiraz Transplant Center.##
19765459##2009-9-22##Experience of living donor liver transplantation in Iran: a single-center report.##
19765458##2009-9-22##Pediatric liver transplantation in Iran: a 9-year experience.##
19645496##2009-8-4##Solution structures of the actuator domain of ATP7A and ATP7B, the Menkes and Wilson disease proteins.##ATP7A and ATP7B are two human P(1B)-type ATPases that have a crucial role in maintaining copper(I) homeostasis. Among the various domains of these enzymes, one, called the Actuator or A-domain, has a regulatory function and is required for the phosphatase step of the catalytic cycle (dephosphorylation of the intermediate formed during ATP hydrolysis). Here we report the solution structures of the A-domain of both proteins, solved by heteronuclear NMR spectroscopy and a characterization of the dynamics of the A-domain of ATP7A. We observed that the catalytically important TGE loop protrudes from the structure ready for interaction with the phosphorylated site in the ATP-binding domain. The loop is rigid, suggesting that the catalytic step does not require substantial structural flexibility or rearrangements. The present structures were useful to rationalize the molecular effects of disease-causing mutations. In particular, it can be concluded that mutations occurring in the A-domain either destabilize the fold of the domain (such as Gly860Val in ATP7A) or affect the network of communication within the domain (such as Leu873Arg in ATP7A) or with the other domains of the enzyme (such as Gly853Arg in ATP7A).
19700008##2009-8-25##Mutational analysis for Wilson's disease.##
19918393##2009-4-14##Sarcoidosis-induced pericarditis in a patient with portopulmonary hypertension: a case report.##Portopulmonary hypertension is a rare and severe complication of patients with cirrhosis. Sarcoidosis, a disease of unknown etiology, is also a cause of pulonary hypertension and right heart dysfunction. We report the case of a 51-year-old male patient, suffering from cirrhosis due to Wilson's disease, portal hypertension and pulmonary hypertension (PH), who developed severe pericarditis. Wilson's disease was diagnosed 8 years before his last admission to our hospital and was being successfully treated with D-penicillamine. PH was recognized 2 years before admission and being treated with bosentan. The patient complained for dyspnea at rest and the 2D echocardiogram revealed a significant amount of pericardial fluid. All other causes of acute pericarditis were excluded and his laboratory, imaging and histopathological investigation showed evidence of sarcoidosis. He underwent a therapy with corticosteroids (methylprednisolone) and his follow-up examination showed remarkable decrease of the levels of mean pulmonary artery pressure and pericardial fluid.
19514071##2009-6-11##"Acquired" hepatocerebral degeneration in a patient heterozygote carrier for a novel mutation in ATP7B gene.##
19918395##2009-1-20##Placenta abruption in a woman with Wilson's disease: a case report.##Wilson's disease is a rare genetic disorder of copper metabolism that causes primary hepatic cirrhosis, secondary menstrual abnormalities and infertility. Following the appropriate therapy patients are asymptomatic and pregnancy may be achieved. We present a case of placental abruption in a pregnant woman with Wilson's disease and we review the management dilemmas and treatment options of pregnant women with Wilson's disease.
19520855##2009-6-11##High yield heterologous expression of wild-type and mutant Cu+-ATPase (ATP7B, Wilson disease protein) for functional characterization of catalytic activity and serine residues undergoing copper-dependent phosphorylation.##ATP7B is a P-type ATPase required for copper homeostasis and related to Wilson disease of humans. In addition to various domains corresponding to other P-type ATPases, ATP7B includes an N terminus extension (NMBD) with six copper binding sites. We obtained high yield expression of WT and mutant ATP7B in COS1 cells infected with adenovirus vector. ATP7B, isolated with the microsomal fraction of cell homogenates, accounts for 10-20% of the total protein. Copper-dependent, steady-state ATPase yields 30 nmol of P(i)/mg of protein/min at 37 degrees C, pH 6.0. ATP7B phosphorylation with ATP occurs with diphasic kinetics and is totally copper-dependent. Alkali labile phosphoenzyme (catalytic intermediate of P-ATPases) accounts for a small fraction of the total phosphoprotein and is prevented by D1027N (P domain) or C983A/C985A (CXC copper binding motif in TM6) mutations. Decay of [(32)P]phosphoenzyme following chase with non-radioactive ATP occurs with an initial burst involving alkali labile phosphoenzyme (absent in D1027N and C983A/C985A mutants) and continues at a slow rate involving alkali-resistant phosphoenzyme. If a copper chelator is added with the ATP chase, the initial burst is smaller, and further cleavage is totally inhibited. Analysis by proteolysis and mass spectrometry demonstrates that the alkali stable phosphoenzyme involves Ser(478) and Ser(481) (NMBD), Ser(1121) ("N" domain) and Ser(1453) (C terminus), and occurs with the same pattern ex vivo (COS-1) and in vitro (microsomes). The overall copper dependence of phosphorylation and hydrolytic cleavage suggests long range conformational effects, including interactions of NMBD and headpiece domains, with strong influence on catalytic turnover.
19596747##2009-7-13##The conquest of Wilson's disease.##
20027333##2009-12-23##Changes in copper metabolism in different compartments of the brain in rats with induced fibrillogenesis.##Fibrillogenesis was induced in rats by injection of a fragment of neurotoxic protein, beta-amyloid protein precursor, into the cerebral ventricle. Copper, iron, and zinc concentrations and relative activities of genes of copper-transporting protein and extracellular and intracellular cuproenzymes were evaluated in different brain compartments of these animals. Copper and zinc concentrations decreased significantly in different compartments of the brain of rats with experimental fibrillogenesis, while iron content did not change. According to the data of RT-PCR analysis, activities of genes of copper-transporting protein and extracellular coenzyme decreased. The expression of intracellular cuproenzyme genes and the content of SOD1 protein did not change, SOD1 activity in the cytosol decreased, and active SOD1 was detected in the mitochondrial intermembrane space. The relationship between fibrillogenesis and copper metabolism is discussed.
19449145##2008-8-18##Comparative study on low back pain misdiagnosed as spondyloarthropathy.##This study aims to investigate features of different diseases with low back pain misdiagnosed as spondyloarthropathy so as to improve the accuracy of diagnosis for spondyloarthropathy. The clinical and laboratory data of 24 cases misdiagnosed as spondyloarthropathy in recent 3 years were comparatively and retrospectively analyzed. The diagnostic accuracy of the European Spondyloarthropathy Study Group (ESSG) criteria, Amor criteria, and the combination of them in these misdiagnosed cases was also analyzed. The final diagnoses of these 24 cases were listed below: four malignant tumors (retroperitoneal adipose sarcoma, advanced gastric carcinoma, ovarian papillary epithelioma, acute lymphocytic leukemia), six benign tumors (two parathyroid adenoma with hyperparathyroidism, one intraspinal lipoma, intraspinal ependymomas, sacral tubulocyst, and intraspinal schwannoglioma, respectively). The other 14 cases included fibromyalgia syndrome (3), osteitis condensans (3), diffuse idiopathic skeletal hyperostosis (2), lumbar intervertebral disk protrusion (1), congenital scoliosis (1), Wilson's disease (1), ochronosis (1), Fanconi syndrome (1) and hypophosphatemic rachiopathy (1). Among patients with tumor, all except three patients had persistent low back pain without morning stiffness, which aggravated at night and could not be relieved by rest or exercise. The symptoms could not be relieved by administration of multiple nonsteroidal anti-inflammatory drugs. Eleven patients had inflammatory low back pain defined by Calin. Of the total misdiagnosed cases, 54.17-83.33% could be prevented by application of ESSG criteria or Amor criteria, or a combination of them. From the data, we could see that the clinical features of different diseases with low back pain were different from each other and from those of spondyloarthropathy. The various criteria for spondyloarthropathy may be more effective in combination, along with other clinical information like these clinical features.
19768148##2009-3-08##Aetiology and outcome of acute liver failure.##
19763020##2009-9-19##Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats.##The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats.
19609919##2009-7-18##Axonal sensory motor neuropathy in copper-deficient Wilson's disease.##Copper deficiency may cause myeloneuropathy or progressive limb weakness. By contrast, Wilson's disease (WD) is characterized by progressive copper accumulation with hepatic and neurological impairment and requires life-long treatment with zinc and/or chelator agents. We report a WD patient who developed axonal sensory motor neuropathy in the context of copper deficiency due to his treatment with zinc and chelators. Exhaustive testing for other etiologies was negative. After treatment adjustment, only mild clinical improvement was noted during long-term follow-up. Muscle Nerve 40: 294-296, 2009.
19207220##2008-12-16##New-onset diabetes mellitus presenting with diabetic ketoacidosis after pediatric liver transplantation.##The development of NODM is a common metabolic complication after liver transplantation. Presentation of post-liver transplant diabetes mellitus with DKA is rare especially among pediatric patients. We reported three pediatric patients who presented with DKA after liver transplantation. The underlying diseases leading to transplantation were cryptogenic liver cirrhosis, Wilson disease, and congenital hepatic fibrosis. None of the three patients had a history of diabetes prior to transplantation and all of them were cases of NODM after transplantation. All three patients presented with severe hyperglycemia, significant ketosis, and metabolic acidosis of variable severity. All of them received tacrolimus as one of the immunosuppressant agents. The patients received a liver transplant from a DD. The patients were treated with intravenous insulin injection (0.1 U/kg/h) and recovered from DKA, but one case expired in the intensive care unit because of bacterial sepsis after recovery from DKA. Our experience suggests that PTDM may result in ketoacidosis, and we emphasize the importance of paying more attention to glucose metabolism and risk of diabetes mellitus in patients with immunosuppressive therapy, especially tacrolimus.
19710990##2009-8-28##Comment on: Acute cholecystitis in Wilson's disease.##
19595438##2009-3-4##Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine.##It has become clear that serum "free" copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance-if they worsen neurologically as often happens with penicillamine or trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than trientine. In the trientine arm of study 2, mean free copper levels actually went up during trientine therapy. The 5 patients who neurologically worsened on trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way "away from food" tetrathiomolybdate was given.
19421744##2009-2-25##Determination of ultrafiltrable and exchangeable copper in plasma: stability and reference values in healthy subjects.##The knowledge of copper (Cu) distribution in blood contributes to a better understanding of copper metabolism and to a better approach and follow up of related diseases such as Wilson's disease (WD). Many tests can be used to investigate patients who may have WD but they show many drawbacks and do not allow real patient monitoring. Knowing that the Cu overload can result from the free and easily exchangeable form of copper in plasma, a two-step method (ultrafiltration-determination by ETAAS) was carried out to determine these two fractions. The ultrafiltration procedure and the instrumental determination showed good repeatability, and a very low limit of detection was obtained (0.7 nmol/L). In vitro stability of both ultrafiltrable copper (CuUF) and exchangeable copper (CuEXC) was studied. Plasma was ultrafiltered in 44 presumably healthy subjects to determine CuUF and CuEXC and to set reference values ranges. The method was applied on a few patients showing good correlation between both parameters and the clinical and biological features of the patients.
19473354##2009-3-26##Long-term outcome in Serbian patients with Wilson disease.##
19333910##2009-4-1##Screening for Wilson's disease in acute liver failure: a comparison of currently available diagnostic tests.##
20112850##2010-2-2##Wilson's disease--a rare psychiatric presentation.##The development of extrapyramidal syndrome characterised by rigidity, bradykinesia, dysphagia and dysarthria in a male individual with four distinct episodes of (mania like) behavioural disturbances with fairly good remission in a time frame of five years, in a male individual, was suspected to develop the neurological manifestations of Wilson's disease and was investigated. In the absence of Kayser-Fleischer ring by slit-lamp examination and with normal copper and ceruloplasmin serum levels, the diagnosis was possible because of the positive findings of the magnetic resonance imaging (MRI) studies and increased 24 hours urinary copper levels with the penicillamine challenge test. The findings and its implications are highlighted and discussed.
20795462##2010-8-28##Effect of acute hepatitis E infection in patients with liver cirrhosis.##
22666674##2012-6-6##Wilson's disease masquerading as nonalcoholic steatohepatitis.##
19233606##2008-11-4##[Wilson disease].##
20306753##2010-3-24##Clinical profile, prognostic indicators and outcome of Wilson's disease in children: a hospital based study.##
19449859##2009-5-20##Conformational dynamics of metal-binding domains in Wilson disease protein: molecular insights into selective copper transfer.##ATP7A/B are human P(1B)-type ATPases involved in cellular Cu homeostasis. The N-terminal parts of these multidomain proteins contain six metal-binding domains (MBDs) connected by linkers. The MBDs are similar in structure to each other and to the human copper chaperone Atox1, although their distinct roles in Cu transfer appear to vary. All domains have the ferredoxin-like fold and a solvent-exposed loop with a MXCXXC motif that can bind Cu(I). Here, we investigated the dynamic behavior of the individual MBDs (WD1-WD6) in ATP7B in apo forms using molecular dynamic simulations. We also performed simulations of three Cu-bound forms (WD2c, WD4c, and WD6c). Our results reveal molecular features that vary distinctly among the MBDs. Whereas WD1, WD2, and WD6 have well-defined Cu loop conformations stabilized by a network of interactions, WD4 and WD5 exhibit greater loop flexibility and, in WD4, helix alpha1 unwinds and rewinds. WD3, which has the lowest sequence identity, behaves differently and its Cu loop is rigid with respect to the rest of the domain. Cu coordination reduces structural dynamics in all domains but WD4c. In agreement with predictions on individual domains, simulations of the six possible Atox1-WD heterocomplexes show that Atox1 interactions with WD4 are the strongest. This study provides molecular explanations for reported Cu transfer and protein-protein interaction specificity.
19405516##2009-5-2##The loop connecting metal-binding domains 3 and 4 of ATP7B is a target of a kinase-mediated phosphorylation.##Cu-ATPase ATP7B (Wilson's disease protein) transports copper into the trans-Golgi network for biosynthetic incorporation into ceruloplasmin and sequesters excess copper to endocytic vesicles for further export out of the cell. The activity and intracellular location of ATP7B are regulated by copper levels; the trafficking of ATP7B between cellular compartments is coupled to changes in the level of protein phosphorylation. Neither the nature of the kinase(s) phosphorylating ATP7B nor the location of phosphorylation sites is known. We demonstrate that the membrane-bound ATP7B is phosphorylated by an ATP-dependent, GTP-independent kinase that can be either soluble or membrane-associated. Mg(2+) or Mn(2+) is necessary for kinase activity. We further show that the recombinant N-terminal domain of ATP7B (N-ATP7B) is a specific target for a kinase-mediated phosphorylation in vitro and in cells. Although exogenous addition of copper is not required for kinase activity, copper binding to N-ATP7B markedly alters the exposure of loops connecting the metal-binding subdomains (MBDs) to proteolysis and facilitates phosphorylation by 25-30%. MBD1-2 and MBD4-5 linkers become protected, while MBD2-3 and MBD3-4 regions remain exposed. A significant, 5-fold increase in the level of phosphorylation is also observed for the ATP7B variant that lacks the 29 kDa N-terminal fragment (mostly likely comprised of MBD1-3). Analysis of phosphorylated peptides by two-dimensional gel electrophoresis and mass spectrometry points to the loop connecting MBD3 and MBD4 as a region of phosphorylation. Altogether, the results suggest a mechanism in which kinase-mediated phosphorylation of ATP7B is controlled by a conformational state of N-ATP7B.
19296535##2009-3-20##Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy.##Recently, the copper efflux transporters ATP7B and ATP7A have been implicated in the transport of and resistance to platinum drugs in breast and ovarian cancers. Because of the extensive use of oxaliplatin in colorectal cancer (CRC), we examined the expression of both transporters in tumors from CRC patients treated with oxaliplatin/5FU and sought to determine whether their expression can predict clinical outcome in these patients. ATP7B and ATP7A levels were determined by quantitative real-time PCR in 50 primary tumors of previously untreated patients with advanced colorectal adenocarcinoma who were subsequently treated with oxaliplatin/5FU. Additionally, ATP7B protein expression was assessed by immunohistochemical staining using a tissue microarray. Patients with the lowest mRNA expression levels of ATP7B had a significantly longer time to progression (TTP) (p = 0.0009) than patients with the highest levels (12.14 months vs. 6.43 months) who also had an increased risk of progression (HR = 3.56; 95% CI, 1.6-7.9; p = 0.002). Furthermore, patients with low levels of both protein and mRNA of ATP7B derived the maximum benefit from oxaliplatin/5FU with the longest TTP as compared with patients with high levels of ATP7B protein and mRNA (14.64 months vs. 4.63 months, respectively, p = 0.01) and showed a nonsignificant trend toward a lower response rate (37.5% and 75%, respectively). In conclusion, ATP7B mRNA and protein expression in colorectal tumors is associated with clinical outcome to oxaliplatin/5FU. Prospective studies are required to evaluate the role of this marker in tailoring chemotherapy.
19364131##2009-4-15##Reaction cycle of Thermotoga maritima copper ATPase and conformational characterization of catalytically deficient mutants.##Copper transport ATPases sustain important roles in homeostasis of heavy metals and delivery of copper to metalloenzymes. The copper transport ATPase from Thermotoga maritima (CopA) provides a useful system for mechanistic studies, due to its heterologous expression and stability. Its sequence comprises 726 amino acids, including the N-terminal metal binding domain (NMBD), three catalytic domains (A, N, and P), and a copper transport domain formed by eight helices, including the transmembrane metal binding site (TMBS). We performed functional characterization and conformational analysis by proteolytic digestion of WT and mutated (NMBD deletion or mutation) T. maritima CopA, comparing it with Archaeoglobus fulgidus CopA and Ca(2+) ATPase. A specific feature of T. maritima CopA is ATP utilization in the absence of copper, to form a low-turnover phosphoenzyme intermediate, with a conformation similar to that obtained by phosphorylation with P(i) or phosphate analogues. On the other hand, formation of an activated state requires copper binding to both NMBD and TMBS, with consequent conformational changes involving the NMBD and A domain. Proteolytic digestion analysis demonstrates A domain movements similar to those of other P-type ATPases to place the conserved TGES motif in the optimal position for catalytic assistance. We also studied an H479Q mutation (analogous to one of human copper ATPase ATP7B in Wilson disease) that inhibits ATPase activity. We found that, in spite of the H479Q mutation within the nucleotide binding domain, the mutant still binds ATP, yielding a phosphorylation transition state conformation. However, covalent phosphoryl transfer is not completed, and no catalytic turnover is observed.
19478447##2009-3-09##Crystallization and preliminary X-ray studies of the N-domain of the Wilson disease associated protein.##Wilson disease associated protein (ATP7B) is essential for copper transport in human cells. Mutations that affect ATP7B function result in Wilson's disease, a chronic copper toxicosis. Disease-causing mutations within the N-domain of ATP7B (WND) are known to disrupt ATP binding, but a high-resolution X-ray structure of the ATP-binding site has not been reported. The N-domain was modified to delete the disordered loop comprising residues His1115-Asp1138 (WNDDelta(1115-1138)). Unlike the wild-type N-domain, WNDDelta(1115-1138) formed good-quality crystals. Synchrotron diffraction data have been collected from WNDDelta(1115-1138) at the Canadian Light Source. A native WNDDelta(1115-1138) crystal diffracted to 1.7 A resolution and belonged to space group P4(2)2(1)2, with unit-cell parameters a = 39.2, b = 39.2, c = 168.9 A. MAD data were collected to 2.7 A resolution from a SeMet-derivative crystal with unit-cell parameters a = 38.4, b = 38.4, c = 166.7 A. The WNDDelta(1115-1138) structure is likely to be solved by phasing from multiwavelength anomalous diffraction (MAD) experiments.
19623464##2009-7-23##Wilson's disease: a case report and a historical review.##
18998134##2008-4-25##Role of copper transporters in resistance to platinating agents.##Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O (6)-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O (6)-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O (6)-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.
19470734##2009-5-26##Therapeutic Targeting of ATP7B in Ovarian Carcinoma.##
19246413##2009-2-25##Recurrent limb weakness in a 17-year-old boy.##Wilson disease is a relatively rare inherited disorder of copper accumulation and toxicity, caused by a defect in an enzyme that is part of the pathway of biliary excretion of excess copper. A 17-year-old boy presented with numerous episodes of hypokalemic weakness of the lower limbs of undetermined etiology since 12 years of age. Clinically, lower-motor neuron type of weakness of the limbs with preserved reflexes and paucity of sensory abnormalities were prominent. The investigations revealed distal renal tubular acidosis, hepatitis, and bilateral Kayser-Fleischer ring. The diagnosis of Wilson disease was confirmed by the demonstration of low serum ceruloplasmin, high serum copper, and high urinary copper excretion per se and after penicillamine challenge. He responded satisfactorily to penicillamine and zinc. Careful search of an underlying etiology in children presenting with hypokalemic weakness of the limbs in the face of metabolic acidosis and unexplained hepatitis may reveal Wilson disease.
19473947##2009-5-27##Status epilepticus in Wilson's disease.##
19307461##2009-3-23##Improvement in dissolution of liver fibrosis in an animal model by tetrathiomolybdate.##The background for this study is that we have observed some improvement in cirrhosis in Wilson's disease patients treated with the anticopper medicine, zinc, and another anticopper drug, tetrathiomolybdate, has completely prevented hepatic fibrosis in the carbon tetrachloride mouse model. We hypothesize that in existing cirrhosis, there may be a fine balance between fibrosis formation and fibrosis dissolution, which may be pushed in the direction of dissolution by anticopper drugs. Thus, in this study, we produced hepatic fibrosis in mice by treatment with carbon tetrachloride, then gave half the fibrotic mice tetrathiomolybdate for 3 months, while the other half of the fibrotic mice received nothing for 3 months and served as controls. Tetrathiomolybdate caused a dramatic and significant reduction in fibrosis as measured by hydroxyproline (the major amino acid constituent of collagen) levels, almost back to baseline levels, compared to controls, who had only a slight and nonsignificant reduction. It is clear from this animal study that dissolution of preexisting fibrosis can be strongly catalyzed by lowering copper levels with tetrathiomolybdate. It now becomes important to evaluate whether this approach will work in the human epidemic of cirrhotic disease resulting from diseases such as alcoholism, nonalcoholic steatohepatitis, and hepatitis C.
19482593##2009-6-2##Molecular mechanisms of copper homeostasis.##The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. The descriptions of the structural and functional organization of the metallothioneins, Cu-chaperones and P-type ATPases as well as of the mechanisms that regulate their distribution and functioning in the cell have enormously advanced our understanding of the Cu homeostasis and metabolism in the last decade. Cu is stored by metallothioneins and distributed by specialized chaperones to specific cell targets that make use of its redox properties. Transfer of Cu to newly synthesized cuproenzymes and Cu disposal is performed by the individual or concerted actions of the P-type ATPases ATP7A and ATP7B expressed in tissues. In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases.
19254344##2009-2-25##Special stain and X-ray probe microanalysis of livers with Wilson disease.##
20150599##2010-2-13##Impact of the discovery of human zinc deficiency on health.##The essentiality of zinc was recognized 46 years ago. Zinc deficiency resulting in growth retardation, hypogonadism, immune dysfunction and cognitive impairment affects nearly 2 billion subjects in the developing world. High phytate content of the cereal proteins consumed in the developing world, results in decreased availability of zinc for absorption. Zinc therapy has been very successful and life saving measure in patients with acrodermatitis enteropathica and Wilson's disease. Beneficial therapeutic responses of zinc supplementation have been ovserved in acute diarrhea in children, chronic hepatitis C, shigellosis, leprosy, leishmaniasis, and common cold. Zinc supplementation was effective in decreasing incidences of infection in elderly and patients with sickle cell disease. Zinc supplementation was effective in preventing blindness in 25% of the elderly with dry type of age related macular degeneration. Zinc supplementation in the elderly decreased oxidative stress and decreased generation of inflammatory cytokines. Zinc is an intracellular signaling molecule in monocytes, dendritic cells and macrophages and it plays an important role in cell-mediated immune functions and oxidative stress. Zinc is also an anti-inflammatory agent. These unique properties of zinc may have significant therapeutic benefits in several diseases in humans. In many diseases concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress and increase generation of inflammatory cytokines. Oxidative stress and chronic inflammation may play important causative roles in many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, and auto-immune diseases. It is therefore, important that status of zinc is assessed and zinc deficiency corrected in these chronic diseases. A controlled clinical trial of zinc supplementation in these disorders in order to document the preventive and therapeutic effects of zinc is warranted.
19400828##2008-12-29##Dermatological signs in Wilson's disease.##
19416479##2009-2-18##Cell-specific trafficking suggests a new role for renal ATP7B in the intracellular copper storage.##Human Cu-ATPases ATP7A and ATP7B maintain copper homeostasis through regulated trafficking between intracellular compartments. Inactivation of these transporters causes Menkes disease and Wilson disease, respectively. In Menkes disease, copper accumulates in kidneys and causes tubular damage, indicating that the renal ATP7B does not compensate for the loss of ATP7A function. We show that this is likely due to a kidney-specific regulation of ATP7B. Unlike ATP7A (or hepatic ATP7B) which traffics from the TGN to export copper, renal ATP7B does not traffic and therefore is unlikely to mediate copper export. The lack of ATP7B trafficking is not on account of the loss of a kinase-mediated phosphorylation or simultaneous presence of ATP7A in renal cells. Rather, the renal ATP7B appears 2-3 kDa smaller than hepatic ATP7B. Recombinant ATP7B expressed in renal cells is similar to hepatic protein in size and trafficking. The analysis of ATP7B mRNA revealed a complex behavior of exon 1 upon amplification, suggesting that it could be inefficiently translated. Recombinant ATP7B lacking exon 1 traffics differently in renal and hepatic cells, but does not fully recapitulate the endogenous phenotype. We discuss factors that may contribute to cell-specific behavior of ATP7B and propose a role for renal ATP7B in intracellular copper storage.
19265190##2009-3-5##Copper dopamine complex induces mitochondrial autophagy preceding caspase-independent apoptotic cell death.##Parkinsonism is one of the major neurological symptoms in Wilson disease, and young workers who worked in the copper smelting industry also developed Parkinsonism. We have reported the specific neurotoxic action of copper dopamine complex in neurons with dopamine uptake. Copper dopamine complex (100 microm) induces cell death in RCSN-3 cells by disrupting the cellular redox state, as demonstrated by a 1.9-fold increase in oxidized glutathione levels and a 56% cell death inhibition in the presence of 500 microm ascorbic acid; disruption of mitochondrial membrane potential with a spherical shape and well preserved morphology determined by transmission electron microscopy; inhibition (72%, p < 0.001) of phosphatidylserine externalization with 5 microm cyclosporine A; lack of caspase-3 activation; formation of autophagic vacuoles containing mitochondria after 2 h; transfection of cells with green fluorescent protein-light chain 3 plasmid showing that 68% of cells presented autophagosome vacuoles; colocalization of positive staining for green fluorescent protein-light chain 3 and Rhod-2AM, a selective indicator of mitochondrial calcium; and DNA laddering after 12-h incubation. These results suggest that the copper dopamine complex induces mitochondrial autophagy followed by caspase-3-independent apoptotic cell death. However, a different cell death mechanism was observed when 100 microm copper dopamine complex was incubated in the presence of 100 microm dicoumarol, an inhibitor of NAD(P)H quinone:oxidoreductase (EC 1.6.99.2, also known as DT-diaphorase and NQ01), because a more extensive and rapid cell death was observed. In addition, cyclosporine A had no effect on phosphatidylserine externalization, significant portions of compact chromatin were observed within a vacuolated nuclear membrane, DNA laddering was less pronounced, the mitochondria morphology was more affected, and the number of cells with autophagic vacuoles was a near 4-fold less.
19306278##2009-3-24##Monozygotic female twins discordant for phenotype of Wilson's disease.##Wilson's disease (WD) is an autosomal recessive disorder characterized by the functional disruption of the copper-transporting protein adenosine triphosphatase 7B (ATP-ase 7B). The disease is caused by mutations in ATP7B gene. It seems that the type of mutation in ATP7B only to some degree determines phenotypic manifestation of WD. We examined two pairs of monozygotic twins discordant for WD phenotype. The first set of twins were ATP7B compound heterozygotes c.3207C>A (p.H1069Q)/c.1211_1212insA (p.N404Kfs). The index case developed severe liver failure followed by depressive symptoms, dysarthria, and tremor at the age of 36. Her sister remained presymptomatic at diagnosis at the age of 39. The second twins were ATP7B c.3207C.A (p.H1069Q) homozygotes. The index case presented with dysarthria and tremor at the age of 26. Her sister remained clinically presymptomatic at diagnosis at the age of 28. We concluded that the phenotypic characteristics of WD are possibly attributable to epigenetic/environmental factors.
19210288##2009-2-7##Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease.##
20141096##2010-2-10##Zinc: an essential micronutrient.##Zinc is an essential micronutrient for human metabolism that catalyzes more than 100 enzymes, facilitates protein folding, and helps regulate gene expression. Patients with malnutrition, alcoholism, inflammatory bowel disease, and malabsorption syndromes are at an increased risk of zinc deficiency. Symptoms of zinc deficiency are nonspecific, including growth retardation, diarrhea, alopecia, glossitis, nail dystrophy, decreased immunity, and hypogonadism in males. In developing countries, zinc supplementation may be effective for the prevention of upper respiratory infection and diarrhea, and as an adjunct treatment for diarrhea in malnourished children. Zinc in combination with antioxidants may be modestly effective in slowing the progression of intermediate and advanced age-related macular degeneration. Zinc is an effective treatment for Wilson disease. Current data do not support zinc supplementation as effective for upper respiratory infection, wound healing, or human immunodeficiency virus. Zinc is well tolerated at recommended dosages. Adverse effects of long-term high-dose zinc use include suppressed immunity, decreased high-density lipoprotein cholesterol levels, anemia, copper deficiency, and possible genitourinary complications.
19342951##2009-4-4##Inherited metabolic disease of the liver.##
19364450##2009-4-15##Drug-induced parkinsonism.##Drug-induced parkinsonism (DIP) is condition that mimics Parkinson's disease. Characterized mainly by rigidity and bradykinesia, it has less prominent tremor and gait instability. DIP is generally caused by lipophilic drugs that "block" dopamine D2 receptors in the brain, although presynaptic dopamine depletion, false transmitters, mitochondrial respiratory chain dysfunction, and overactivity in the gamma-aminobutyric acid (GABA)ergic system or cholinomimetic action have also been postulated as possible mechanisms. The onset of DIP is acute to subacute. It is more common in women and has a bimodal age distribution. Other diseases that can resemble DIP include neuropsychiatric conditions (eg, depression, negative symptoms of schizophrenia) and Wilson's disease. Physicians may be able to prevent DIP by prescribing neuroleptic agents appropriately and with caution. The risk of DIP is presumably lower with the use of "atypical" antipsychotic agents but it is not eliminated, especially in those most vulnerable to parkinsonism (eg, the elderly or cognitively impaired). The best treatment is discontinuation of the provoking medication. Prospective studies are needed to further define the mechanism of DIP, identify individual susceptibility, determine the impact of atypical antipsychotic agents, and develop further treatment options for those unable to stop the offending agent.
18720003##2008-2-23##Conjugated linoleic acid-induced toxic hepatitis: first case report.##A 46-year-old female patient was referred to our department with presenting symptoms of asthenia, jaundice, and pruritus. There was no medical history or clinical evidence of viral hepatitis, autoimmune hepatitis, hemochromatosis, or Wilson's disease. The patient revealed that 14 days prior to admission she had begun self-medicating with conjugated linoleic acid (CLA) to reduce body fat, leading to the suspicion of CLA hepatotoxicity, which was subsequently confirmed by a liver biopsy. After the patient ceased to ingest CLA, liver enzymes levels normalized. To the best of our knowledge, this is the first report of hepatotoxicity due to CLA ingestion.
19237514##2009-2-23##Characterization of sandwich-cultured hepatocytes as an in vitro model to assess the hepatobiliary disposition of copper.##Sandwich-cultured hepatocytes (SCH) from rats (SCRH), dogs (SCDH), and humans (SCHH) were used as an in vitro model to assess the hepatobiliary disposition of copper (Cu). The expression of Cu transporters, ceruloplasmin synthesis, Cu uptake, and biliary excretion and species differences in drug-induced alterations in Cu disposition were determined in SCH from all species. Western blot analysis verified basolateral Cu uptake transporter 1 (CTR1) and canalicular Cu efflux transporter (ATP7B) expression: enzyme-linked immunosorbent assay verified synthesis/secretion of ceruloplasmin (major Cu binding protein found in blood). Endogenous Cu in SCRH, SCDH, and SCHH were 17.2 +/- 7.00, 490 +/- 44.8, and 43.5 +/- 15.8 ng/well, respectively. The hepatobiliary disposition of Cu as measured by uptake (increase in intracellular Cu in comparison to endogenous levels) and biliary excretion (increase in Cu in wash solutions obtained from hepatocytes exposed to calcium-free versus standard buffer) was determined as a function of Cu concentration and incubation time. In general, an increase in Cu concentration or incubation time resulted in an increase in Cu uptake and/or biliary excretion; however, the extent to which they affected Cu disposition was species dependent. 5-(1,1-Dioxido-1,2-thiazinan-2-yl)-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (L-000870810) (an anti-HIV compound, the development of which was halted due to an observed Cu-specific toxicity in the liver and kidneys of dogs after long-term exposure) showed no effect on Cu disposition in SCRH; however, it increased the biliary excretion of Cu in SCDH and SCHH. This is the first report to demonstrate the utility of SCH as a model to assess hepatobiliary disposition of Cu in an in vitro system.
19185006##2009-2-3##Bile salt-induced pro-oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long-Evans Cinnamon rat model.##Insights into disease-specific mechanisms for liver repopulation are needed for cell therapy. To understand the efficacy of pro-oxidant hepatic perturbations in Wilson disease, we studied Long-Evans Cinnamon (LEC) rats with copper toxicosis under several conditions. Hepatocytes from healthy Long-Evans Agouti (LEA) rats were transplanted intrasplenically into the liver. A cure was defined as lowering of copper to below 250 microg/g liver, presence of ATPase, Cu++ transporting, beta polypeptide (atp7b) messenger RNA (mRNA) in the liver and improvement in liver histology. Treatment of animals with the hydrophobic bile salt, cholic acid, or liver radiation before cell transplantation produced cure rates of 14% and 33%, respectively; whereas liver radiation plus partial hepatectomy followed by cell transplantation proved more effective, with cure in 55%, P < 0.01; and liver radiation plus cholic acid followed by cell transplantation was most effective, with cure in 75%, P < 0.001. As a group, cell therapy cures in rats preconditioned with liver radiation plus cholic acid resulted in less hepatic copper, indicating greater extent of liver repopulation. We observed increased hepatic catalase and superoxide dismutase activities in LEC rats, suggesting chronic oxidative stress. After liver radiation or cholic acid, hepatic lipid peroxidation levels increased, indicating further oxidative injury, although we did not observe overt additional cytotoxicity. This contrasted with healthy animals in which liver radiation and cholic acid produced hepatic steatosis and loss of injured hepatocytes. We concluded that pro-oxidant perturbations were uniquely effective for cell therapy in Wilson disease because of the nature of preexisting hepatic damage.
19581671##2009-7-8##Diagnosis of Wilson's disease.##
19046832##2008-8-23##[From gene to disease: copper-transporting P ATPases alteration].##Copper is a trace metal, essential for many biological processes. Copper is also toxic if in excessive amounts; its homeostatic balance requires a delicate regulation. Several severe hereditary human disorders of copper regulatory mechanisms have been identified; they are related to mutations in gene ATP7A and ATP7B coding for copper-transporting proteins. Those mutations result in copper deficiency for ATP7A (Menkes disease) and copper overload for ATP7B (Wilson disease). Usually, clinical and biochemical phenotypes of these diseases are disparate. This article focuses on the molecular pathogenesis of Wilson and Menkes disease, and discusses how causing mutations are correlated with molecular defects and disease phenotypes.
19384160##2009-4-23##Potential feasibility of early bone marrow cell injection into the spleen for creating functional hepatocytes.##
19181666##2009-1-30##An NMR study of the interaction of the N-terminal cytoplasmic tail of the Wilson disease protein with copper(I)-HAH1.##ATP7B is a human P(1B)-type ATPase that has a crucial role in maintaining copper(I) homeostasis. Mutations in the corresponding gene are the cause of Wilson disease. Among its various distinguishing features is a long ( approximately 630 amino acids) N-terminal cytosolic tail containing six domains that are individually folded and capable of binding one copper(I) ion each. We expressed the entire tail as a single construct in Escherichia coli and investigated its interaction with its copper chaperone (i.e. HAH1) by solution NMR spectroscopy. We observed that all six of the metal-binding domains were metallated by Cu(I)-HAH1, with the first, the second, and the fourth domains forming an adduct with it. This behavior is different from that of the highly similar human ATPase ATP7A, in which only two domains form such an adduct. The distinct behaviors of the different domains were analyzed in terms of the energetics of Cu(I) transfer, hinting at a specific role of the interaction with copper(I)-HAH1 in the overall functional process.
19157809##2008-9-12##[Torticollis revealing Wilson's disease].##
19173677##2009-1-29##The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin.##Wilson disease ATPase (ATP7B) has been implicated in the resistance of cancer cells to cisplatin. Using a simple in vivo assay in bacterial culture, in the present study we demonstrate that ATP7B can confer resistance to cisplatin by sequestering the drug in its N-terminal metal-binding domain without active drug extrusion from the cell. Expression of a protein fragment containing four N-terminal MBRs (metal-binding repeats) of ATP7B (MBR1-4) protects cells from the toxic effects of cisplatin. One MBR1-4 molecule binds up to three cisplatin molecules at the copper-binding sites in the MBRs. The findings of the present study suggest that suppressing enzymatic activity of ATP7B may not be an effective way of combating cisplatin resistance. Rather, the efforts should be directed at preventing cisplatin binding to the protein.
19419418##2009-5-8##Carrier frequency of the R778L, A874V, and N1270S mutations in the ATP7B gene in a Korean population.##
19371968##2008-9-12##[Wilson's disease: pediatric experience in Costa Rica].##
19371217##2009-4-18##RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease.##Wilson disease (WD) is an autosomal recessive disorder caused by a defective function of the copper-transporting ATP7B protein. This results in progressive copper overload and consequent liver, brain, and kidney damage. Approximately 300 WD-causing mutations have been described to date. Missense mutations are largely prevalent, while splice-site mutations are rarer. Of these, only a minority are detected in splicing consensus sequences. Further, few splicing mutations have been studied at the RNA level. In this study we report the RNA molecular characterization of three consensus splice-site mutations identified by DNA analysis in WD patients. One of them, c.51 + 4 A --> T, resides in the consensus sequence of the donor splice site of intron 1; the second, c. 2121 + 3 A --> G, occurred in position + 3 of intron 7; and the c.2447 + 5 G --> A is localized in the consensus sequence of the donor splice site of intron 9. Analysis revealed predominantly abnormal splicing in the samples carrying mutations compared to the normal controls. These results strongly suggest that consensus sequence splice-site mutations result in disease by interfering with the production of the normal WD protein. Our data contribute to understanding the mutational spectrum that affect splicing and improve our capability in WD diagnosis.
19141620##2009-1-13##Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug.##Cisplatin is a widely used chemotherapeutic agent for treatment of ovarian, testicular, lung, and stomach cancers. The initial response to the drug is robust; however, tumor cells commonly develop resistance to cisplatin, which complicates treatment. Recently, overexpression of the Cu-ATPase ATP7B in ovary cells was linked to the increased cellular resistance to cisplatin; and the role for Cu-ATPases in the export of cisplatin from cells was proposed. Our results support functional interactions between cisplatin and ATP7B but argue against the active transport through the copper translocation pathway as a mechanism of drug resistance. In hepatocytes, we observed no correlation between the levels of endogenous ATP7B and the resistance of cells to cisplatin. Unlike copper, cisplatin does not induce trafficking of ATP7B in hepatoma cells, neither does it compete with copper in a transport assay. However, cisplatin binds to ATP7B and stimulates catalytic phosphorylation with EC(50) similar to that of copper. Mutations of the first five N-terminal copper-binding sites of ATP7B do not inhibit the cisplatin-induced phosphorylation of ATP7B. In contrast, the deletion of the first four copper-binding sites abolishes the effect of cisplatin on the ATP7B activity. Thus, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug. The link between changes in copper homeostasis and cisplatin resistance was confirmed by treating the Huh7 cells with copper chelator and increasing their resistance to cisplatin.cisplatin.
19289731##2009-3-18##Teaching NeuroImages: face of the giant panda and her cub: MRI correlates of Wilson disease.##
19115420##2008-12-31##A novel Global Assessment Scale for Wilson's Disease (GAS for WD).##Wilson's disease (WD) is an inherited disorder of copper metabolism. Despite being treatable, patients with WD suffer severe disabilities due to delay in initiation and difficulty in monitoring treatment. We propose a two tier, Global Assessment Scale for Wilson's Disease (GAS for WD) that grades the multisystemic manifestations of the disease. Tier 1 scores the global disability in four domains: Liver, Cognition and behavior, Motor, and Osseomuscular. Tier 2 is multidimensional scale for a fine grained evaluation of the neurological dysfunction. We prospectively validated this scale in 30 patients with WD. Both tiers had a high inter-rater reliability (Intraclass correlation coefficient ICC (A, 2) = 0.96-1.0). Tier 2 items were internally consistent (Cronbach's alpha = 0.89) and factorial analysis showed that 90.3% of the Tier 2 total score variance was determined by seven factors. Scores of both tiers were commensurate with the disease burden as assessed by standard disability scales (Child Pugh, UPDRS, SS3, and CGI) and satisfied criteria for validity. Longitudinal follow-up over 1.5 years showed that the scale was sensitive to clinical change. This suggests that GAS for WD is a practical tool with potential applications in management of patients, and in testing and comparison of treatment regimens.
19295322##2009-3-20##Outcomes of living-related liver transplantation for Wilson's disease: a single-center experience in China.##
19595231##2009-7-15##[Probing into indication of living-related liver transplantation for Wilson's disease].##
19429000##2008-11-23##Evaluation of tetrathiomolybdate in the R6/2 model of Huntington disease.##Huntington disease is an uncommon autosomal dominant neurodegenerative disorder caused by expanded polyglutamine repeats in the huntingtin protein. The proximate mechanisms responsible for neurodegeneration are unknown. Copper ions may play a role in Huntington disease by promoting oligomerization of expanded polyglutamine repeat protein fragments. Ammonium tetrathiomolybdate is a copper complexing agent with demonstrated tolerability and efficacy in another neurodegenerative disorder, Wilson disease. We evaluated ammonium tetrathiomolybdate in the R6/2 transgenic mouse model of Huntington disease. Ammonium tetrathiomolybdate treatment delayed the onset of motor dysfunction in R6/2 mice. There was a trend towards reduced striatal degeneration, suggesting a neuroprotective effect of ammonium tetrathiomolybdate in this model. Given its known tolerability in humans with neurodegeneration, ammonium tetrathiomolybdate could be considered as a candidate for clinical trials in Huntington disease.
18545997##2008-2-21##Cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+,K+-ATPase activity rather than copper-transporting P-type ATPases, ATP7A and ATP7B.##
19118916##2008-12-4##Role of genotyping in Wilson's disease.##
19118915##2008-7-29##Genotype-phenotype correlation in Italian children with Wilson's disease.##
19267864##2009-3-10##Clinical features and predictors of outcome in acute hepatitis A and hepatitis E virus hepatitis on cirrhosis.##
19272514##2009-3-11##Movement disorders.##Abnormal involuntary movements are major features of a large group of neurologic disorders, some of which are neurodegenerative and pose a significant diagnostic and treatment challenge to treating physicians. This article presents a concise review of clinical features, pathogenesis, epidemiology, and management of seven of the most common movement disorders encountered in a primary care clinic routinely. The disorders discussed are Parkinson disease, essential tremor, restless legs syndrome, Huntington disease, drug-induced movement disorder, Wilson disease, and Tourette syndrome.
19352551##2009-4-9##Mimicry of acute cholecystitis from Wilson's disease.##We present a 33-year-old Chinese woman with Wilson's disease in whom ultrasonography and computed tomography showed gallbladder features suggestive of acute cholecystitis. Incongruence in liver function prompted further investigations with the final diagnosis of Wilson's disease, complicated by oedema of the gallbladder mimicking acute cholecystitis. The patient was subsequently treated nonoperatively, and is well on follow-up.
19329346##2008-7-27##[Acute recurrent hemolytic anemia as the first manifestation of Wilson's disease: Report of a case].##
19248187##2009-2-28##Liver disease in pregnancy.##Liver diseases in pregnancy may be categorized into liver disorders that occur only in the setting of pregnancy and liver diseases that occur coincidentally with pregnancy. Hyperemesis gravidarum, preeclampsia/eclampsia, syndrome of hemolysis, elevated liver tests and low platelets (HELLP), acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy are pregnancy-specific disorders that may cause elevations in liver tests and hepatic dysfunction. Chronic liver diseases, including cholestatic liver disease, autoimmune hepatitis, Wilson disease, and viral hepatitis may also be seen in pregnancy. Management of liver disease in pregnancy requires collaboration between obstetricians and gastroenterologists/hepatologists. Treatment of pregnancy-specific liver disorders usually involves delivery of the fetus and supportive care, whereas management of chronic liver disease in pregnancy is directed toward optimizing control of the liver disorder. Cirrhosis in the setting of pregnancy is less commonly observed but offers unique challenges for patients and practitioners. This article reviews the epidemiology, pathophysiology, diagnosis, and management of liver diseases seen in pregnancy.
19095659##2008-12-18##Dominant mutants of ceruloplasmin impair the copper loading machinery in aceruloplasminemia.##The multicopper oxidase ceruloplasmin plays a key role in iron homeostasis, and its ferroxidase activity is required to stabilize cell surface ferroportin, the only known mammalian iron exporter. Missense mutations causing the rare autosomal neurodegenerative disease aceruloplasminemia were investigated by testing their ability to prevent ferroportin degradation in rat glioma C6 cells silenced for endogenous ceruloplasmin. Most of the mutants did not complement (i.e. did not stabilize ferroportin) because of the irreversible loss of copper binding ability. Mutant R701W, which was found in a heterozygous very young patient with severe neurological problems, was unable to complement per se but did so in the presence of copper-glutathione or when the yeast copper ATPase Ccc2p was co-expressed, indicating that the protein was structurally able to bind copper but that metal loading involving the mammalian copper ATPase ATP7B was impaired. Notably, R701W exerted a dominant negative effect on wild type, and it induced the subcellular relocalization of ATP7B. Our results constitute the first evidence of "functional silencing" of ATP7B as a novel molecular defect in aceruloplasminemia. The possibility to reverse the deleterious effects of some aceruloplasminemia mutations may disclose new possible therapeutic strategies.
19146437##2009-1-17##Tracing copper-thiomolybdate complexes in a prospective treatment for Wilson's disease.##Wilson's disease is a human genetic disorder which results in copper accumulation in liver and brain. Treatments such as copper chelation therapy or dietary supplementation with zinc can ameliorate the effects of the disease, but if left untreated, it results in hepatitis, neurological complications, and death. Tetrathiomolybdate (TTM) is a promising new treatment for Wilson's disease which has been demonstrated both in an animal model and in clinical trials. X-ray absorption spectroscopy suggests that TTM acts as a novel copper chelator, forming a complex with accumulated copper in liver. We have used X-ray absorption spectroscopy and X-ray fluorescence imaging to trace the molecular form and distribution of the complex in liver and kidney of an animal model of human Wilson's disease. Our work allows new insights into metabolism of the metal complex in the diseased state.
19271449##2009-3-11##["Father would have never wanted this". Substituted judgement from family members about the treatment of Wilson disease patients].##
19141375##2009-1-15##Direct measurement of free copper in serum or plasma ultrafiltrate.##Copper is an essential element and, under conditions of overload, a toxicant. A dramatic example of copper toxicity is Wilson disease (WD), a treatable but often fatal condition that is difficult to diagnose and monitor. A method for direct measurement of free copper concentrations in serum or plasma ultrafiltrate by inductively coupled mass spectrometry was developed and validated to assist with diagnosis and monitoring WD. The method was shown to be accurate (94%-109% recoveries), linear (0.5-800 microg/dL [0.08-126 micromol/L]), and precise (coefficient of variation, < 15% over the analytic measurement range). A reference interval (0-10 microg/dL [0-1.6 micromol/L]) was determined parametrically with 137 healthy adult (20-59 years) blood donors. No statistically significant difference was observed in males (n = 69) vs females (n = 68). Free copper concentrations for patients diagnosed with WD were at least 6-fold greater than the upper limit of the reference interval before treatment but fell within the reference interval after treatment.
19033537##2008-11-25##Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B.##ATP7B is a copper-transporting P-type ATPase present predominantly in liver. In basal copper, hepatic ATP7B is in a post-trans-Golgi network (TGN) compartment where it loads cytoplasmic Cu(I) onto newly synthesized ceruloplasmin. When copper levels rise, the protein redistributes via unique vesicles to the apical periphery where it exports intracellular Cu(I) into bile. We want to understand the mechanisms regulating the copper-sensitive trafficking of ATP7B. Earlier, our laboratory reported the presence of apical targeting/TGN retention information within residues 1-63 of human ATP7B; deletion of these residues resulted in a mutant protein that was not efficiently retained in the post-TGN in low copper and constitutively trafficked to the basolateral membrane of polarized, hepatic WIF-B cells with and without copper (13). In this study, we used mutagenesis and adenovirus infection of WIF-B cells followed by confocal immunofluorescence microscopy analysis to identify the precise retention/targeting sequences in the context of full-length ATP7B. We also analyzed the expression of selected mutants in livers of copper-deficient and -loaded mice. Our combined results clearly demonstrate that nine amino acids, F(37)AFDNVGYE(45), comprise an essential apical targeting determinant for ATP7B in elevated copper and participate in the TGN retention of the protein under low-copper conditions. The signal is novel, does not require phosphorylation, and is highly conserved in approximately 24 species of ATP7B. Furthermore, N41S, which is part of the signal we identified, is the first and only Wilson disease-causing missense mutation in residues 1-63 of ATP7B. Expression of N41S-ATP7B in WIF-B cells severely disabled the targeting and retention of the protein. We present a working model of how this physiologically relevant signal might work.
19263737##2009-3-7##Wilson's disease followed by liver transplant in a 20-year-old female: considerations for bone health--case report and review of the literature.##Osteopenia and osteoporosis have a high prevalence in patients with chronic liver disease and post transplantation. We report the case of a 20-year-old female who underwent urgent liver transplant after presenting with fulminant hepatic failure secondary to Wilson's Disease. She was seen in consultation in the Osteoporosis Clinic eight months after liver transplantation with low bone-mineral density. Risks for osteoporosis in patients with chronic liver disease include hypogonadism, vitamin D deficiency and medications, and fracture rates are twice those of age-matched controls. In patients who undergo liver transplant, bone loss is more pronounced in the first year post-transplant, consistent with aggressive medical therapy, immobilization and hypogonadism secondary to immunosupressants. Wilson's disease is also known to cause bone loss independent of liver dysfunction. Evaluation of patients with Wilson's disease who have undergone transplantation is indicated for the prevention and treatment of bone loss.
19235665##2009-2-23##Chronic rejection preceded by central perivenulitis, rapidly ensuing after liver transplantation in a pediatric patient.##A 15-year-old boy who underwent liver transplantation for fulminant Wilson's disease, presented with elevated transaminases 2 months post-transplant. He had recently seroconverted from previous Epstein-Barr virus (EBV) naive status and by polymerase chain reaction (PCR) had increasing viral load copies of EBV in blood. A liver biopsy was obtained 6 weeks post-transplant, which showed isolated central perivenulitis (CP). His immunosuppresion was reduced and antiviral therapy was added with subsequent increase in liver transaminases. A second liver biopsy 6 weeks later again showed isolated CP. Subsequent further reduction in immunosuppression was followed by the appearance of portal-based moderate acute cellular rejection that was resistant to immunosuppressive treatment and rapidly evolved into ductopenic chronic rejection. This case report underlines the difficulties in interpreting isolated perivenulitis, especially in the setting of EBV seroconversion, and suggests that it may not only represent a form of acute rejection but also a predictor of rapidly progressing chronic rejection.
19152453##2009-1-20##Nonalcoholic fatty liver disease in asymptomatic Brazilian adolescents.##
19155982##2009-1-22##Long-term outcomes for 32 cases of Wilson's disease after living-donor liver transplantation.##
19007772##2008-4-3##Niemann-Pick C1 protein transports copper to the secretory compartment from late endosomes where ATP7B resides.##Wilson disease is a genetic disorder characterized by the accumulation of copper in the body by defective biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. However, copper metabolism in hepatocytes has been still unclear. Niemann-Pick disease type C (NPC) is a lipid storage disorder and the most commonly mutated gene is NPC1 and its gene product NPC1 is a late endosome protein and regulates intracellular vesicle traffic. In the present study, we induced NPC phenotype and examined the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp. The vesicle traffic was modulated using U18666A, which induces NPC phenotype, and knock down of NPC1 by RNA interference. ATP7B colocalized with the late endosome markers, but not with the trans-Golgi network markers. U18666A and NPC1 knock down decreased holo-Cp secretion to culture medium, but did not affect the secretion of other secretory proteins. Copper accumulated in the cells after the treatment with U18666A. These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via NPC1-dependent pathway and incorporated into apo-Cp to form holo-Cp.
19227635##2009-2-21##[Wilson disease to Fabry disease. Metabolic disorders diagnosed at a glance].##
19170410##2009-1-28##Bullous pemphigoid induced by penicillamine in a patient with Wilson disease.##We report a 47-year-old man with Wilson disease who developed bullous lesions on the trunk and extremities after 20 years of penicillamine treatment. The histologic and immunofluorescence findings were diagnostic of bullous pemphigoid. When penicillamine was replaced by zinc sulfate, the patient's bullous skin lesions improved rapidly. However, after 2 months of zinc sulfate treatment, the patient's skin condition remained improved but his neurologic disease became worse and penicillamine was reinstituted. Bullous lesions recurred within 1 week and the diagnosis of penicillamine-induced bullous pemphigoid was confirmed. This is the first report of penicillamine-induced bullous pemphigoid in a patient with Wilson disease.
20151006##2008-8-12##Fine motor skills disorders in the course of Wilson's disease.##
19439930##2008-10-24##A 15-year-old girl with severe hemolytic Wilson's crisis recovered without transplantation after extracorporeal circulation with the Prometheus system.##
21687048##2009-2-02##Cold comfort pharm.##In Wilson's disease copper accumulates within the basal ganglia resulting in a movement disorder. Treatment is with copper chelation. In the case described here treatment with trientene failed because the medication was stored at the incorrect temperature.
19634275##2009-7-29##[Introduction of DNA microarray in molecular diagnostics of Wilson disease].##
20662462##2010-7-29##[Wilson's disease].##Wilson's disease is an inherited disorder leading to accumulation of copper in tissues, mainly in the liver and brain. Genetic defect is in the gene coding ATPase type P (ATP7B). The inheritance is autosomal recessive. Up to now, more then 500 mutations causing Wilson's disease were described. The most frequent mutation in Central Europe is mutation H1069Q. The manifestation of Wilson's disease is usually hepatic or neurologic. Hepatic form is manifested by acute or chronic hepatitis, steatosis or cirrhosis. Neurologic involvement is manifested usually after 20 year of age by motor disturbances (tremor, disturbed speech, problems with writing), which could progress into severe extrapyramidal syndrome with tremor, rigidity, dysartria, dysfagia and muscle contracture. Diagnosis is based on clinical and laboratory examinations (neurologic symptoms, liver disease, low serum ceruloplasmin levels, elevated free copper concentration in serum, high urine copper excretion, and presence of Kayser-Fleischer rings). Confirmation of diagnosis is done by hepatic copper concentration in liver biopsy or by genetic examination. Untreated disease leads to the death of a patient. Treatment is based on chelating agents decreasing the copper content by excretion into urine (D-penicillamine, trientine) or on agents preventing absorption of copper from food (zinc, ammonium-tetrahiomolybdene). Patients with asymptomatic Wilson's disease have to be treated as well. In Czech Republic either penicillamine or zinc are used. Liver transplantation is indicated in patients with fulminant liver failure or decompensated cirrhosis. Screening in families of affected patients (all siblings) is obvious.
19710527##2009-4-19##Suicide for survival--death of infected erythrocytes as a host mechanism to survive malaria.##The pathogen of malaria, Plasmodium, enters erythrocytes and thus escapes recognition by the immune system. The pathogen induces oxidative stress to the host erythrocyte, which triggers eryptosis, the suicidal death of erythrocytes. Eryptosis is characterized by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing erythrocytes are identified by macrophages which engulf and degrade the eryptotic cells. To the extent that infected erythrocytes undergo eryptosis prior to exit of Plasmodiaand subsequent infection of other erythrocytes, the premature eryptosis may protect against malaria. Accordingly, any therapeutical intervention accelerating suicidal death of infected erythrocytes has the potential to foster elimination of infected erythrocytes, delay the development of parasitemia and favorably influence the course of malaria. Eryptosis is stimulated by a wide variety of triggers including osmotic shock, oxidative stress, energy depletion and a wide variety of xenobiotics. Diseases associated with accelerated eryptosis include sepsis, haemolytic uremic syndrome, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency and Wilson's disease. Among the known stimulators of eryptosis, paclitaxel, chlorpromazine, cyclosporine, curcumin, PGE2 and lead have indeed been shown to favourably influence the course of malaria. Moreover, sickle-cell trait, beta-thalassemia trait, glucose-6-phosphate dehydrogenase (G6PD)-deficiency and iron deficiency confer some protection against a severe course of malaria. Importantly, counteracting Plasmodia by inducing eryptosis is not expected to generate resistance of the pathogen, as the proteins involved in suicidal death of the host cell are not encoded by the pathogen and thus cannot be modified by mutations of its genes.
19817707##2009-10-13##Human metallothionein expression under normal and pathological conditions: mechanisms of gene regulation based on in silico promoter analysis.##Metallothioneins (MTs) are ubiquitous metal-binding proteins that have been highly conserved throughout evolution. Although their physiological function is not completely understood, they are involved in diverse processes including metal homeostasis and detoxification, the oxidative stress response, inflammation, and cell proliferation. Te human MT gene family consists of at least 18 isoforms, containing pseudogenes as well as genes encoding functional proteins. Most of the MT isoforms can be induced by a wide variety of substances, such as metals, cytokines, and hormones. Different cell types express discrete MT isoforms, which reflects the specifically adapted functions of MTs and a divergence in their regulation. Te aberrant expression of MTs has been described in a number of diseases, including Crohn's disease, cancer, Alzheimer's disease, amyotrophic lateral sclerosis, Menkes disease, and Wilson's disease. Therefore, a thorough understanding of MT gene regulation is imperative. To date, the transcriptional regulation of MTs has primarily been studied in mice. While only four murine MT isoforms exist, the homology between murine and human MTs allows for the evaluation of the regulatory regions in their respective promoters. Here, we review the aberrant expression of MTs in human diseases and the mechanisms that regulate MT1 expression based on an in silico evaluation of transcription factor binding sites.
20045993##2010-1-5##Genetic polymorphisms of copper- and platinum drug-efflux transporters ATP7A and ATP7B in Japanese cancer patients.##ATP7A and ATP7B are involved in cellular resistance to platinum compounds such as cisplatin. By sequencing ATP7A, 38 genetic variations, including 30 novel ones were detected from 203 Japanese cancer patients. Of these, seven nonsynonymous variations were found: novel 1030A>G (R344G), 2111A>G (Q704R), 2200C>A (Q734K), 2948C>T (T983M) and 3112G>A (V1038I) at 0.004 frequencies and known 2299G>C (V767L) and 4390A>G (I1464V) at 0.351 and 0.075 frequencies, respectively. Regarding ATP7B, 28 novel and 33 known genetic variations were detected including 13 nonsynonymous ones: novel 1258A>G (M420V), 1426G>A (A476T), and 2401A>C (T801P) were found at 0.002, 0.005, and 0.002, respectively and known 1216G>T (A406S), 1366G>C (V456L), 2495A>G (K832R), 2785A>G (I929V), 2855G>A (R952K), 2871delC (P957PfsX9), 3419T>C (V1140A), 3836A>G (D1279G), 3886G>A (D1296N) and 3889G>A (V1297I) at 0.483, 0.463, 0.387, 0.005, 0.384, 0.005, 0.387, 0.002, 0.012, and 0.015 frequencies, respectively. Linkage disequilibrium between detected variations was also analyzed. Our results would provide fundamental and useful information for genotyping ATP7A and ATP7B in the Japanese and probably other Asian populations.
17981419##2007-9-16##Imaging findings of liver involvement of Wilson's disease.##
19053885##2008-12-5##The use of copper-lowering therapy with tetrathiomolybdate in medicine.##
23105801##2009-5-8##Usefulness of ferroxidase activity of ceruloplasmin in the diagnosis of Wilson's disease.##Serum ceruloplasmin is one of the most commonly used screening tests for Wilson's disease. However immunological assays for ceruloplasmin are not recommended for diagnosis and management of Wilson's disease through calculation of free copper index. Enzymatic methods using non-physiological substrates have toxicity and stability problems, making them difficult to automate. Ferroxidase assays may be a satisfactory alternative for measuring serum ceruloplasmin. The o-dianisidine hydrochloride manual method for estimation of serum ceruloplasmin enzyme activity was compared with an automated method using the ferroxidase activity of ceruloplasmin in measurement in a double blind study in 91 consecutive patients screened for Wilson's disease. The o-dianisidine and ferroxidase methods both successfully identified 7 patients with Wilson's disease. Values for these 7 patients in the o-dianisidine and ferroxidase methods were median 5.0 (range 0-16.0 U/L) and median 45.0 (range 4-166 U/L) respectively. There were 7 other positive values (<62 U/L) with the o-diansidine method and 2 (<200 U/L) with the ferroxidase method, where WD was not confirmed. ROC curves for both methods showed area under the curve of 0.998 for o-dianisidine and 0.997 for ferroxidase. Using literature cut off values of 62 U/L and 200 U/L respectively both methods had 100% sensitivity and specificity was 91.7% (o-dianisidine) and 97.6% (ferroxidase). For the o-dianisidine assay, specificity was improved to 98.8% using a cut off of 22.5 U/L. In the 84 persons (46 adults and 38 children) in whom the diagnosis of Wilson's disease was not established, the mean value for ceruloplasmin activity by the o-dianisidine and ferroxidase methods was 124.7 ± 48.7 U/L and 571.4 ± 168.1 U/L respectively. There were no significant differences between sex or age of patients (p > 0.29). In a subsequent evaluation with 372 specimens, the Pearson correlation coefficient between the assays was 0.908, p < 0.01, slope 4.06, intercept 265.8, with the manual assay as the x-axis. The ferroxidase assay is a suitable replacement for the o-dianisidine assay in detecting patients with Wilson's disease.
19156772##2009-1-22##Clinical improvement of a patient with severe Wilson's disease after a single session of therapeutic plasma exchange.##Here, we report a case of a 17-year old female with Wilson's disease presenting with progressive Coombs' negative hemolytic anemia and hepatic cirrhosis who was treated with one session of therapeutic plasma exchange (TPE) and clinically improved. In clinical situations where multiple sessions of TPE may not be possible, the use of a single session of TPE in conjunction with conventional therapy may be of benefit in preventing further clinical deterioration.
18948065##2008-5-23##Wilson disease as a cause of liver injury in cystic fibrosis.##Cystic fibrosis-related liver disease affects approximately one third of all patients with cystic fibrosis. Initial signs of other liver diseases including the genetically determined disorders of the liver co-inherited with cystic fibrosis may be obscured by or ascribed to cystic fibrosis-related liver disease. We report a patient shown to suffer simultaneously from cystic fibrosis and hepatic Wilson disease. Our case documents that in patients with cystic fibrosis presenting with liver disease, when unusual clinical and/or laboratory abnormalities appear and fail to respond to standard therapy, a second disease, including rare inherited metabolic disorders such as the hepatic form of Wilson disease or alpha(1)-antitrypsin deficiency, should be suspected.
19888908##2009-11-6##Regulation of heme synthesis and proteasomal activity by copper: possible implications for Wilson's disease.##Wilson's disease (Wd) is a genetic disorder resulting in Cu2+ accumulation, and is caused by mutations in the ATP7B gene, the copper transporter. In vivo studies show a correlation between Cu2+ accumulation and malfunction of the heme biosynthesis pathway. In this study, we describe multiple effects of Cu2+ accumulation on heme synthesis, which, in turn, affect proteasomal activity. Cu2+ toxicity was examined in two hepatocellular carcinoma cell lines, HepG2 and Hep3B, with Hep3B cells containing an integrated hepatitis B virus genome. Exposure of HepG2 and Hep3B cells to Cu2+ inhibited the enzymes PBGD and ALAD of the heme synthesis pathway and, in parallel, upregulated heme oxygenase-1 (HO-1). Proto-porphyrin IX (PpIX) and the heme pool were reduced as a result of these processes. PpIX synthesis was found to be lower in cells expressing the mutant ATP7B (P1134P), compared to those expressing the WT enzyme. Proteasomal activity was inhibited under Cu2+ treatment in HepG2 cells; however, Cu2+ induced marked proteosomal acceleration in Hep3B cells. Under these conditions, Ub-conjugated proteins were gradually accumulated, whereas treatment with bathocuproine disulfonic acid (BCS), a Cu2+ chelator, reversed this effect. In conclusion, our data suggest that copper downregulates the heme synthesis pathway in hepatocellular cells and further reduces it in the presence of mutated ATP7B.
19026449##2008-6-3##Reactivity and kinetic studies of (NH4)2(MoS4) in acidic aqueous solution: possible relevance to the angiostatic function of the MoS4(2-) ligand.##Although addition of mineral acids to WS(4)(2-) in water is known to lead to aggregation and formation of various polynuclear thiotungstate anions, acid hydrolysis of the MoS(4)(2-) anion is reported to give mainly MoS(3) or MoS(2) as hydrolysis products. Knowledge of the resulting product(s) from such reactions has implications on the use of tetrathiomolybdate (MoS(4)(2-)) as both a potential anti-tumor drug and for the treatment of Wilson's disease. In this investigation, reaction of HCl with MoS(4)(2-) in water was monitored as a function of time. Reaction mixtures of both 1:1 and 2:1 mole ratios of the acid to MoS(4)(2-) were examined, as well as MoS(4)(2-) reactions in simulated human stomach fluids at pH of approximately 2 and 3. Monitoring by electrospray mass spectrometry (ESMS), Fourier transform infrared (FTIR), and UV-visible spectroscopy clearly has revealed the formation of complex mixtures of polynuclear thiomolybdates (Mo(2)-Mo(18)). Generally, a two-stage consecutive reaction sequence occurs. A faster stage (k=7.0-7.9 x 10(-2)min(-1)), which seems to extend to trinuclear thiomolybdate species, followed by a slower second stage (k=5.4-15.2 x 10(-4)min(-1)) to higher polynuclear thiomolybdates. Under acidic conditions (e.g. pH approximately 3) that could also mimic some human stomach fluids, and under anaerobic atmosphere where the generated hydrogen sulfide is prevented from escaping from the reaction vessel, Mo(3)S(9)(2-) predominates over an extended reaction period. In similar reactions under aerobic conditions and where the hydrogen sulfide is irretrievably lost from the reaction mixture the binuclear (Mo(2)O(a)S(10-a)(2-);a=0-3) and trinuclear (Mo(3)O(b)S(9-b)(2-);b=1-3) anions predominate.
19172127##2009-1-28##Wilson disease in children: analysis of 57 cases.##
19571475##2009-7-3##Children's toxicology from bench to bed--Liver Injury (4): Mitochondrial respiratory chain disorder and liver disease in children.##
19571474##2009-7-3##Children's toxicology from bench to bed--Liver Injury (3): Oxidative stress and anti-oxidant systems in liver of patients with Wilson disease.##The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper, which generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic anti-oxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in groups II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-SOD, and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.
20130778##2009-3-30##Regression of Hypervascular Nodules in a Patient with Wilson's Disease Awaiting Liver Transplantation.##This paper describes the regressive course over one year of hypervascular nodules in a patient with Wilson's disease. CT revealed multiple, enhancing nodules (up to 3 cm in diameter) detected in the liver in the early arterial phase after the administration of intravenous contrast material. Most of these nodules became isodense in the portal venous phase. After one year of efficient therapy combining d-penicillamine and zinc acetate, most of the nodules had disappeared, while the liver contours had become more regular. To our knowledge, the regression of large hypervascular nodules has not previously been reported in patients with Wilson's disease.
19114980##2008-12-31##Roles and mechanisms of copper transporting ATPases in cancer pathogenesis.##Copper (Cu) is an essential trace element for cell metabolism as a cofactor to many key metabolic enzymes. Numerous physiological processes rely on the adequate and timely transport of copper ions mediated by copper-transporting ATPases (Cu-ATPases), which are essential for human cell growth and development. Inherited gene mutations of ATP7A and ATP7B result in clinical diseases related to damage in the multiple organ systems. Increased expression of these genes has been recently observed in some human cancer specimens, and may be associated with tumorigenesis and chemotherapy resistance. However, underlying mechanisms of Cu-ATPases in human cancer progression and treatment are largely unknown. In this review, we summarize current progress on the copper transport system, the structural and functional properties of the Cu-ATPases, ATP7A and ATP7B, in copper homeostasis, and their roles in anti-tumor drug resistance and cancer metastasis. This review provides valuable information for clinicians and researchers who want to recognize the newest advances in this new field and identify possible lines of investigation in copper transport as important mediators in human physiology and cancer.
21305118##2009-4-16##Zinc and tetrathiomolybdate for the treatment of Wilson's disease and the potential efficacy of anticopper therapy in a wide variety of diseases.##Wilson's disease, an autosomal recessive disease of copper accumulation and copper toxicity primarily in the liver and brain, has been the engine that has driven the development of anticopper drugs. Here we first briefly review Wilson's disease, then review the four anticopper drugs used to treat Wilson's disease. We then discuss the results of therapy with anticopper drugs in Wilson's disease, with special emphasis on the newer and better drugs, zinc and tetrathiomolybdate. We then discuss new areas of anticopper therapy, lowering copper availability with tetrathiomolybdate as a therapy in fibrotic, inflammatory, and autoimmune disorders. Many of the cytokines which promote these disorders are copper dependent, and lowering copper availability lessens the activity of these cytokines, favorably influencing a variety of disease processes. Copper in the blood can be thought of as in two pools. One pool is covalently bound in ceruloplasmin, a protein containing six coppers, synthesized by the liver and secreted into the blood. Ceruloplasmin copper accounts for almost 85 to 90% of the blood copper in normal people. This copper is tightly bound and not readily available for cellular uptake and copper toxicity. The other 10-15% of copper is more loosely bound to albumin and other small molecules in the blood, and is readily and freely available to cells and available to cause copper toxicity, if this pool of copper is increased. We call this latter pool of copper "free" copper because of its more ready availability. However, it should be understood that it is not completely free, always being bound to albumin and other molecules. It is this pool of free copper that is greatly expanded in untreated Wilson's patients undergoing copper toxicity.
19557100##2009-4-8##Ceruloplasmin and superoxide dismutase (SOD1) in heterozygotes for Wilson disease: A case control study.##At the time of this study, there were five known patients with Wilson disease (WD) in Iceland. The mutation, a 7-bp deletion in exon 7 on chromosome 13 for WD, is only known in Iceland. In twenty healthy Icelandic heterozygotes for WD and their age- and gender-matched controls, copper concentration in plasma, ceruloplasmin (CP) concentration, CP oxidative activity and CP-specific oxidative activity in serum and superoxide dismutase (SOD1) activity in erythrocytes were determined. The same determinations were done on the five WD patients. There was no significant difference in these parameters between the heterozygotes and the controls, although an inclination toward lower CP determinations and higher SOD1 activity in the heterozygotes was noted. As expected the WD patients were low on the copper and CP parameters, but their SOD1 activity was within the upper normal range. In conclusion, the CP parameters and SOD1 activity are within the normal range in Icelandic heterozygotes for WD, although with a trend toward mild dyshomeostasis. This may indicate subclinical copper retention in the heterozygotes, but a bigger study group is needed to confirm this.
20098536##2010-1-26##Risperidone and Lithium for personality and behavioral changes with Wilson's Disease.##
19858010##2009-10-28##Liver transplantation for neurologic Wilson's disease: reflections on two cases within a mexican cohort.##
19722128##2009-9-2##Impact of apolipoprotein E genotypes on phenotypic expression in Turkish patients with Wilson's disease.##
19249530##2008-8-13##Feasibility of auxiliary partial living donor liver transplantation for fulminant hepatic failure as an aid for small-for-size graft: single center experience.##Auxiliary partial orthotopic liver transplantation (APOLT) or heterotopic auxiliary partial liver transplantation (HAPLT) was initially indicated for potentially reversible fulminant hepatic failure (FHF). We started auxiliary partial living donor liver transplantation (LDLT) for FHF in February 2002. Since then, 5 FHF patients (3 females and 2 males) underwent auxiliary partial LDLT: 3 cases of APOLT and 2 cases of HAPLT. All of them received a small-for-size graft: graft-to-recipient weight ratio (GRWR) < or = 1.0%. The etiologies of FHF were hepatitis B virus (HBV) in 1, Wilson's disease in 1, and unknown origin in 3 cases. Three were the acute type and 2 the subacute type of FHF. Median age was 45 years (range, 14-54 years). Blood type was identical in all cases. A left lobe graft was used in 4 instances and a right lobe graft in 1 case. Median GRWR was 0.74 (range, 0.42-0.85). Median follow-up was 42 months (range, 3 days to 70 months). Three of 5 patients (60%) were alive (at 42, 67, and 70 months) and 1 was free of immunosuppression after sufficient recovery of the native liver. Two cases succumbed: 1 at postoperative day 3 because of cytomegalovirus pneumonia and 1 at 10 months after APOLT because of sepsis. Complications were seen in all 5 patients: Relaparotomy for hemostasis in 3, decompression surgery of the abdominal cavity in 1, rehepaticojejunostomy in 1, and biliary strictures in 2 cases. Auxiliary partial LDLT may be a choice as an aid for a small-for-size graft in FHF.
19211426##2009-2-13##Aetiology of paediatric portal hypertension - experience of a tertiary care centre in South India.##The aetiological profile of paediatric portal hypertension in our hospital, a tertiary care centre in South India, showed that the commonest causes were extrahepatic portal venous obstruction (EHPVO) and cirrhosis. Wilson's disease was the most common cause of cirrhosis.
19195257##2009-2-7##Botulinum toxin in the treatment of sialorrhea.##
19197125##2009-2-7##[Clinical character and therapeutic effect of late-onset Wilson disease].##
18534902##2008-2-8##Raman, IR, UV-vis and EPR characterization of two copper dioxolene complexes derived from L-dopa and dopamine.##The anionic complexes [Cu(L(1-))3](1-), L(-)=dopasemiquinone or L-dopasemiquinone, were prepared and characterized. The complexes are stable in aqueous solution showing intense absorption bands at ca. 605 nm for Cu(II)-L-dopasemiquinone and at ca. 595 nm for Cu(II)-dopasemiquinone in the UV-vis spectra, that can be assigned to intraligand transitions. Noradrenaline and adrenaline, under the same reaction conditions, did not yield Cu-complexes, despite the bands in the UV region showing that noradrenaline and adrenaline were oxidized during the process. The complexes display a resonance Raman effect, and the most enhanced bands involve ring modes and particularly the nuCC+nuCO stretching mode at ca. 1384 cm(-1). The free radical nature of the ligands and the oxidation state of the Cu(II) were confirmed by the EPR spectra that display absorptions assigned to organic radicals with g=2.0005 and g=2.0923, and for Cu(II) with g=2.008 and g=2.0897 for L-dopasemiquinone and dopasemiquinone, respectively. The possibility that dopamine and L-dopa can form stable and aqueous-soluble copper complexes at neutral pH, whereas noradrenaline and adrenaline cannot, may be important in understanding how Cu(II)-dopamine crosses the cellular membrane as proposed in the literature to explain the role of copper in Wilson disease.
18974300##2008-10-30##Copper-induced translocation of the Wilson disease protein ATP7B independent of Murr1/COMMD1 and Rab7.##Wilson disease is a genetic disorder of copper metabolism. Impaired biliary excretion results in a gradual accumulation of copper, which leads to severe disease. The specific gene defect lies in the Wilson disease protein, ATP7B, a copper-transporting ATPase that is highly active in hepatocytes. The two major functions of ATP7B in the liver are the copper loading of ceruloplasmin in the Golgi apparatus, and the excretion of excess copper into the bile. In response to elevated copper levels, ATP7B shows a unique intracellular trafficking pattern that is required for copper excretion from the Golgi apparatus into dispersed vesicles. We analyzed the translocation of ATP7B by both confocal microscopy and RNA interference, testing current models that suggest the involvement of Murr1/COMMD1 and Rab7 in this pathway. We found that although the ATP7B translocation is conserved among nonhepatic cell lines, there is no co-localization with Murr1/COMMD1 or the Rab marker proteins of the endolysosomal system. Consistent with this finding, the translocation of ATP7B was not impaired by the depletion of either Murr1/COMMD1 or Rab7, or by a dominant-negative Rab7 mutant. In conclusion, our data suggest that the translocation of ATP7B takes place independently of Rab7-regulated endosomal traffic events. Murr1/COMMD1 plays a role in a later step of the copper excretion pathway but is not involved in the translocation of the Wilson disease protein.
19021531##2008-11-22##Atp7b-/- mice as a model for studies of Wilson's disease.##Wilson's disease is a severe human disorder of copper homoeostasis. The disease is associated with various mutations in the ATP7B gene that encodes a copper-transporting ATPase, and a massive accumulation of copper in the liver and several other tissues. The most frequent disease manifestations include a wide spectrum of liver pathologies as well as neurological and psychiatric abnormalities. A combination of copper chelators and zinc therapy has been used to prevent disease progression; however, accurate and timely diagnosis of the disease remains challenging. Similarly, side effects of treatments are common. To understand better the biochemical and cellular basis of Wilson's disease, several animal models have been developed. This review focuses on genetically engineered Atp7b(-/-) mice and describes the properties of these knockout animals, insights into the disease progression generated using Atp7b(-/-) mice, as well as advantages and limitations of Atp7b(-/-) mice as an experimental model for Wilson's disease.
19219216##2009-2-17##Transcranial sonography in movement disorders.##
19042985##2008-12-2##Newborn screening for Wilson disease: does liquid chromatography-tandem mass spectrometry provide the solution?##
18845768##2008-10-9##Tryptic peptide analysis of ceruloplasmin in dried blood spots using liquid chromatography-tandem mass spectrometry: application to newborn screening.##
18760268##2008-3-14##Rapid diagnosis of Wilson disease by a 28-mutation panel: real-time amplification refractory mutation system in diagnosing acute Wilsonian liver failure.##
19338486##2009-4-3##Effect of D-penicillamine on liver fibrosis and inflammation in Wilson disease.##
19067230##2008-7-11##Long-standing mild hypertransaminasaemia caused by congenital disorder of glycosylation (CDG) type IIx.##A 32 year-old asymptomatic male came to our attention with a 21-year history, documented elsewhere, of puzzling increases in his serum transaminase level. At first, very low serum ceruloplasmin level suggested Wilson disease. Two liver biopsies showed mild portal inflammation, steatosis and mild fibrosis. Further investigation revealed low levels of the glycoproteins AT III and clotting factor XI, leading to a diagnosis of congenital disorder of glycosylation (CDG) type II. Further studies as to the cause of this 'apparently new' CDG, are ongoing. On the basis of our data and a literature review, we suggest that subjects with asymptomatic hypertransaminasaemia be screened for CDG.
19014823##2007-12-27##Hypothyroidism and dyshormonogenesis induced by D-penicillamine in children with Wilson's disease and healthy infants born to a mother with Wilson's disease.##Two siblings born to a mother with Wilson's disease, who was taking D-penicillamine, developed transient goitrous hypothyroidism. A prospective evaluation of 5 patients with Wilson's disease taking and not taking D-penicillamine for as long as 9.5 years showed subclinical hypothyroidism. D-penicillamine probably inhibited thyroperoxidase activity in utero in healthy infants and during childhood in patients with Wilson's disease.
19131782##2009-1-10##Acute Wilson disease associated with E beta-thalassemia.##We report on an 11-year-old girl with concomitant Ebeta thalassemia (EbetaT) and Wilson disease (WD). She was diagnosed with EbetaT at 2 years of age, but the coexistence of WD could only be established at 11 years. The diagnosis of the later was based on the clinical presentation of hepatitis and severe Coomb's negative hemolytic anemia, coupled with laboratory evidence of WD. To our knowledge, this is the first report on the cooccurrence of EbetaT and WD. As both the conditions are associated with variable degrees of hemolysis, WD in the setting of EbetaT may remain masked and consequently remain undiagnosed for a long time. Sudden, severe hemolysis in a patient of thalassemia may be explained by the coexistence of additional pathology, in this case WD.
18839167##2008-7-22##'Face of the giant panda' sign in Wilson disease.##
19100498##2008-1-18##Auxiliary partial orthotopic living donor liver transplantation in a patient with Wilson's disease: a case report.##A patient with end-stage liver cirrhosis and neurological disorder due to Wilson's disease (WD) underwent auxiliary partial orthotopic liver transplantation (APOLT) using a living donor. He first visited our institute complaining of hand tremor, which was diagnosed as WD. Despite medical therapy, hepatic impairment progressed toward portal hypertensive complications. He was considered a suitable candidate for living donor-related liver transplantation. However, because of the impossibility of mobilization of the lateral section due to severe splenomegaly at the time of the recipient operation, we performed an APOLT using a right lobe graft. After transplantation, he suffered hepatic vein stenosis and biliary stenosis, receiving interventional therapy. The remnant native liver volume decreased, and the volume of the graft increased serially after transplantation. At the time of reporting, the patient had a normal working life with normal serum ceruloplasmin level and without neurologic problems at 26 months posttransplantation. APOLT may be a therapeutic option for patients with WD.
18692069##2008-5-7##Stability and ATP binding of the nucleotide-binding domain of the Wilson disease protein: effect of the common H1069Q mutation.##Perturbation of the human copper-transporter Wilson disease protein (ATP7B) causes intracellular copper accumulation and severe pathology, known as Wilson disease (WD). Several WD mutations are clustered within the nucleotide-binding subdomain (N-domain), including the most common mutation, H1069Q. To gain insight into the biophysical behavior of the N-domain under normal and disease conditions, we have characterized wild-type and H1069Q recombinant N-domains in vitro and in silico. The mutant has only twofold lower ATP affinity compared to that of the wild-type N-domain. Both proteins unfold in an apparent two-state reaction at 20 degrees C and ATP stabilizes the folded state. The thermal unfolding reactions are irreversible and, for the same scan rate, the wild-type protein is more resistant to perturbation than the mutant. For both proteins, ATP increases the activation barrier towards thermal denaturation. Molecular dynamics simulations identify specific differences in both ATP orientation and protein structure that can explain the absence of catalytic activity for the mutant N-domain. Taken together, our results provide biophysical characteristics that may be general to N-domains in other P(1B)-ATPases as well as identify changes that may be responsible for the H1069Q WD phenotype in vivo.
18827576##2008-10-2##The risks of free copper in the body and the development of useful anticopper drugs.##
19061688##2008-4-30##Delusional disorder and alcohol abuse in a patient with Wilson's disease.##
18282208##2008-2-15##Long term follow-up of glomerular and tubular functions in liver transplanted patients with Wilson's disease.##The aim of this study was to determine the long term outcome of renal glomerular and tubular functions in children receiving an LT for WD. Renal functions were examined in nine children with WD before and long after LT and compared with those of nine liver transplanted children with hepatic diseases other than WD. The duration of follow-up was at least two yr for both groups. GFR, fractional TRP and tubular maximum rate of phosphate reabsorption in relation to GFR (TP/GFR) as well as daily protein and Ca excretion were studied in both groups before and after LT. Pretransplant mean GFR, TRP and TP/GFR were significantly lower in the study group than the controls. A significant increase in the post-transplant TRP and TP/GFR was observed in the study group and the difference between the groups disappeared during the long term follow-up. Urinary protein excretion decreased in both groups after LT. Tubular dysfunction is frequent in patients with WD. LT for hepatic failure secondary to WD is a lifesaving procedure correcting the underlying hepatic defect as well as renal defects.
19209540##2009-2-13##[Wilson's disease in paediatric age: diagnosis and treatment. Recent advances].##Wilson's disease is an autosomal-recessive disorder caused by mutation in the ATP7B gene, with resultant impairment of biliary excretion of copper. Subsequent copper accumulation, first in the liver but ultimately in the brain and other tissues, produces clinical manifestations that may include hepatic, neurological, psychiatric, ophthalmological, and other derangements. This article discusses the recent progress in diagnosis and treatment of this disease in paediatric age.
19198096##2009-2-10##[Diagnosis and treatment of dystonia].##Diagnosis of dystonia is not difficult by recognizing the pattern of clinical presentation. Dopa-responsive dystonia (DRD) and Wilson disease are important in differential diagnosis because of their specific treatment. The most common are the focal dystonias, including blepharospasm and spasmodic torticollis. Dystonia comprises mobile involuntary movements and abnormal postures, the latter is better described as hypokinetic disorder. The pathogenesis of dystonia is now being clarified, and includes abnormal neuroplasticity caused by the relative excess of dopamine in the matrix compartment of the striatum, the possible primary lesion being the striosome. In a dopa-responsive dystonia model, dopaminergic projection is more deficient to the striosome than to the matrix, which could produce imbalance between the direct versus. indirect pathway activities. The treatment options include trihexyphenidyl, minor tranquilizers, botulinum toxin injection, and deep brain stimulation.
19010295##2008-8-8##Efficacy of tetrathiomolybdate in a mouse model of multiple sclerosis.##Tetrathiomolybdate (TM) is a potent anticopper drug developed for Wilson's disease. We have found multiple efficacious results from decreasing copper levels with TM in mouse models of disease, using serum Cp as a surrogate marker of copper status and targeting Cp values of 20% to 50% of baseline. We have found efficacious results of TM therapy in mouse models of fibrosis; inflammation; damage from exogenous agents, such as acetaminophen and doxorubicin; and immune-modulated diseases, such as concanavalin A hepatitis, collagen II-induced arthritis, and the non-obese diabetic (NOD) mouse model of type I diabetes. In the current study, we examine TM efficacy in the EAE mouse model of multiple sclerosis (MS). We find that clinical scores of neurologic damage are significantly inhibited by TM therapy, whether therapy is started before MS-inducing antigen administration or after symptoms from antigen administration develop. Furthermore, we find that experimental autoimmune encephalomyelitis (EAE) treatment produces a marked increase of oxidant damage, as measured by urine isoprostane levels, and TM suppresses these isoprostane increases strongly and significantly. Finally, we find marked increases of inflammatory and immune-related cytokines in this model, and we find that TM strongly and significantly suppresses these increases.
18759342##2008-9-2##Abnormal antisaccades and smooth pursuit eye movements in patients with Wilson's disease.##Neurological symptoms in Wilson's disease (WD) may include oculomotor abnormalities. However, to date, eye movements in WD patients were rarely investigated and the data concerning this issue are sparse. The purpose of this study was to evaluate reflexive and voluntary eye movements in WD patients. We examined horizontal saccadic and smooth pursuit eye movements using infra-red oculography in 50 WD patients, including 29 neurologically symptomatic (WDn) and 21 asymptomatic ones (WDa), and in 29 healthy controls. We found statistically significant increase in mean antisaccadic latency (378 ms) and in mean antisaccadic error rate (22.5) in the WDn group, when compared with WDa group (317 ms and 9.1, respectively) and controls (318 ms and 9.7, respectively). In contrast, there were no statistically significant differences in mean latency of prosaccades and in size of the gap effect. Patients with neurological manifestations had also abnormal smooth pursuit-increased number of saccadic intrusions (mean: 8.6) and decreased gain (mean: 0.69) comparing with WDa patients (4.1 and 0.83, respectively) and controls (2.2 and 0.91, respectively). The data suggest that WD is associated both with impairment of voluntary control of saccades and with disturbed smooth pursuit eye movements while reflexive saccades seem to be preserved.
19080264##2008-12-17##Pediatric liver transplantation in 31 consecutive children.##
18855987##2008-10-16##High frequency of the c.3207C>A (p.H1069Q) mutation in ATP7B gene of Lithuanian patients with hepatic presentation of Wilson's disease.##
18821941##2008-9-30##Do cytokines have any role in Wilson's disease?##The aim of this study was to determine the serum cytokine levels in patients with Wilson's disease (WD) and correlate with phenotype, therapeutic status and laboratory data. In this cross-sectional study, the serum levels of cytokines were estimated in 34 patients (M : F, 23 : 11; drug-naive, 11) with WD (mean age: 13.8 +/- 8.6 and 19.6 +/- 9.03 years) and compared with 30 controls. The following serum cytokines were analysed using enzyme-linked immunosorbent assay: (i) tumour necrosis factor (TNF)-alpha, (ii) interferon (IFN)-gamma, (iii) interleukin (IL)-2, (iv) IL-6 and (v) IL-4. Serum TNF-alpha (P < 0.001), IFN-gamma (P = 0.005) and IL-6 (P < 0.001) were detectable in WD compared with controls. However, serum level elevation of IL-4 (P = 0.49) and IL-2 (P = 0.11), although detectable compared with controls, was statistically insignificant. The disease severity and therapeutic status did not affect the cytokines. Presence of anaemia, leucopenia, thrombocytopenia, pancytopenia and hepatic dysfunction did not influence cytokine levels. There was a significant negative correlation between IL-6 and ceruloplasmin (P = 0.04) and anti-inflammatory cytokines (IL-4) and copper level (P = 0.01). Serum cytokines, both proinflammatory and anti-inflammatory subtypes, were elevated significantly in patients with WD. Further studies would establish their role in its pathogenesis.
18774359##2008-2-12##Large (>or=2 cm) non-hypervascular nodules depicted on MRI in the cirrhotic liver: fate and implications.##
19062534##2008-12-10##From clinical and biochemical to molecular genetic diagnosis of Wilson disease in Latvia.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism characterized by hepatic and/or neurological damage. More than 300 mutations in the gene ATP7B causing this defect have been reported. The data on correlation between WD patient genotypes and clinical presentation are controversial. In this paper the results of ATP7B mutation analysis by testing for mutation H1069Q and direct sequencing of six exons together with the clinical data of 40 Latvian WD patients are presented. Two previously described and two novel mutations as well as one previously reported polymorphism were identified. The H1069Q mutation was present at 52.5% of the disease alleles. One individual among 157 healthy Latvians was also found to be a mutation H1069Q carrier. The estimated incidence of WD in Latvia is approximately 1 in 25600. Wide clinical variability was observed among individuals with the same ATP7B genotype, thus supporting the suggestion that modifying factors play an additional role in the pathogenesis of WD. An algorithm for the diagnosis of WD, including testing for mutation H1069Q, is recommended for the populations where mutation H1069Q accounts for 50% of WD alleles or more.
18564142##2008-6-28##Living donor liver transplantation for fulminant hepatic failure.##
18821595##2008-9-30##Rapid diagnosis of Wilson disease in acute liver failure: no more waiting for the ceruloplasmin level?##
18798336##2008-9-18##Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests.##
18846616##2008-10-11##Gene symbol: ATP7B. Disease: Wilson disease.##
19196945##2009-2-7##Mania in a patient with Wilson's disease awaiting liver transplant.##
19196936##2009-2-7##Treating mania in Wilson's disease with lithium.##
18825711##2008-10-1##Use of the molecular adsorbents recirculating system as a treatment for acute decompensated Wilson disease.##Acute decompensated Wilson disease presenting as fulminant liver failure is a life-threatening condition for which liver transplantation is the ultimate treatment. It is listed as a status 1 indication according to the United Network for Organ Sharing classification. A massive amount of copper released during the attack induces hemolytic anemia and acute renal failure. Conventional chelating therapy attempting to remove copper from the patient is not satisfactory because there is inadequate time for these drugs to take action and patients are usually oliguric. The Molecular Adsorbents Recirculating System (MARS) is a form of modified dialysis that removes putative albumin-bound toxins associated with liver failure. It is believed that extracorporeal albumin dialysate absorbs the circulating copper molecules that are trapped in the patient's circulation. We report 2 patients with acute decompensated Wilson disease treated with MARS. In the first case, the patient was started on MARS once conventional treatment failed. A significant amount of copper was removed from her circulatory system, and her condition stabilized afterwards. The treatment gained her extra time, and she was eventually bridged to liver transplantation. In the second case, the patient was started on MARS treatment early in the course of his illness, and his condition soon stabilized after the treatment. He was able to return to his home country for liver transplantation. In both cases, MARS was used as a means of preventing deterioration rather than salvaging devastation. In conclusion, MARS may confer benefits to patients with acute decompensated Wilson disease if it is started early in the course of illness.
18805369##2008-3-10##Cystic white-matter changes in childhood Wilson's disease.##Altered signals in magnetic resonance imaging are present in most symptomatic patients with neurologic manifestations of Wilson's disease. The changes primarily involve the basal ganglia, but they can be diverse and can involve a host of other structures. We describe a 12-year-old boy with Wilson's disease who manifested prominent white-matter cystic changes. These changes can cause diagnostic confusion, and may also present prognostic implications.
19017841##2008-11-20##Effect of a different caeruloplasmin assay method on the relationship between serum copper and caeruloplasmin.##
18929872##2008-10-22##Successful super-small-for-size graft liver transplantation by decompression of portal hypertension via splenectomy and construction of a mesocaval shunt: a case report.##We performed a successful super-small-for-size graft liver transplantation by decompressing portal hypertension via splenectomy and a mesocaval shunt. A 46-year-old woman with Child-Pugh class C liver cirrhosis associated with Wilson's disease underwent a living donor liver transplantation (LDLT). The donor had an anomalous portal vein, hepatic vein, and bile duct, so we had to use the right lateral segment for the graft. Preoperative computed tomographic (CT) volumetry showed the volume of this area to be 433 mL; graft-to-recipient weight ratio (GRWR) was 0.72; and graft-to-standard liver volume (GV/SLV) was 39.0%. However, the real volume of the resected right lateral segment was 281 g; GRWR was 0.47; and GV/SLV was 25.3%--a super-small-for-size graft. After implantation, congestion of the small graft was severe due to excessive portal hypertension. Therefore, we tried decompressing the portal vein. First, we performed splenectomy which reduced the portal pressure which remained excessive. Second, a mesocaval shunt was constructed decreasing the portal pressure from 38 to 30 cm H2O. Additionally, we initiated continuous portal injection of prostaglandin E1. The postoperative course was not smooth, but the general status slowly recovered. Over 25 cm H2O of portal hypertension was observed until postoperative day 21 when it improved. At last, the recipient was discharged on postoperative day 156. Accurate preoperative CT volumetry is important to obtain sufficient graft volume. Our case may be one of the smallest-for-size grafts that was successfully transplanted. Management of excessive portal hypertension is important for LDLT, especially using a small-for-size graft. Splenectomy and construction of a mesocaval shunt may be useful strategies to decompress the portal vein.
19472820##2009-5-29##[Celiac disease associated to Wilson disease].##
18841564##2008-10-9##[Mutation screening and prenatal diagnosis of Wilson's disease by denature high performance liquid chromatography].##
18841562##2008-10-9##[Rapid detection of common ATP7B mutations in Wilson disease by high resolution melting analysis].##
18477063##2008-5-12##Children with chronic organ failure possibly ending in organ transplantation: a survey in an Italian region of 5,000,000 inhabitants.##
18779307##2008-9-10##Liver as a key organ in the supply, storage, and excretion of copper.##The liver plays an important role in the disposition of copper. Most dietary copper passes through the liver where it can be used for protein and energy production or excreted through the biliary route. Because copper is a prooxidant, its intracellular handling is tightly managed. In Wilson disease, in which synthesis of ceruloplasmin and biliary excretion of copper are defective, copper accumulates in the liver and leads to progressive liver damage. The features of hepatic Wilson disease are highly variable. The spectrum of liver disease includes mild inflammation, fatty liver, an autoimmune disorder, and cirrhosis. Wilson disease thus resembles drug hepatotoxicity, and indeed it can be regarded as a prototypic example of endogenous hepatotoxicity. Biomarkers developed for detecting drug hepatotoxicity may be relevant to Wilson disease. Biomarkers developed through metalloproteomics, which for copper seeks to define a set of proteins that have copper-binding capacity, or through genomic studies may also be relevant to Wilson disease and other disorders of copper handling, whether copper is deficient or overloaded.
18779305##2008-9-10##Relevance of animal models for understanding mammalian copper homeostasis.##As a trace element, copper has a crucial role in mammalian metabolism, but it can be toxic in excess. The importance of a balanced copper homeostasis is illustrated by several copper-associated disorders in man, such as Menkes and Wilson disease, and in a wide variety of animal models (eg, mice, dogs, and sheep). Proteins involved in controlling copper metabolism have been well studied in yeast and in vitro. Recently, naturally occurring mutants and transgenic mouse models have been used to study the physiologic role of copper transporters in copper homeostasis. We discuss the most common mammalian animal models used to study copper-related diseases, evaluate what these model systems have recently shown about copper metabolism, and discuss the importance of these models for identifying specific and sensitive biomarkers associated with copper status in the near future.
18779302##2008-9-10##Role of copper transporters in copper homeostasis.##Copper is a redox active metal that is essential for biological function. Copper is potentially toxic; thus, its homeostasis is carefully regulated through a system of protein transporters. Copper is taken up across the lumen surface of the small intestinal microvilli as cuprous ion by Ctr1. Cupric ion may also be taken up, but those processes are less well understood. Within the cell, intestinal as well as others, copper is escorted to specific compartments by metallochaperones. One, CCS, donates copper to superoxide dismutase. Another, COX17, delivers copper to additional chaperones within the mitochondria for synthesis of cytochrome c oxidase. A third chaperone, Atox1, delivers copper to the secretory pathway by docking with 2 P-type ATPases. One, ATP7A, is the protein nonfunctional in Menkes disease. This protein is required for cuproenzyme biosynthesis, and in the enterocyte it is required for copper efflux to portal blood. The second, ATP7B, predominantly expressed in liver, is required for copper metallation of ceruloplasmin and biliary copper excretion. Mutations in ATP7B lead to Wilson disease. Additional intracellular hepatic copper-binding proteins COMMD1 (copper metabolism MURR1 domain) and XIAP (X-linked inhibitor of apoptosis protein) may also be required for excretion. Other proteins involved in copper homeostasis may include metallothionein and amyloid precursor protein. Plasma protein transport of copper from the intestine to liver and in systemic circulation probably includes both albumin and alpha2-macroglobulin. Changes in the expression of copper "transporters" may be useful to monitor copper status of humans, provided a suitable cell type can be sampled.
18030470##2007-7-10##Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines.##
18652531##2008-7-26##Estimation of Wilson's disease incidence and carrier frequency in the Korean population by screening ATP7B major mutations in newborn filter papers using the SYBR green intercalator method based on the amplification refractory mutation system.##Wilson's disease (WD), an autosomal recessive disorder of copper transport, is one of the most common inherited metabolic disorders in Korea. Despite its frequency, the incidence and carrier frequency of WD has not yet been estimated in the Korean population. We therefore screened for four major missense mutations (p.Arg778Leu, p.Ala874Val, p.Leu1083Phe, and p.Asn1270Ser) of the ATP7B gene in 476 newborn filter papers by real-time multiplex PCR and melting curve analysis using the SYBR Green intercalator method based on the amplification refractory mutation system test. Newborn filter papers with abnormal melting curves were subjected to subsequent sequence analysis. Three mutated alleles, one p.Arg778Leu and two p.Ala874Val, were detected among the 476 newborn filter papers (952 alleles). The carrier frequency and incidence of WD in the Korean population were determined as 1 in 88.2 and 30,778, respectively, by reversely calculating based on the Hardy-Weinberg law.
18673401##2008-7-25##Localization of the Wilson disease protein in murine intestine.##Wilson disease is an inherited disorder of human copper metabolism, characterized by gradual accumulation of copper in tissues, predominantly liver and brain. The gene defect lies in the Wilson disease protein ATP7B, a copper transporting ATPase highly active in hepatocytes. In the liver, ATP7B is essential for excretion of excess copper into the bile and for copper loading of ceruloplasmin in the Golgi apparatus. The extrahepatic role of ATP7B is not yet completely understood. We analysed the intestinal expression of ATP7B in mice using RT-PCR, Western blot and indirect immunofluorescence. We found abundant expression of ATP7B in stomach and small intestine, but not in colon. Using confocal microscopy we demonstrate a Golgi localization of ATP7B in enterocytes. In response to elevated copper, the Wilson disease protein shows an intracellular trafficking pattern in the intestinal polarized cell line CaCo-2, moving away from the Golgi apparatus to dispersed vesicles. This suggests a role for intestinal ATP7B in sequestration of copper in intracellular vesicles for maintenance of copper homeostasis in the enterocyte. In conclusion, the expression of ATP7B in the small intestine might represent an additional regulatory mechanism to fine-tune intestinal copper absorption.
18556226##2007-10-16##Estimation of free copper ion concentrations in blood serum using T(1) relaxation rates.##The water proton relaxation rate constant R(1)=1/T(1) (at 60 MHz) of blood serum is substantially increased by the presence of free Cu2+ ions at concentrations above normal physiological levels. Addition of chelating agents to serum containing paramagnetic Cu2+ nulls this effect. This was demonstrated by looking at the effect of adding a chelating agent-D-penicillamine (D-PEN) to CuSO4 and CuCl2 aqueous solutions as well as to rabbit blood serum. We propose that the measurement of water proton spin-lattice relaxation rate constants before and after chelation may be used as an alternative approach for monitoring the presence of free copper ions in blood serum. This method may be used in the diagnosis of some diseases (leukaemia, liver diseases and particularly Wilson's disease) because, in contrast to conventional methods like spectrophotometry which records the total number of both bound and free ions, the proton relaxation technique is sensitive solely to free paramagnetic ions dissolved in blood serum. The change in R(1) upon chelation was found to be less than 0.06 s(-1) for serum from healthy subjects but greater than 0.06 s(-1) for serum from untreated Wilson's patients.
18728530##2008-8-30##High incidence and allelic homogeneity of Wilson disease in 2 isolated populations: a prerequisite for efficient disease prevention programs.##
18809983##2008-9-24##Value of molecular analysis of Wilson's disease in the absence of tissue copper deposits: a novel ATP7B mutation in an adult patient.##Wilson's disease (WD) is a disorder of copper metabolism leading to copper accumulation in the liver and in extrahepatic organs, such as brain and cornea. We present a patient with liver disease who did not fulfil the biochemical criteria for WD. Mutational analysis was necessary to make the diagnosis and show a new mutation. Our case supports the use of mutation analysis in cases with unclear liver disease and suggests that the spectrum of WD is broader than currently assumed.
18809982##2008-9-24##Haemolytic anaemia as a first sign of Wilson's disease.##A 19-year-old female presented with haemolytic anaemia and subsequently developed liver failure. This raised suspicion of Wilson's disease, which was confirmed by Kayser-Fleischer rings, a low ceruloplasmin level, raised 24-hour urinary copper excretion and two mutations in the 'Wilson gene'. She was successfully treated with D-penicillamine and zinc. In young patients with unexplained haemolysis, liver dysfunction or neuro-psychiatric symptoms, Wilson's disease should be considered.
18772711##2008-9-6##Corneal copper deposition secondary to oral contraceptives.##
18650808##2008-1-04##Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes.##Copper is a cofactor for many cellular enzymes and transporters. It can be loaded onto secreted and endomembrane cuproproteins by translocation from the cytosol into membrane-bound organelles by ATP7A or ATP7B transporters, the genes for which are mutated in the copper imbalance syndromes Menkes disease and Wilson disease, respectively. Endomembrane cuproproteins are thought to incorporate copper stably on transit through the trans-Golgi network, in which ATP7A accumulates by dynamic cycling through early endocytic compartments. Here we show that the pigment-cell-specific cuproenzyme tyrosinase acquires copper only transiently and inefficiently within the trans-Golgi network of mouse melanocytes. To catalyse melanin synthesis, tyrosinase is subsequently reloaded with copper within specialized organelles called melanosomes. Copper is supplied to melanosomes by ATP7A, a cohort of which localizes to melanosomes in a biogenesis of lysosome-related organelles complex-1 (BLOC-1)-dependent manner. These results indicate that cell-type-specific localization of a metal transporter is required to sustain metallation of an endomembrane cuproenzyme, providing a mechanism for exquisite spatial control of metalloenzyme activity. Moreover, because BLOC-1 subunits are mutated in subtypes of the genetic disease Hermansky-Pudlak syndrome, these results also show that defects in copper transporter localization contribute to hypopigmentation, and hence perhaps other systemic defects, in Hermansky-Pudlak syndrome.
18562314##2008-6-18##Intermediate phosphorylation reactions in the mechanism of ATP utilization by the copper ATPase (CopA) of Thermotoga maritima.##Recombinant and purified Thermotoga maritima CopA sustains ATPase velocity of 1.78-2.73 micromol/mg/min in the presence of Cu+ (pH 6, 60 degrees C) and 0.03-0.08 micromol/mg/min in the absence of Cu+. High levels of enzyme phosphorylation are obtained by utilization of [gamma-32P]ATP in the absence of Cu+. This phosphoenzyme decays at a much slower rate than observed with Cu.E1 approximately P. In fact, the phosphoenzyme is reduced to much lower steady state levels upon addition of Cu+, due to rapid hydrolytic cleavage. Negligible ATPase turnover is sustained by CopA following deletion of its N-metal binding domain (DeltaNMBD) or mutation of NMBD cysteines (CXXC). Nevertheless, high levels of phosphoenzyme are obtained by utilization of [gamma-3)P]ATP by the DeltaNMBD and CXXC mutants, with no effect of Cu+ either on its formation or hydrolytic cleavage. Phosphoenzyme formation (E2P) can also be obtained by utilization of Pi, and this reaction is inhibited by Cu+ (E2 to E1 transition) even in the DeltaNMBD mutant, evidently due to Cu+ binding at a (transport) site other than the NMBD. E2P undergoes hydrolytic cleavage faster in DeltaNMBD and slower in CXXC mutant. We propose that Cu+ binding to the NMBD is required to produce an "active" conformation of CopA, whereby additional Cu+ bound to an alternate (transmembrane transport) site initiates faster cycles including formation of Cu.E1 approximately P, followed by the E1 approximately P to E2-P conformational transition and hydrolytic cleavage of phosphate. An H479Q mutation (analogous to one found in Wilson disease) renders CopA unable to utilize ATP, whereas phosphorylation by Pi is retained.
18546325##2008-6-12##MR spectroscopy in monitoring the treatment of Wilson's disease patients.##The aim of this study was to determine the effectiveness of brain proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring therapy in Wilson's disease (WD) patients. Voxels were located in the globus pallidus (right, left). We followed 17 newly diagnosed WD cases for 1-year period. During this observation period, 6 neurological and 9 hepatic patients improved, while 2 neurological patients deteriorated. The pretreatment (1)H-MRS analysis showed a statistically significant lower level of mI/Cr, NAA/Cr, and higher Lip/Cr in all WD patients with improvement compared with controls. In patients with hepatic signs, a statistically significant increase of mI/Cr and Glx/Cr was observed in the second (1 year posttreatment) (1)H-MRS. In patients with neurological improvement after treatment in the follow-up (1)H-MRS, a statistically significant increase of NAA/Cr was noted. During neurological deterioration, a decrease of Glx/Cr and NAA/Cr was seen, in contrast to another neurologically impaired patient with liver failure exacerbation, where a decrease of mI/Cr and increase of Glx/Cr was observed. The alternations of NAA/Cr ratio in neurologically impaired patients and mI/Cr and Glx/Cr in patients with liver failure could be a sensitive marker of the clinical recovery and deterioration in those WD patients. (1)H-MRS is a technique that can be used for accurate monitoring of treatment efficacy in WD patients.
18685091##2008-8-6##Conserved residues modulate copper release in human copper chaperone Atox1.##It is unclear how the human copper (Cu) chaperone Atox1 delivers Cu to metal-binding domains of Wilson and Menkes disease proteins in the cytoplasm. To begin to address this problem, we have characterized Cu(I) release from wild-type Atox1 and two point mutants (Met(10)Ala and Lys(60)Ala). The dynamics of Cu(I) displacement from holo-Atox1 were measured by using the Cu(I) chelator bicinchonic acid (BCA) as a metal acceptor. BCA removes Cu(I) from Atox1 in a three-step process involving the bimolecular formation of an initial Atox1-Cu-BCA complex followed by dissociation of Atox1 and the binding of a second BCA to generate apo-Atox1 and Cu-BCA(2). Both mutants lose Cu(I) more readily than wild-type Atox1 because of more rapid and facile displacement of the protein from the Atox1-Cu-BCA intermediate by the second BCA. Remarkably, Cu(I) uptake from solution by BCA is much slower than the transfer from holo-Atox1, presumably because of slow dissociation of DTT-Cu complexes. These results suggest that Cu chaperones play a key role in making Cu(I) rapidly accessible to substrates and that the activated protein-metal-chelator complex may kinetically mimic the ternary chaperone-metal-target complex involved in Cu(I) transfer in vivo.
18698682##2008-8-14##Genotype phenotype correlation in Wilson's disease within families--a report on four south Indian families.##
20103920##2010-1-28##Syndrome-causing mutations in Werner syndrome.##Complete loss of function in the WRN: RecQ3 DNA/RNA helicase gene causes Werner Syndrome (WS). WS patients with genetic instability manifest an early onset of age-related diseases including diabetes mellitus (DM), osteoporosis, atherosclerosis, and malignancy as well as early death. In 1,420 patients, WS was reported to be associated with chromosomal abnormality syndrome and other genetic diseases including Klinefelter syndrome in 2 patients, retinitis pigmentosa in 3, Wilson's disease in 1, xeroderma pigmentosum in 3, and porokeratosis Mibelli in 1. These clinical findings may support the concept of genetic instability in WS.
18556333##2008-6-12##Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects.##
18683094##2008-8-7##Tetrathiomolybdate, a copper chelator for the treatment of Wilson disease, pulmonary fibrosis and other indications.##Tetrathiomolybdate (TTM) is a copper chelator that has also demonstrated antiangiogenic, antifibrogenic and anti-inflammatory actions in preclinical studies. The drug, from the University of Michigan was licensed to Pipex Pharmaceuticals Inc for development for several indications; development of the drug for cancer was later licensed to Attenuon LLC. In a phase III clinical trial, TTM stabilized neurological function in patients with Wilson disease, causing significant recovery in 81% of patients at 3 years post initiation of therapy; a second phase III trial was ongoing at the time of publication. A phase I/II clinical trial demonstrated the efficacy of TTM in patients with idiopathic pulmonary fibrosis, and led the FDA to grant TTM Orphan Drug status for this disease. Several phase II clinical trials had also been completed in patients with various cancers, and revealed mixed efficacy. TTM was also assessed in a phase I clinical trial for age-related macular degeneration, but the results reported from the trial were negative; no further development has occurred for this indication. TTM was assessed for the treatment of psoriasis in a phase II clinical trial, but no data have been reported. At the time of publication, phase II and phase III clinical trials were ongoing in patients with Alzheimer's disease and primary biliary cirrhosis, respectively. The most common clinical side effects observed for TTM over the range of indications have been anemia, neutropenia, leukopenia and transaminase elevations. These side effects were generally resolved with either a dose adjustment or temporary suspension of the dosing regimen. TTM is predicted to most likely find a niche in the therapy of Wilson disease, for which current treatment options are limited.
18591939##2008-6-30##The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes.##Copper is an essential element and an integral component of various enzymes. However, excess copper is neurotoxic and has been implicated in the pathogenesis of Wilson's disease, Alzheimer's disease, prion conditions, and other disorders. Although mechanisms of copper neurotoxicity are not fully understood, copper is known to cause oxidative stress and mitochondrial dysfunction. As oxidative stress is an important factor in the induction of the mitochondrial permeability transition (mPT), we determined whether mPT plays a role in copper-induced neural cell injury. Cultured astrocytes and neurons were treated with 20 microM copper and mPT was measured by changes in the cyclosporin A (CsA)-sensitive inner mitochondrial membrane potential (Delta Psi m), employing the potentiometric dye TMRE. In astrocytes, copper caused a 36% decrease in the Delta Psi m at 12 h, which decreased further to 48% by 24 h and remained at that level for at least 72 h. Cobalt quenching of calcein fluorescence as a measure of mPT similarly displayed a 45% decrease at 24 h. Pretreatment with antioxidants significantly blocked the copper-induced mPT by 48-75%. Copper (24 h) also caused a 30% reduction in ATP in astrocytes, which was completely blocked by CsA. Copper caused death (42%) in astrocytes by 48 h, which was reduced by antioxidants (35-60%) and CsA (41%). In contrast to astrocytes, copper did not induce mPT in neurons. Instead, it caused early and extensive death with a concomitant reduction (63%) in ATP by 14 h. Neuronal death was prevented by antioxidants and nitric oxide synthase inhibitors but not by CsA. Copper increased protein tyrosine nitration in both astrocytes and neurons. These studies indicate that mPT, and oxidative and nitrosative stress represent major factors in copper-induced toxicity in astrocytes, whereas oxidative and nitrosative stress appears to play a major role in neuronal injury.
18636185##2008-7-19##Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) correlates with cisplatin resistance in human non-small cell lung cancer xenografts.##Copper-transporting P-type adenosine triphosphatase (ATP7B) is reportedly associated with platinum drug resistance in various solid carcinomas. However, the impact of ATP7B on platinum drug resistance in non-small cell lung cancer (NSCLC) remains unknown. We investigated ATP7B expression in nine human NSCLC xenografts using real-time polymerase chain reaction (PCR) and immunohistochemistry, and examined the relationship between the expression level of ATP7B and in vivo cisplatin (CDDP) sensitivity. ATP7B mRNA expression was significantly correlated with in vivo cisplatin sensitivity [coefficient of determination (R(2))=0.949, p=0.005]. ATP7B protein was detected in the nine xenografts. The ATP7B protein expression level was comparable to that of ATP7B mRNA. ATP7B mRNA and protein expression levels in the CDDP-resistant xenografts were significantly higher than those in the CDDP-sensitive xenografts (p=0.0389 and p=0.0357, respectively, Mann-Whitney U test). These results suggest that ATP7B is a CDDP-resistance marker in human NSCLC xenografts in vivo.
18417262##2008-1-5##Multidisciplinary approach of organic catatonia in children and adolescents may improve treatment decision making.##Catatonia is an infrequent but severe condition in young people. Organic diseases may be associated and need to be investigated though no specific recommendations and guidelines are available. We extensively reviewed the literature of all the cases of organic catatonia in children and adolescents from January 1969 to June 2007. We screened socio-demographic characteristics, organic diagnosis, clinical characteristics and treatment. We found 38 cases of children and adolescents with catatonia due to an organic condition. The catatonic syndrome occurred in 21 (57%) females and 16 (43%) males. The mean age of patients was 14.5 years (+/-3.39) [range=7-18 years], and three died from their condition. The organic conditions included infectious diseases (N=10), neurological conditions (N=10), toxic induced states (N=12) and genetic conditions including inborn errors of metabolism (N=6). The onset was dominantly acute, and the clinical presentation most frequently stuporous. Although benzodiazepines were recommended as primary symptomatic treatment, they were rarely prescribed. In several cases, therapeutic approach was related to organic cause (e.g., plasma exchange in lupus erythematosus; copper chelators in Wilson's disease). Based on this review and on our own experience of catatonia in youth, we proposed a consensual and multidisciplinary diagnostic strategy to help practitioners to identify underlying organic diseases.
18942896##2008-10-24##[Clinical presentation, diagnosis, and long-term outcome of 29 patients with Wilson's disease].##
18942895##2008-10-24##[Wilson's disease--a rare thought present condition].##
19086167##2008-12-17##Long-term follow-up of patients with acute liver failure of indeterminate aetiology.##
17572118##2007-3-3##Polymorphisms in canine ATP7B: candidate modifier of copper toxicosis in the Bedlington terrier.##A COMMD1(MURR1) deletion has been reported as the cause of copper toxicosis (CT) in Bedlington terriers. Recent studies identified Bedlington terriers with copper accumulation without homozygous COMMD1 deletions. Wilson disease in humans is a copper storage disorder similar to CT caused by mutations in ATP7B, and COMMD1 has been shown to interact with the ATP7B protein. ATP7B may act as a modifier in CT, allowing for copper accumulation in Bedlington terriers with one deletion or other variations in COMMD1. In this study, ATP7B was cloned and sequence analysis conducted in a subset of Bedlington terriers from a pedigree that does not show complete association between the COMMD1 deletion and CT. Eleven polymorphisms, two in the coding region, were identified in the Bedlington terrier ATP7B gene. However, these are not unique to the Bedlington terrier and pedigree analysis suggests that ATP7B is not a modifier of COMMD1 in this subset of dogs.
18637198##2008-2-08##Wilson protein expression, copper excretion and sweat production in sweat glands of Wilson disease patients and controls.##
18558714##2008-6-18##Metal binding domains 3 and 4 of the Wilson disease protein: solution structure and interaction with the copper(I) chaperone HAH1.##The Wilson disease protein or ATP7B is a P 1B-type ATPase involved in human copper homeostasis. The extended N-terminus of ATP7B protrudes into the cytosol and contains six Cu(I) binding domains. This report presents the NMR structure of the polypeptide consisting of soluble Cu(I) binding domains 3 and 4. The two domains exhibit ferredoxin-like folds, are linked by a flexible loop, and act independently of one another. Domains 3 and 4 tend to aggregate in a concentration-dependent manner involving nonspecific intermolecular interactions. Both domains can be loaded with Cu(I) when provided as an acetonitrile complex or by the chaperone HAH1. HAH1 forms a 70% complex with domain 4 that is in fast exchange with the free protein in solution. The ability of HAH1 to form a complex only with some domains of ATP7B is an interesting property of this class of proteins and may have a signaling role in the function of the ATPases.
18627307##2008-7-17##In vitro differentiation of reprogrammed murine somatic cells into hepatic precursor cells.##Recently, a new approach to reprogram somatic cells into pluripotent stem cells was shown by fusion of somatic cells with embryonic stem (ES) cells, which results in a tetraploid karyotype. Normal hepatocytes are often polyploid, so we decided to investigate the differentiation potential of fusion hybrids into hepatic cells. We chose toxic milk mice (a model of Wilson's disease) and performed initial transplantation experiments using this potential cell therapy approach. Mononuclear bone marrow cells from Rosa26 mice were fused with OG2 (Oct4-GFP transgenic) ES cells. Unfused ES cells were eliminated by selection with G418 for OG2-Rosa26 hybrids and fusion-derived colonies could be subcloned. Using an endodermal differentiation protocol, hepatic precursor cells could be generated. After FACS depletion of contaminating Oct4-GFP-positive cells, the hepatic precursor cells were transplanted into immunosuppressed toxic milk mice by intrasplenic injection. However, five out of eight mice showed teratoma formation within 3-6 weeks after transplantation in the spleen and liver. In conclusion, a hepatic precursor cell type was achieved from mononuclear bone marrow cell-ES cell hybrids and preliminary transplantation experiments confirmed engraftment, but also showed teratoma formation, which needs to be excluded by using more stringent purification strategies.
18593893##2008-7-3##Single-cell transcription site activation predicts chemotherapy response in human colorectal tumors.##Candidate gene and pathway approaches, and unbiased gene expression profiling, have identified marker signatures predictive of tumor phenotypes, such as drug sensitivity and invasive or metastatic potential. However, application of such information to evaluation of tumors in the clinic is limited by cell heterogeneity in the tumor. We have developed a novel method of fluorescence in situ hybridization (FISH) that can detect transcriptional activation of individual genes at their site in single cells in the interphase nucleus. A major obstacle in the treatment of colorectal cancer is relative insensitivity to the chemotherapeutic agent 5-Fluorouracil (5-FU). Here, we have developed a sensitive approach to predict relative sensitivity of colorectal cancer cells to 5-FU, using FISH with probes targeted to nascent mRNAs to measure the number of individual cells with active transcription sites for a panel of candidate genes. These results reveal that the transcriptional status of four key genes, thymidylate synthase (TYMS), MORF-related gene X (MRGX), Bcl2-antagonist/killer (BAK), and ATPase, Cu(2+) transporting beta polypeptide (ATP7B), can accurately predict response to 5-FU. As proof of principle, we show that this transcriptional profile is predictive of response to 5-FU in a small number of patient colon tumor tissues. This approach provides a novel ability to identify and characterize unique minor cell populations in the tumor that may exhibit relative resistance to chemotherapy.
18560753##2008-6-19##Early effects of copper accumulation on methionine metabolism.##Wilson's disease is characterized by longterm hepatic accumulation of copper leading to liver disease with reduction of S-adenosylmethionine synthesis. However, the initial changes in this pathway remain unknown and constitute the objective of the present study. Using the Long Evans Cinnamon rat model, early alterations were detected in the mRNA and protein levels, as well as in the activities of several enzymes of the methionine cycle. Notably, the main change was a redox-mediated 80% decrease in the mRNA levels of the methionine adenosyltransferase regulatory subunit as compared to the control group. Moreover, changes in S-adenosylmethionine, S-adenosylhomocysteine, methionine and glutathione levels were also observed. In addition, in vitro experiments show that copper affects the activity and folding of methionine adenosyltransferase catalytic subunits. Taken together, these observations indicate that early copper accumulation alters methionine metabolism with a pattern distinct from that described previously for other liver diseases.
18840558##2008-10-9##Deparaffination time: a crucial point in histochemical detection of tissue copper.##The search for a sensitive histochemical method for revealing tissue copper has been the object of many workers in the past. In spite of multiple methods available, the occurrence in clinical practice of negative histochemical stains, even in cases with high copper levels demonstrated by quantitative methods is very high.This study was aimed at verifying the role of technical variations in the sensitivity of the Timm method and, in particular, the role of the dewaxing time of paraffin sections. To this end, 15 liver specimens, 10 from patients affected by Wilson's disease and 5 newborn livers were fixed in 10% formalin, paraffin embedded and routinaly processed. Four 4-micron sections from each case were rinsed in xylene for 10, 20, 60 min, and for 24 hrs. All sections were stained with Timm's method. In 13 out of the 15 liver biopsies utilized in this study, the sensitivity of Timm's method in revealing copper deposits in liver cells appeared to be dependent on the dewaxing time. In two other cases, reactivity of copper granules to Timm solution did not change significantly with the different deparaffination times. The best results were obtained by rinsing sections in xylene for 24 hrs, the worst in sections treated with xylen for 10 minutes. In particular, in five cases of Wilson's disease, Timm stain applied to sections following ten minutes of xylene were completely negative, while copper granules were clearly evidenced in the same section following an overnight bath in xylene. Our data show that an overnight bath of paraffin sections in xylene may completely change the sensitivity of Timm stain in revealing copper deposits in the liver, relaunching copper histochemistry in the diagnosis of copper-related liver diseases.
17944925##2007-10-18##ATP7B antisense oligodeoxynucleotides increase the cisplatin sensitivity of human ovarian cancer cell line SKOV3ipl.##The objective of this study was to investigate the effect of ATP7B antisense oligodeoxynucleotides (ASODNs) on regulating the sensitivity to cisplatin in ovarian carcinoma cell line SKOV3ip1. The ATP7B ASODNs and the corresponding sense oligodeoxynucleotide (SODN) as control were transfected into SKOV3ip1 cells by lipofectamine-2000. The changes of ATP7B were detected by reverse transcription-polymerase chain reaction, flow cytometry, and Western blotting. The survival rate of the SKOV3ip1 cells was assessed by MTT assay. Compared with nontransfected cell, the transfer of ASODN/lipofectin (LF) into SKOV3ip1 cells resulted in (1) 73.70% and 48.30% reduction of ATP7B in messenger RNA and protein, respectively, (2) an obviously decreased intracellular fluorescence intensity from 79.42 to 50.87 (P < 0.01), and (3) a decreased IC(50) value for cisplatin from 126.63 to 80.90 micromol/L (P < 0.01), while no significant changes were detected for groups treated with SODN/LF and LF only. ASODN transfection can inhibit the expression of ATP7B and increase the cisplatin sensitivity in SKOV3ip1 cells.
18626182##2008-7-16##Kayser-Fleischer ring.##Kayser-Fleischer (K-F) ring seen in Wilson's disease (WD) is due to copper deposition in the Descemet's membrane in the sclero-corneal junction. Although believed to be pathognomic of WD, it may be seen in many other hepatic conditions and intraocular copper-containing foreign bodies. The K-F ring detected in pre-symptomatic cases of WD may lead to speedy diagnosis and early management. Co-relation of K-F ring in WD to the disease severity, disappearance with successful treatment, reappearance with non-compliant treatment may aid in optimum management of WD. The importance of K-F ring detection in first-degree relatives of the index case cannot be over-emphasized.
18424137##2007-12-31##Early and presymptomatic detection of Wilson's disease at the mandatory 3-year-old medical health care examination in Hokkaido Prefecture with the use of a novel automated urinary ceruloplasmin assay.##Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) accumulation leading to liver and/or brain damage. Oral chelating agents and diet are effective in treating WND. However, once irreversible damage has occurred, the effect of treatment is diminished and the patient's quality of life is compromised. For these reasons an effective method for screening has been needed for early detection of presymptomatic patients. We conducted an early and presymptomatic detection of WND using a novel automated assay of ceruloplasmin (Cp) concentration in urine and selected the mandatory medical health care examination for 3-year-old children in Hokkaido Prefecture (the largest administrative division in Japan) as a sampling point. We measured urinary Cp concentrations in 11,362 children using an immunological latex agglutination assay kit developed by us. Among these children we identified a positive case with markedly reduced urinary Cp concentration. Detailed medical examination provided no clinical manifestations to support the diagnosis of WND, although serum Cp and Cu levels were remarkably low in this case. Therefore, we analyzed the WND gene in order to confirm the diagnosis. Sequence analysis revealed that the case was compound heterozygous for the WND gene mutations 2871del.C and D1296N. According to the Ferenci scoring system for WND diagnosis, the case was established as a WND patient at the presymptomatic stage. Consequently, the patient has maintained a good quality of life under medical treatment with polaprezinc administration to date. Our investigation suggests that the screening system for WND using the automated urinary assay at the mandatory medical health care examination for 3-year-old children is a noninvasive and efficient method for the early and presymptomatic diagnosis of WND.
18839617##2008-10-9##[Hyperprolactinaemia--like symptoms in Wilson's disease].##Wilson's disease is a rare genetic disorder of copper metabolism with a hepatic or neurological presentation. Wilson's disease may occur under a variety of clinical conditions. The complex clinical presentation causes that the diagnosis rests on a high index of suspicion. We present an atypical case of this disorder in a 22-year-old woman, in whom initial clinical picture (oligomenorrhea/amenorrhea symptoms and galactorrhea) suggested the presence of prolactinoma or the other forms of hyperprolactinaemia. After the diagnosis was established and zinc sulphate treatment implemented, her clinical status improved considerably. The present report suggests that Wilson's disease should be taken into account in a differential diagnosis of galactorrhea of an unknown origin and in patients with hyperprolactinaemia-like symptoms when prolactin level is within the normal limits.
18626543##2008-7-16##Determination of liver enzymes, serum ceruloplasmin and urine copper in parents of children with Wilson's disease.##
18565219##2008-2-01##Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells.##
18565211##2007-11-16##Hereditary alpha-1-antitrypsin deficiency and its clinical consequences.##Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.
18686645##2008-8-9##Wilson's disease in Taiwan.##Wilson's disease (WD) has been studied in Taiwan since 1960s. The study can be divided into three periods: (1) The first period was 1960s, represented by the work of Dr. JB Tu who worked in the U.S. Naval Medical Research Unit No. 2 (NAMRU-2); (2) The second period was 1970s, represented by the work of Dr. ML Leu who also worked in NAMRU-2. During these two periods, d-penicillamine was introduced to Taiwan via NAMRU-2, primarily as study drug; and (3) The third period was 1980s and afterwards. Tu and Leu reported the clinical manifestations, tissue concentrations of copper, and therapeutic effects of d-penicillamine including cupriuresis, reduction of copper content in tissues, and prognosis. Our studies after 1980s included clinical manifestations, evoked potentials to detect the extent of CNS involvement, effect of superimposed hepatitis B infection on clinical manifestations and prognosis, and WD with cerebral white matter involvement. The present review highlights above investigations.
17934856##2007-4-29##Serum copper, ceruloplasmin and 24-h urine copper evaluations in celiac patients.##The aim of the study is to evaluate the serum copper, ceruloplasmin and 24-h urine copper levels in celiac patients. Serum copper, ceruloplasmin and 24-h urine measurements were evaluated in patients with celiac (n = 32), Crohn's (n = 25), Wilson's (n = 11) and in a healthy group (n = 35). Serum and 24-h urine zinc levels, AST, ALT, BUN, creatinine, iron, hemoglobin, hematocrit, lymphocyte, sedimentation and CRP levels were also measured. Results were evaluated statistically and significance was accepted as meaningful if P < 0.05. In celiacs, levels of urine copper were high (52 +/- 29 microg/day, P < 0.000) but serum copper was the same as in controls (105 +/- 16 microg/dl, P < 0.158). High urinary copper of celiacs were coming out in women (56 +/- 30 microg/day) and in man (33 +/- 17 microg/day, P < 0.115). Most celiacs were female (P < 0.001). Serum copper and ceruloplasmin levels in all groups were higher in women than in men and this was meaningful for serum copper in the control group (P < 0.045) and for ceruloplasmin in Crohn's (P < 0.055) and control groups (P < 0.031). Serum (70 +/- 14 microg/dl, P < 0.000) and urine zinc levels (25 +/- 15 microg/dl, P < 0.039) of celiacs were low. Ceruloplasmin levels were higher in celiacs (337 +/- 64 U/1) and Crohn's patients (366 +/- 47 U/l, P < 0.000). Correlations observed in the groups of celiac (P < 0.029) and Crohn's (P < 0.024), celiac and Wilson's (P < 0.001) and Crohn's and Wilson's (P < 0.001) between the ceruloplasmin and 24-h urine copper parameters. AST and ALT levels were higher in celiac and Wilson's patients than in Crohn's patients and controls. Mean CRP levels were significantly higher in Crohn's than others. Lymphocyte counts were meaningfully higher in celiacs. Statistically, while mean iron, hemoglobulin and hematocrit levels of celiac and Crohn groups were meaningfully lower than the normal and Wilson's group, it was similar in Wilson's and the control group. Serum copper (85 +/- 26 microg/dl, P < 0.158) and ceruloplasmin (219 +/- 83 U/l, P < 0.001) levels were low and 24-h urine copper levels were high (415 +/- 346 microg/day) in Wilson's group. Increased urinary loss may be another cause of copper deficiency in female celiacs besides malabsorption and this topic needs more investigation. Increased urinary copper levels in celiac women should not always be regarded as a diagnosis of Wilson's disease.
18284630##2008-2-12##Hematological manifestations of copper deficiency: a retrospective review.##Copper deficiency is an established cause of hematological abnormalities but is frequently misdiagnosed. Copper deficiency can present as a combination of hematological and neurological abnormalities and it may masquerade as a myelodysplastic syndrome. We reviewed the records of patients with hypocupremia and hematologic abnormalities identified between 1970 and 2005. Patients with hypocupremia unrelated to copper deficiency (e.g. Wilson's disease) were excluded. Forty patients with copper deficiency and hematological abnormalities were identified. Ten patients (25%) had undergone bariatric (weight reduction) surgery and an additional 14 patients (35%) had undergone surgery on the gastrointestinal tract, most commonly gastric resection. In 12 cases, no cause for copper deficiency was identified. Anemia and neutropenia were the most common hematologic abnormalities identified and the majority of the patients also had neurologic findings, most commonly due to myeloneuropathy. Abnormalities observed on bone marrow examination including vacuoles in myeloid precursors, iron-containing plasma cells, a decrease in granulocyte precursors and ring sideroblasts may be valuable clues to the diagnosis. Copper deficiency is an uncommon but very treatable cause of hematologic abnormalities.
21904522##2011-9-10##Wilson disease and hepatocellular carcinoma.##
21904521##2011-9-10##Hepatocellular Carcinoma in Wilson Disease-related Liver Cirrhosis.##
18506894##2008-5-29##Diagnosis and treatment of Wilson disease: an update.##
18822621##2008-10-1##Transjugular liver biopsy using Tru-cut biopsy needle: KEM experience.##
18991198##2008-11-7##Wilson's disease: appreciable improvement of sub-cortical white matter abnormalities after copper chelating treatment: five years follow-up.##Severe sub-cortical white matter abnormalities are unusual features in Wilson's disease and are reported to be poorly or not responsive to copper chelating therapy or to be worsened by it. We report on a 12-year-old boy with Wilson's disease and extensive sub-cortical white matter involvement. After five years of copper chelating therapy, an appreciable improvement of these lesions was obtained. The physiopathology of these unusual cerebral white matter abnormalities is discussed.
18299897##2007-7-24##Single pass albumin dialysis (SPAD) in fulminant Wilsonian liver failure: a case report.##Since fulminant Wilsonian liver failure has an extremely poor prognosis, the use of a liver support system that can bridge patients to liver transplant is life saving. We report here the case of a 17-year-old female who presented with fulminant Wilsonian liver failure and intravascular hemolysis. With the subsequent development of encephalopathy and oliguria, single pass albumin dialysis (SPAD) was initiated for 5 days to augment copper removal. Continuous venovenous hemodialysis (CVVHD) was performed using the PRISMA machine, with a blood flow of 100 ml/min and a dialysate flow of 2 L/h for 8 h, then 1 L/h. A 5% albumin dialysate was made by exchanging 1 L of 25% albumin for 1 L of Hemosol BO in a 5-L bag. Single pass albumin dialysis resulted in reductions in serum copper (154 to 59 microg/dL), conjugated bilirubin (37 to 23 mg/dL), lactate dehydrogenase (1305 to 729 units/L), and creatinine (1.1 to 0.9 mg/dL) as well as reduced blood transfusion requirements. Cessation of SPAD was followed by three plasmapheresis treatments for further copper removal. We conclude that SPAD is potentially an effective treatment in fulminant Wilson disease with hemolysis but that it should be used in combination with chelation to optimize the removal of copper.
18402634##2008-4-12##Mania as the first manifestation of Wilson's disease.##
18371106##2007-3-25##Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease.##Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism that is caused by mutations in the ATP7B gene. To date, more than 300 mutations have been described in this gene. Molecular diagnostics of WD utilizes restriction enzyme digestion, multiplex ligation-dependent probe amplification or a direct sequencing of the whole gene. To simplify and speed up the screening of ATP7B mutations, we have developed a genotyping microarray for the simultaneous detection of 87 mutations and 17 polymorphisms in the ATP7B gene based on the arrayed primer extension reaction. The patient's DNA is amplified in four multiplex polymerase chain reactions, fragmented products are annealed to arrayed primers spotted on a chip, which enables DNA polymerase extension reactions with fluorescently labeled dideoxynucleotides. The Wilson microarray was validated by screening 97 previously genetically confirmed WD patients. In total, we detected 43 mutations and 15 polymorphisms that represent a majority of the common mutations occurring in the Czech and Slovak populations. All screened sequence variants were detected with 100% accuracy. The Wilson chip appears to be a rapid, sensitive and cost-effective tool, representing the prototype of a disease chip that facilitates and speeds up the screening of potential WD patients.
18408455##2008-4-15##Inherited metabolic disease of the liver.##
18437637##2008-5-28##[Morphological magnetic resonance imaging: its value for the diagnosis of neurodegenerative diseases].##Magnetic resonance imaging (MRI) plays an important role in differentiating idiopathic Parkinson's disease (PD) from its atypical forms. Causes like chronic vascular disease and normal-pressure hydrocephalus are easily visualized. Furthermore, specific atrophy patterns can be found with multi-system atrophies, corticobasal degeneration and progressive supranuclear palsy. In addition the review also deals with specific imaging criteria of other neurodegenerative disorders, such as Wilson's disease, neurodegeneration with iron accumulation in the brain and Huntington's chorea. MRI is of minor importance for differentiating Alzheimer's disease from frontotemporal dementia or dementia with Lewy bodies. However, specific patterns are found in cerebral amyloid angiopathy and prion diseases..
18564443##2008-6-20##Neurological deterioration during treatment in Wilson's disease: question.##
18299419##2008-2-25##Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis.##Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilson's disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle alpha-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-alpha and TGF-beta1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.
18688737##2008-1-29##Quantitative relationship between mutated amino-acid sequence of human copper-transporting ATPases and their related diseases.##Copper-transporting ATPase 1 and 2 (ATP7A and ATP7B) are two highly homologous P-type copper ATPase exporters. Mutations in ATP7A can lead to Menkes disease which is an X-linked disorder of copper deficiency. Mutations in ATP7B can cause Wilson disease which is an autosomal recessive disorder of copper toxicity. In this study, we attempt to build a quantitative relationship between mutated ATPase and Menkes/Wilson disease. First, we use the amino-acid distribution probability as a measure to quantify the difference in ATPase before and after mutation. Second, we use the cross-impact analysis to define the quantitative relationship between mutant ATPase protein and Menkes/Wilson disease, and compute various probabilities. Finally, we use the Bayesian equation to determine the probability that Menkes/Wilson disease is diagnosed under a mutation. The results show (i) the vast majority of mutations lead to the amino-acid distribution probability increase in mutant ATP7As and decrease in ATP7Bs, and (ii) the probability that a mutation causes Menkes/Wilson disease is about nine tenth. Thus we provide a way to use the descriptively probabilistic method to couple the mutation with its clinical outcome after quantifying mutations in proteins.
18452122##2008-5-3##Cholestatic liver injury associated with whey protein and creatine supplements.##We present a case of acute cholestatic liver injury associated with the combination of whey protein and creatine supplements. The difficulty of diagnosing drug-induced liver injury is emphasized. The patient is a healthy, 27-year-old man who presented with painless jaundice. He had no occupational exposures to solvents, was not taking prescription medications, and did not use recreational drugs or alcohol. He was an enthusiastic weight-lifter and had been taking creatine for 8 to 9 months and whey protein supplements for 4 weeks prior to the development of symptoms. Laboratory tests revealed elevated total bilirubin (54.7 mg/dL) and alkaline phosphatase (436 U/L), minimally elevated transaminases, and a creatinine of 3.1 mg/dL. Serologic work-up was negative for viral hepatitis and autoimmune liver disease, and Wilson's disease was ruled out. Magnetic resonance cholangiopancreatogram was unremarkable, but a liver biopsy showed marked cholestasis with ductular proliferation. He had dramatic clinical improvement with intravenous fluids and discontinuation of the nutritional supplements. In patients with acute liver injury, clinicians should inquire about dietary supplement usage and consider immediate discontinuation of all unnecessary products. We describe a case of profound jaundice related to a commonly used and reportedly safe combination of such supplements.
18452115##2008-5-3##Acute liver failure in children.##Acute liver failure (ALF) in children differs from that observed in adults in both the etiologic spectrum and the clinical picture. Children, particularly very young ones, do not demonstrate classical features of encephalopathy and the definition of ALF has been revised to include patients with advanced coagulopathy, regardless of mental status. A significant number of these children will go on to require transplant or die. Etiologies vary by age with metabolic and infectious diseases prominent in the first year of life and acetaminophen overdose and Wilson's disease occurring in adolescents. In almost 50% of cases, however, the child has an indeterminate cause for ALF. Management requires a multidisciplinary approach and is directed at establishing the etiology where possible and monitoring, anticipating, and managing the multisystem complications that occur in children with ALF. Overall, short-term outcomes are better in children than adults but are dependent upon the degree of encephalopathy and diagnosis.
18661763##2008-7-30##Analysis of renal impairment in children with Wilson's disease.##
18311837##2008-3-4##Late onset Wilson's disease: therapeutic implications.##The clinical symptoms of Wilson's disease (WD) usually develop between 3 and 40 years of age and include signs of liver and/or neurologic and psychiatric disease. We report on an 84-year-old woman with WD. Despite the absence of treatment, the only symptom she presented with, until the age of 74 years, was Kayser-Fleisher rings. At the age of 74, she developed slightly abnormal liver function. This case raises the following issues: (a) Should WD be considered in all patients of all ages who manifest signs related to the disease? (b) Are ATP7B mutations fully penetrant? (c) Should all patients diagnosed presymptomatically receive anticopper therapy?
18416466##2008-4-18##Analysis of the human Atox 1 homologue in Wilson patients.##
18181205##2008-1-9##Neurological presentation of Wilson's disease in a patient after liver transplantation.##We report of a 32-year-old man who showed dystonic symptoms within few days after liver transplantation (LT). The clinical, biochemical, and, finally, genetic evaluation confirmed Wilson's disease diagnosis in this patient. We suspect that extrapyramidal signs in this case could be a result of acute brain injury because of the massive copper release from liver to the circulation just before and during LT.
18194834##2007-12-6##A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: inhibition of NF-kappaB?##The liver is susceptible to chronic damage through exposure to a variety of toxins (e.g. alcohol) and viruses (e.g. hepatitis C). Obesity, autoimmune diseases (e.g. autoimmune hepatitis) and a variety of genetic diseases (e.g. Wilson's disease) also lead to chronic liver damage. This damage results in scarring fibrogenesis, structural disruption and functional impairment of the organ. Recent work suggests that there is cross-talk between the PXR and NF-kappaB pathways. This cross-talk may explain the observation that PXR activators inhibit liver fibrosis in in vitro and in vivo animal models of the disease. This reveiw will focus on the two transcription factors and their potential interaction.
19338202##2009-4-3##[A remarkable case of diagnostic difficulties in chronic hepatic pathology caused by a metabolic disorder (Wilson's disease)--evaluation of medical management].##Wilson's disease is a rare genetic disorder. It is characterized by excessive copper deposits--mainly in parenchymal organs--leading to their damage and serious dysfunction. Because of its uncommonness, slow and insidious course and diversified clinical manifestation, diagnosing the condition is not easy, even for experienced physicians. As it is indicated by medical practice, such a situation may occur even in tertiary care centers, which have at their disposal extensive and highly specialist diagnostic tools and vast clinical experience in diagnosing such diseases. As an example, the authors present a case of a 38-year-old man, suffering from Wilson's disease, who was misdiagnosed and treated for another metabolic disease. Although the presented case was difficult and diagnostically complex, it should be emphasized that a diagnostic error led to inappropriate therapeutic decisions and in consequence delayed proper treatment.
18222167##2007-7-4##Delivery of the Cu-transporting ATPase ATP7B to the plasma membrane in Xenopus oocytes.##Cu-transporting ATPase ATP7B (Wilson disease protein) is essential for the maintenance of intracellular copper concentration. In hepatocytes, ATP7B is required for copper excretion, which is thought to occur via a transient delivery of the ATP7B- and copper-containing vesicles to the apical membrane. The currently available experimental systems do not allow analysis of ATP7B at the cell surface. Using epitope insertion, we identified an extracellular loop into which the HA-epitope can be introduced without inhibiting ATP7B activity. The HA-tagged ATP7B was expressed in Xenopus oocytes and the presence of ATP7B at the plasma membrane was demonstrated by electron microscopy, freeze-fracture experiments, and surface luminescence measurements in intact cells. Neither the deletion of the entire N-terminal copper-binding domain nor the inactivating mutation of catalytic Asp1027 affected delivery to the plasma membrane of oocytes. In contrast, surface targeting was decreased for the ATP7B variants with mutations in the ATP-binding site or the intra-membrane copper-binding site, suggesting that ligand-stabilized conformation(s) are important for ATP7B trafficking. The developed system provides significant advantages for studies that require access to both sides of ATP7B in the membrane.
17987273##2006-5-23##Liver ischemia and ischemia-reperfusion induces and trafficks the multi-specific metal transporter Atp7b to bile duct canaliculi: possible preferential transport of iron into bile.##Both Atp7b (Wilson disease gene) and Atp7a (Menkes disease gene) have been reported to be trafficked by copper. Atp7b is trafficked to the bile duct canaliculi and Atp7a to the plasma membrane. Whether or not liver ischemia or ischemia-reperfusion modulates Atp7b expression and trafficking has not been reported. In this study, we report for the first time that the multi-specific metal transporter Atp7b is significantly induced and trafficked by both liver ischemia alone and liver ischemia-reperfusion, as judged by immunohistochemistry and Western blot analyses. Although hepatocytes also stained for Atp7b, localized intense staining of Atp7b was found on bile duct canaliculi. Inductive coupled plasma-mass spectrometry analysis of bile copper, iron, zinc, and manganese found a corresponding significant increase in biliary iron. In our attempt to determine if the increased biliary iron transport observed may be a result of altered bile flow, lysosomal trafficking, or glutathione biliary transport, we measured bile flow, bile acid phosphatase activity, and glutathione content. No significant difference was found in bile flow, bile acid phosphatase activity, and glutathione, between control livers and livers subjected to ischemia-reperfusion. Thus, we conclude that liver ischemia and ischemia-reperfusion induction and trafficking Atp7b to the bile duct canaliculi may contribute to preferential iron transport into bile.
18180918##2007-8-7##Brain MRI and SPECT in the diagnosis of early neurological involvement in Wilson's disease.##
18403153##2007-10-15##Long-term results of liver transplantation for Wilson's disease.##
18395105##2008-4-9##Could ATP7B export Cu(I) at the tight junctions and the apical membrane?##
18395099##2007-10-10##ATP7B copper-regulated traffic and association with the tight junctions: copper excretion into the bile.##
18203200##2008-1-19##Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system.##ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. A total of 11 missense variants of ATP7B, originally identified in WND patients, were examined for their capacity to functionally complement a yeast mutant strain in which the yeast gene ortholog, CCC2, was disrupted. Solution structures of ATP7B domains were used to predict the effects of each variant on ATP7B structure. Three variants lie within the copper-binding domain and eight within the ATP-binding domain of ATP7B. All three ATP7B variants within the copper-binding domain and four within the ATP-binding domain showed full complementation of the yeast ccc2 phenotype. For the remaining four located in the ATP-binding domain, p.Glu1064Lys and p.Val1106Asp were unable to complement the yeast ccc2 high-affinity iron uptake deficiency phenotype, apparently due to mislocalization and/or change in conformation of the variant protein. p.Leu1083Phe exhibited a temperature-sensitive phenotype with partial complementation at 30 degrees C and a severe deficit at 37 degrees C. p.Met1169Val only partially complemented the ccc2 phenotype at 30 degrees C and 37 degrees C. Therefore, four variant positions were identified as important for copper transport and as disease-causing changes. Since the yeast assay specifically evaluates copper transport function, variants with normal transport could be defective in some other aspect of ATP7B function, particularly trafficking in mammalian cells. Functional assessment is critical for reliable use of mutation analysis as an aid to diagnosis of this clinically variable condition.
18242093##2006-3-25##Wilson's disease: a clinico-neuropathological autopsy study.##Wilson's disease (WD), a familial neurological disorder involving the brain and liver secondary to altered copper metabolism, is common in South India. In view of the paucity of studies on this condition, the pathomorphological features of eight cases of WD were studied in detail at autopsy (brain alone, 1; brain and liver biopsy, 1; brain and visceral organs, 6), and are described with a discussion of the differential features of the neurological and hepatic forms. Of the six patients presenting with neurological manifestations, five had central pontine myelinolysis, five had subcortical white matter cavitations, four had putaminal softening, and six had variable ventricular dilatation, unlike the hepatic form. The presence of Opalski cells and pontine myelinolysis appear to be specific to the neurological form of WD. Liver abnormalities were observed in all cases (cirrhosis, 6; steatosis, 4; chronic active hepatitis, 2). Contrary to the rubric 'hepatolenticular degeneration', involvement of the lenticular nucleus was not universal, and nor was the pathology restricted to these anatomical areas.
18180385##2008-1-7##ATP7B expression in human breast epithelial cells is mediated by lactational hormones.##A role for the copper transporter, ATP7B, in secretion of copper from the human breast into milk has previously not been reported, although it is known that the murine ortholog of ATP7B facilitates copper secretion in the mouse mammary gland. We show here that ATP7B is expressed in luminal epithelial cells in both the resting and lactating human breast, where it has a perinuclear localization in resting epithelial cells and a diffuse location in lactating tissue. ATP7B protein was present in a different subset of vesicles from those containing milk proteins and did not overlap with Menkes ATPase, ATP-7A, except in the perinuclear region of cells. In the cultured human mammary line, PMC42-LA, treatment with lactational hormones induced a redistribution of ATP7B from a perinuclear region to a region adjacent, but not coincident with, the apical plasma membrane. Trafficking of ATP7B was copper dependent, suggesting that the hormone-induced redistribution of ATP7A was mediated through an increase in intracellular copper. Radioactive copper ((64)Cu) studies using polarized PMC42-LA cells that overexpressed mAtp7B protein showed that this transporter facilitates copper efflux from the apical surface of the cells. In summary, our results are consistent with an important function of ATP7B in the secretion of copper from the human mammary gland.
18392750##2007-11-13##Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia--a new metabolic disorder.##We report a new constellation of clinical features consisting of hypermanganesaemia, liver cirrhosis, an extrapyramidal motor disorder and polycythaemia in a 12 year-old girl born to consanguineous parents. Blood manganese levels were >3000 nmol/L (normal range <320 nmol/L) and MRI revealed signal abnormalities of the basal ganglia consistent with manganese deposition. An older brother with the same phenotype died at 18 years, suggesting a potentially lethal, autosomal recessive disease. This disorder is probably caused by a defect of manganese metabolism with the accumulation of manganese in the liver and the basal ganglia similar to the copper accumulation in Wilson disease. In order to assess the genetic basis of this syndrome we investigated two candidate genes: ATP2C2 and ATP2A3 encoding the manganese-transporting calcium-ATPases, SPCA2 and SERCA3, respectively. Genotyping of the patient and the family for microsatellite markers surrounding ATP2C2 and ATP2A3 excluded these genes. The patient was found to be heterozygous for both gene loci. Despite the unknown pathophysiology, we were able to develop a successful treatment regime. Chelation therapy with disodium calcium edetate combined with iron supplementation is the treatment of choice, lowering blood manganese levels significantly and improving clinical symptoms.
18036136##2007-11-23##Swallowing dysfunction in Wilson's disease: a scintigraphic study.##Although dysphagia is a common complaint of patients with Wilson's disease (WD) and pneumonia is an important cause of death in these patients, swallowing function remains an underinvestigated field in this condition. The aim of this study was to characterize swallowing dynamics in WD patients. Eight WD patients and 15 age-matched controls underwent scintigraphic evaluation of oral and pharyngeal deglutition. Patients had significantly slower oral transit (P = 0.008) and a greater percentage of oral residue (P = 0.006) when compared to controls. Two of eight patients were free of neurological symptoms at time of examination. Impaired oropharyngeal function was found in patients without dysphagia and without neurological symptoms. Our findings indicate that WD may present with objective swallowing dysfunction, even in the absence of neurological manifestations. Further studies are necessary to investigate the impact of this dysfunction on morbidity and mortality in WD.
18453502##2008-5-6##The clinical spectrum of chronic liver disease in children presenting to a tertiary level teaching hospital in New Delhi.##We report on the clinical spectrum of chronic liver disease (CLD) in children presenting to a tertiary level teaching hospital. Children aged <14 years with suspected CLD presenting to the paediatric gastroenterology department of Maulana Azad Medical College between January 1999 and December 2004, were prospectively studied. They were all given liver function tests, abdominal ultrasonography, endoscopy, viral markers and were checked for Wilson's disease, autoimmune hepatitis and liver biopsy wherever feasible. Other tests for metabolic liver diseases were done when indicated. CLD was diagnosed in 174 children over the six-year period. Cryptogenic cirrhosis was the most common entity, followed by hepatitis B-induced liver disease and Wilson's disease. Most patients presented late with evident portal hypertension.
17904160##2007-2-27##Dominant psychiatric manifestations in Wilson's disease: a diagnostic and therapeutic challenge!##
18339142##2008-3-15##A single-center experience with liver transplantation for Wilson's disease.##Wilson's disease is an inherited disorder of copper metabolism, presenting with prominent hepatic and neurologic manifestations. There is an established place for liver transplantation in the presence of liver disease, while the indication for neurologic manifestations is debated. Between 1993 and 2005, 11 patients were liver transplanted for Wilson's disease at our institution. We retrospectively reviewed the medical records of the patients. The pathology of the explanted livers was analyzed. The patients were divided into three groups based on the evolution of the disease. Postoperative data gathered included patient and graft outcome, complications, neurologic status, and copper metabolism. Six males and five females were transplanted at a mean age of 29.7 yr (range 15-48 yr). Three patients had a fulminant presentation, two patients had decompensation of established disease, and six patients had chronic disease. Neurologic features were prominent in five patients. The pathologic analysis of the explanted graft showed cirrhosis in all patients. The five patients with fulminant and acute on chronic presentations also showed necrosis in the explant. The mean postoperative follow-up was 56.8 months (range 10-129 months). Two patients were re-transplanted. One patient died because of severe sepsis. Two patients with severe neurologic dysfunction showed significant remission of symptoms. Liver transplantation is a safe and effective treatment for both acute and chronic presentations of Wilson's disease. Acute presentation correlates with the presence of necrosis in the explanted liver. In our series, there was a relevant improvement of the neurologic features after transplantation.
18004558##2007-8-30##Copper transport and Alzheimer's disease.##This brief review discusses copper transport in humans, with an emphasis on knowledge learned from one of the simplest model organisms, yeast. There is a further focus on copper transport in Alzheimer's Disease (AD). Copper homeostasis is essential for the well-being of all organisms, from bacteria to yeast to humans: survival depends on maintaining the required supply of copper for the many enzymes, dependent on copper for activity, while ensuring that there is no excess free copper, which would cause toxicity. A virtual orchestra of proteins are required to achieve copper homeostasis. For copper uptake, Cu(II) is first reduced to Cu(I) via a membrane-bound reductase. The reduced copper can then be internalised by a copper transporter where it is transferred to copper chaperones for transport and specific delivery to various organelles. Of significance are internal copper transporters, ATP7A and ATP7B, notable for their role in disorders of copper deficiency and toxicity, Menkes and Wilson's disease, respectively. Metallothioneins and Cu/Zn superoxide dismutase can protect against excess copper in cells. It is clear too, increasing age, environmental and lifestyle factors impact on brain copper. Studies on AD suggest an important role for copper in the brain, with some AD therapies focusing on mobilising copper in AD brains. The transport of copper into the brain is complex and involves numerous players, including amyloid precursor protein, A beta peptide and cholesterol.
18405241##2008-4-15##Prevalence and risk factors of renal dysfunction after liver transplant: a single-center experience.##
18405239##2008-4-15##Pediatric liver transplant: results of a single center.##
18341842##2008-3-18##[The Euro-Wilson project: a European project for the study of Wilson's disease].##
18373411##2008-4-1##New mutations in the Wilson disease gene, ATP7B: implications for molecular testing.##Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new mutations not previously reported were identified: European white (p.L217X, c.918_931, c.1073delG, c.3082_3085delAAGAinsCG, p.V536A, p.S657R, p.A971V, p.T974M, p.Q1004P, p.D1164N, p.E1173G, p.I1230V, p.M1359I, c.2355+4A>G), Sephardic Jewish (p.Q286X), Filipino (p.G1149A), Lebanese (p.R1228T), Japanese (p.D1267V) and Taiwanese (p.A1328T). All but one missense variant have strong evidence for classification as disease-causing mutations. In the patients reported here, we also identified 20 nucleotide substitutions, six not previously reported, which cause silent amino acid changes or intronic changes. Documentation and characterization of all variants is essential for accurate DNA diagnosis in WND because of the wide range of clinical and biochemical variability.
19669281##2007-5-1##Correction of copper metabolism is not sustained long term in Wilson's disease mice post bone marrow transplantation.##
18308209##2007-6-4##Living donor liver transplantation for acute liver failure: a 10-year experience in a single center.##
18079318##2007-12-13##Neurologic complications of liver transplantation in pediatric patients with the hepatic form of Wilson's disease.##The literature contains very little documentation on neurologic complications in liver transplant recipients for Wilson's disease. We retrospectively reviewed 17 consecutive cases of pediatric liver transplantation for the hepatic form of Wilson's disease to assess the types of neurologic complications that occurred, the incidence of those problems, and associated factors in this patient group. The patients were 12 boys and 5 girls; indications for liver transplantation were fulminant hepatic failure in 3 patients and chronic hepatic failure in 14 patients. Neurologic complications were observed in 10 of the 17 patients as 16 episodes. The most common neurologic complications were seizure (7 episodes in 6 patients) and sudden-onset headache (5 episodes in 4 patients). Tacrolimus was identified as the only possible cause of headache in 3 episodes. Encephalitis was the cause in 1 and intracranial hemorrhage was the cause in the other headache episode. We also noted 1 episode of tremor, 1 episode of acute dystonic reaction, 1 episode of diffuse encephalopathy, and 1 episode of common peroneal nerve palsy. Immunosuppressive agents were the primary cause of 12 of the 16 episodes of neurologic complications. Uremia with hypertension, compression of the right common peroneal nerve, encephalitis, and intracranial hemorrhages attributable to coagulopathy caused 1 neurologic episode each. Neurologic complications in patients with the hepatic form of Wilson's disease were frequent during the first 30 days after pediatric liver transplantation but did not affect survival. Transplantation teams should be aware of the high incidence of neurologic complications in pediatric patients with the hepatic form of Wilson's disease.
18332839##2008-3-12##Frontal-subcortical dementias.##Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction. Classic frontal-subcortical dementias include Huntington chorea, Parkinson disease dementia, progressive supranuclear palsy, thalamic degeneration, subcortical vascular dementia, multiple sclerosis, the acquired immunodeficiency syndrome dementia complex, depressive pseudodementia, and some other rare dementias like spinocerebellar degenerative syndromes, Hallervorden-Spatz disease, choreoacanthocytosis, idiopathic basal ganglia calcification, Guamanian parkinsonism-dementia complex, corticobasal degeneration multiple system atrophy, Wilson disease, metachromatic leukodystrophy, adrenoleukodystrophy, hypoparathyroidism, sarcoidosis, and other CNS inflammatory disorders. Anatomic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. However, most frontal-subcortical dementias show cortical atrophy in later stages, and cortical dementias have subcortical pathology at some point. In fact, the concept might be seen as a continuum, and only the 2 extremes would be represented by pure cortical or subcortical pathology. Anyway, subcortical disorders may still be more similar to one another than they are to AD. Possibly, frontal-subcortical and cortical dementias are the description of the prior main target of the disease process, ending up in both cases in a global dementia. Although the dichotomy cortical versus frontal-subcortical dementia is not strict, the 2 concepts still seem to have advantages.
18307400##2008-3-1##Development of cell therapy strategies to overcome copper toxicity in the LEC rat model of Wilson disease.##
18664082##2008-7-31##An unusual presentation of Wilson's disease in childhood: nodular fatty infiltration in liver.##Wilson's disease is a rare inherited disorder characterized by progressive accumulation of copper in the body tissues. Liver and brain are the most commonly involved organs and the disease is presented predominantly by hepatic manifestations in childhood. Histopathological findings of hepatic involvement may vary from steatosis to end stage cirrhosis. Although diffuse fatty infiltration is a typical finding of Wilson's disease, it can very rarely present in nodular pattern. We report the first case with Wilson's disease who presented with nodular fatty infiltration in the liver in childhood.
18300353##2008-2-27##P wave dispersion is prolonged in patients with Wilson's disease.##
18247622##2008-2-05##Probing transient copper chaperone-Wilson disease protein interactions at the single-molecule level with nanovesicle trapping.##
18289222##2008-2-22##Once daily trientine for maintenance therapy of Wilson disease.##
23133010##2007-1-30##Management of hemorrhage of retro hepatic inferior vena cava injury during piggy-back technique for liver transplantation.##
18310797##2008-3-4##Failure of prophylactic zinc in Wilson disease.##Early institution of prophylactic therapy of asymptomatic Wilson disease patients can prevent the expression of the disease. Zinc is currently preferred therapy for presymptomatic patients. We report onset of symptomatic disease in a presymptomatic patient and deterioration of biochemical parameters in another, despite appropriate zinc therapy.
18209591##2008-1-23##Bone mineral density of children with Wilson disease: efficacy of penicillamine and zinc therapy.##
18630776##2008-7-18##Anesthesia for a patient with Wilson's disease--a case report.##
17978167##2007-10-31##Transport of cisplatin by the copper efflux transporter ATP7B.##ATP7B is a P-type ATPase that mediates the efflux of copper. Recent studies have demonstrated that ATP7B regulates the cellular efflux of cisplatin (DDP) and controls sensitivity to the cytotoxic effects of this drug. To determine whether DDP is a substrate for ATP7B, DDP transport was assayed in vesicles isolated from Sf9 cells infected with a baculovirus that expressed either the wild-type ATP7B or a mutant ATP7B that was unable to transport copper as a result of conversion of the transmembrane metal binding CPC motif to CPA. Only the wild-type ATP7B-expressing vesicles exhibited copper-dependent ATPase activity, copper-induced acyl-phosphate formation, and ATP-dependent transport of copper. The amount of DDP that became bound was higher for vesicles expressing either type of ATP7B than for those not expressing either form of ATP7B, but only the vesicles expressing wild-type ATP7B mediated ATP-dependent accumulation of the drug. At pH 4.6, the vesicles expressing the wild-type ATP7B exhibited ATP-dependent accumulation of DDP with an apparent K(m) of 1.2 +/- 0.5 (S.E.M.) muM and V(max) of 0.03 +/- 0.002 (S.E.M.) nmol/mg of protein/min. DDP also induced the acyl-phosphorylation of ATP7B but at a much slower rate than copper. Copper and DDP each inhibited the ATP-dependent transport of the other. These results establish that DDP is a substrate for ATP7B but is transported at a much slower rate than copper.
18210110##2008-1-23##[Hereditary hemochromatosis, alpha-1-antitrypsin deficiency and Wilson's disease. Pathogenesis, clinical findings and pathways to diagnosis].##Primary hemochromatosis, alpha-1-antitrypsin (AAT) deficiency, and Wilson's disease are the most common hereditary causes of unclear hepatopathy. Classical primary hemochromatosis (type I) on the basis of a homozygous mutation of the HFE gene, usually presents in adults with increasing hepatocellular siderosis and chronic progressive necroinflammatory liver disease. Homozygous AAT deficiency type PiZZ becomes manifest in newborns as a giant cell hepatitis or findings similar to bile duct atresia, in adults as chronic hepatitis or "cryptogenic cirrhosis". The heterozygous PiZ mutation can lead to PAS-positive hepatocellular AAT deposits increasing over the life time. Immunohistochemical detection of AAT deposits by specific PiZ antibodies is a highly sensitive and specific supplementary method. Molecular analysis of AAT and HFE genes in paraffin-embedded tissue or blood can confirm the diagnosis and allows the zygosity status to be defined. Wilson's disease has to be considered in children and young adults with unexplained histologic findings of chronic hepatitis or steatohepatitis. Rhodanin staining is the most effective histochemical method to detect free copper deposits, but negative staining results do not exclude Wilson's disease. In cases suspected of Wilson's disease further clinical exploration must be initiated. The diagnosis is based on a combination of clinical and biochemical findings, which can be supplemented by mutation analysis of the ATP7B gene.
18186898##2008-1-12##Renal Fanconi syndrome and myopathy after liver transplantation: drug-related mitochondrial cytopathy?##Advances in the field of transplantation provide a better quality of life and allow more favorable conditions for growth and development in children. However, combinations of different therapeutic regimens require consideration of potential adverse reactions. We describe a 15-yr-old girl who had orthotopic liver transplantation because of Wilson's disease. Tacrolimus, MMF, and steroids were given as immunosuppressant. Lamivudine was added because of de nova hepatitis B infection during her follow-up. Three yr after transplantation she developed renal Fanconi syndrome with severe metabolic acidosis, hypophosphatemia, glycosuria, and aminoaciduria. Although tacrolimus was suspected to be the cause of late post-transplant renal acidosis and was replaced by sirolimus, acidosis, and electrolyte imbalance got worse. Proximal muscle weakness has developed during her follow-up. Fanconi syndrome, as well as myopathy, is well recognized in patients with mitochondrial disorders and caused by depletion of mtDNA. We suggest that our patient's tubular dysfunction and myopathy may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine.
18230710##2008-1-31##Cold comfort pharm.##In a difficult case when either the diagnosis remains elusive, or the treatment does not seem to work, sit down and carefully review all the records-a lesson from Wilson's disease. Practical issues to do with drug treatment may be just as important as its efficacy.
18683710##2008-8-8##[Pediatric liver transplantation in 20 consecutive children].##
18683696##2008-8-8##[Ophthalmic manifestations of Wilson's disease].##
17765927##2007-6-12##Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap.##
17928409##2007-10-10##Intracellular targeting of copper-transporting ATPase ATP7A in a normal and Atp7b-/- kidney.##Kidneys regulate their copper content more effectively than many other organs in diseases of copper deficiency or excess. We demonstrate that two copper-transporting ATPases, ATP7A and ATP7B, contribute to this regulation. ATP7A is expressed, to a variable degree, throughout the kidney and shows age-dependent intracellular localization. In 2-wk-old mice, ATP7A is located in the vicinity of the basolateral membrane, whereas in 20-wk-old mice, ATP7A is predominantly in intracellular vesicles. Acute elevation of serum copper, via intraperitoneal injection, results in the in vivo redistribution of ATP7A from intracellular compartments toward the basolateral membrane, illustrating a role for ATP7A in renal response to changes in copper load. Renal copper homeostasis also requires functional ATP7B, which is coexpressed with ATP7A in renal cells of proximal and distal origin. The kidneys of Atp7b(-/-) mice, an animal model of Wilson disease, show metabolic alterations manifested by the appearance of highly fluorescent deposits; however, in marked contrast to the liver, renal copper is not significantly elevated. The lack of notable copper accumulation in the Atp7b(-/-) kidney is likely due to the compensatory export of copper by ATP7A. This interpretation is supported by the predominant localization of ATP7A at the basolateral membrane of Atp7b(-/-) cortical tubules. Our results suggest that both Cu-ATPases regulate renal copper, with ATP7A playing a major role in exporting copper via basolateral membranes and protecting renal tissue against copper overload.
18953373##2008-11-26##[Adult-onset metabolic diseases].##Inborn errors of metabolism (IEM) can have their onset in adolescence or in adulthood. Although it is difficult to contribute exact data on prevalence -because there are few studies in this respect, and IEM are regarded as infrequent- their detection is important due to the possibilities for therapy and family genetic counselling. The main symptoms of IEM in the adult are neurological, followed by hepatic. Two basic modes of onset can be established. One is acute, normally taking the form of consciousness alteration, lethargy, coma of unknown etiology in a previously healthy patient (urea cycle deficits, homocysteine remethylation disorders and porphyries are the most frequent causes). The other is an insidious, often progressive, chronic symptomathology that can involve complex clinical features, and more rarely a symptom that is isolated in a persistent way (Wilson's disease, mitochondrial diseases, lysosomal storage disorders, Refsum's disease and glycogenosis are some examples of this group). It is especially important to determine the forms of acute onset as these can present situations of extreme emergency where appropriate conduct can prevent the death of the patient. In this case, simple laboratory examinations, such as determination of ammonia, homocysteine, lactate, acylcarnitines, amino acids, organic and porfirines, can guide the diagnosis and enable the start of intensive treatment. This article provides a practical approach that deals with the general characteristics and the clinical keys for suspecting the most usual IEMs in the adult.
18376363##2008-4-1##Oxidative stress: a radical way to stop making bile.##Oxidative stress is a common feature in most hepatopathies. In recent years, evidence has accumulated that reactive oxygen species (ROS) induce a number of functional changes either deleterious or adaptive in the capability of the hepatocytes to produce bile and to secrete exogenous and endogenous compounds. This review is aimed to describe the mechanisms involved in these alterations. For this purpose, we will summarize: 1) The current evidence that acutely-induced oxidative stress is cholestatic, by describing the mechanisms underlying the hepatocyte secretory failure, including the disorganization of the actin cytoskeleton and its most noticeable consequences, the impairment of tight-junctional structures and the endocytic internalization of canalicular transporters relevant to bile formation. 2) The role for oxidative-stress-activated signalling pathways in the pathomechanisms described above, particularly those involving Ca2+ elevation and its consequent activation of Ca2+ -dependent PKC isoforms. 3) The mechanisms involved in the adaptive response against oxidative stress mediated by ROS-responsive transcription factors, involving up-regulation of GSH-synthesizing enzymes, GSH-detoxifying enzymes and the hepatocellular efflux pumps; this response enhances the co-coordinated inactivation by GSH conjugation of lipid peroxides and their further cellular extrusion. 4) The manner this adaptive response can be surpassed by the sustained production of ROS, thus inducing transcriptional and posttranscriptional changes in transporters relevant to bile formation, as has been shown to occur, for example, after long-term administration of aluminum to rats, in the Long-Evans Cinnamon rat (a model of chronic hepatic copper accumulation mimicking Wilson's disease), and in ischemia-reperfusion injury.
19966977##2007-12-10##Quality of life in Wilson's disease.##
18566556##2008-4-29##Liver transplantation for fulminant Wilson's disease in children.##
17945465##2006-9-15##A case of spatial neglect dysgraphia in Wilson's Disease.##We report here on a single neuropsychological case study of a young girl, KH, who presented with Wilson's Disease (WD) associated with a peripheral spatial neglect dysgraphia without major problems in the standard clinical tests of spatial neglect. Few studies have demonstrated a visuospatial deficit in WD and to date there has been no report of neglect syndrome arising from WD. However, recent studies have demonstrated that neglect is frequently associated with brain damage including the primary site of WD, the basal ganglia. KHs writing abilities were evaluated just after her admission to the rehabilitation department and 6 months later. The baseline evaluation demonstrated that KH had neglect dysgraphia with verbal stimuli (e.g., words or sentences) although her deficit was less evident in drawing multiple geometric shapes. Six months after the initial evaluation, KH showed evidence of neglect dysgraphia only when writing was associated with a secondary memory task. KHs writing performance is discussed with reference to previous cases of spatial neglect dysgraphia and in the context of spatial neglect. We suggest that the asymmetry between verbal writing and nonverbal drawing disturbances was caused by different attentional loads.
19166126##2009-1-27##Haemolytic anaemia and acute liver failure--the initial manifestations of Wilson's disease.##We describe a case of a 16-year-old girl with Wilson disease, which was initially presented as Coombs-negative haemolytic anaemia and acute liver failure. The diagnosis was based on the findings of low ceruloplasmin serum level and high copper levels both in serum and 24-hour urinary excretion. The patient underwent orthotopic liver transplantation. A DNA-based diagnostic tool confirmed Wilson's disease: the patient was p.H1069Q homozygote. Based on further molecular-genetic examinations in the family, Wilson disease was diagnosed seven days later in one of the patient's asymptomatic brothers. The proband's cousin was confirmed as a carrier of the p.H1069Q mutation (Fig. 1, Ref. 24).
19088418##2008-10-20##Eryptosis, a window to systemic disease.##Similar to apoptosis of nucleated cells, suicidal erythrocyte death or eryptosis is characterized by cell shrinkage, membrane blebbing and membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Signaling of eryptosis involves formation of prostaglandin E(2) with subsequent activation of cation channels and Ca(2+)-entry and/or release of platelet activating factor (PAF) with subsequent activation of sphingomyelinase and formation of ceramide. Ca(2+) and ceramide stimulate cell membrane scrambling. Ca(2+) further activates Ca(2+)-sensitive K(+)-channels leading to cellular KCl loss and cell shrinkage and stimulates the protease calpain resulting in degradation of the cytoskeleton. Injuries triggering eryptosis may similarly compromise survival of nucleated cells. The case is made that analysis of enhanced eryptosis may direct to the pathophysiology of systemic disease. Examples presented include drug side effects, sepsis, haemolytic uremic syndrome, Wilson's disease, phosphate depletion and a rare condition caused by a mutation in GLUT1 turning the carrier into a cation channel.
18568852##2008-6-24##Diagnosis of Wilson's disease: a comprehensive review.##Wilson's disease is an autosomal recessive disorder of copper metabolism. The culprit gene is ATP7B. The worldwide prevalence is about 1 in 30,000, which may vary by population. Higher prevalence rates were reported using more sensitive screening techniques and pilot population screening. Typical presentations include neuropsychiatric and hepatic dysfunction, whereas atypical presentations are protean. Diagnosis relies on a high clinical suspicion, typical neurological symptoms, presence of Kayser-Fleischer rings, and reduced serum ceruloplasmin concentration. The conventional value of < 0.20 g/l is not a universal diagnostic value. Age of the subjects and analytical variations should be considered when interpreting these levels. Patients with inconclusive findings require further investigations such as 24 h urinary free-copper excretion, penicillamine challenge test, liver copper measurement, and detection of gene mutations. Direct molecular diagnosis remains the most decisive tool. Other tests such as non-ceruloplasmin-bound copper are unreliable. Potential pitfalls and limitations of these diagnostic markers are critically reviewed in this paper. The mainstays of therapy are trientine, penicillamine, and/or zinc. Liver transplantation is lifesaving for those with advanced disease. Ceruloplasmin oxidase activity and serum free-copper concentration should be monitored in patients on long-term de-coppering therapy to prevent iatrogenic copper deficiency.
19075668##2008-12-17##Copper transport systems are involved in multidrug resistance and drug transport.##Copper is an essential trace element and several copper containing proteins are indispensable for such processes as oxidative respiration, neural development and collagen remodeling. Copper metabolism is precisely regulated by several transporters and chaperone proteins. Copper Transport Protein 1 (CTR1) selectively uptakes copper into cells. Subsequently three chaperone proteins, HAH1 (human atx1 homologue 1), Cox17p and CCS (copper chaperone for superoxide dismutase) transport copper to the Golgi apparatus, mitochondria and copper/zinc superoxide dismutase respectively. Defects in the copper transporters ATP7A and ATP7B are responsible for Menkes disease and Wilson's disease respectively. These proteins transport copper via HAH1 to the Golgi apparatus to deliver copper to cuproenzymes. They also prevent cellular damage from an excess accumulation of copper by mediating the efflux of copper from the cell. There is increasing evidence that copper transport mechanisms may play a role in drug resistance. We, and others, found that ATP7A and ATP7B are involved in drug resistance against the anti-tumor drug cis-diamminedichloroplatinum (II) (CDDP). A relationship between the expression of ATP7A or ATP7B in tumors and CDDP resistance is supported by clinical studies. In addition, the copper uptake transporter CTR1 has also been reported to play a role in CDDP sensitivity. Furthermore, we have recently found that the effect of ATP7A on drug resistance is not limited to CDDP. Using an ex vivo drug sensitivity assay, the histoculture drug response assay (HDRA), the expression of ATP7A in human surgically resected colon cancer cells correlated with sensitivity to 7-ethyl-10-hydroxy-camptothecin (SN-38). ATP7A-overexpressing cells are resistant to many anticancer drugs including SN-38, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), vincristine, paclitaxel, etoposide, doxorubicin (Dox), and mitoxantron. The mechanism by which ATP7A and copper metabolism modulate drug transport appears to involve modulation of drug cellular localization via modulation of the vesicle transport system. In ATP7A overexpressing cells, Dox accumulates in the Golgi apparatus. In contrast, in the parental cells, Dox is localized in the nuclei, where the target molecules of Dox, topoisomerase II and DNA, are found. Disruption of the intracellular vesicle transport system with monensin, a Na+/H+ ionophore, induced the relocalization of Dox from the Golgi apparatus to the nuclei in the ATP7A overexpressing cells. These data suggested that ATP7A-related drug transport is dependent on the vesicle transport system. Thus copper transport systems play important roles in drug transport as well as in copper metabolism. Components of copper metabolism are therefore likely to include target molecules for the modulation of drug potency of not only anti-cancer agents but also of other drugs.
19079689##2007-10-19##Copper Induces Apoptosis of Neuroblastoma Cells Via Post-translational Regulation of the Expression of Bcl-2-family Proteins and the tx Mouse is a Better Model of Hepatic than Brain Cu Toxicity.##The basic mechanism(s) by which altered Cu homeostasis is toxic to hepatocytes and neurons, the two major cell types affected in copper storage diseases such as Wilson's disease (WD), remain unclear. Using human M17 neuroblastoma cells as a model to examine Cu toxicity, we found that there was a time- and concentration-dependent induction of neuronal death, such that at 24 h there was a approximately 50 % reduction in viability with 25 muM Cu-glycine(2). Cu-glycine(2) (25:50 muM) treatment for 24 h significantly altered the expression of 296 genes, including 8 genes involved with apoptosis (BCL2-associated athanogene 3, BCL2/adenovirus E1B 19kDa interacting protein caspase 5, regulator of Fas-induced apoptosis, V-jun sarcoma virus 17 oncogene homolog, claudin 5, prostaglandin E receptor 3 and protein tyrosine phosphatase, non-receptor type 6). Surprisingly, changes in the expression of more 'traditional' apoptotic genes (Bcl-2, Bax, Bak and Bad) did not vary more than 20 %. To test whether the induction of apoptosis in neuroblastoma cells was via post-translational mechanisms, we measured the protein expression of these apoptotic markers in M17 neuroblastoma cells treated with Cu-glycine(2) (0-100 muM) for 24-48 h. Compared with glycine treated cells, Cu-glycine(2) reduced Bcl-2 expression by 50 %, but increased Bax and Bak expression by 130% and 400 %, respectively. To assess whether Cu also induced apoptotic cell death in a mouse model of WD, we measured the expression of these apoptotic markers in the liver and brain of mice expressing an ATP7b gene mutation (tx(J) mice) at 10 months of age (near the end of their lives when overt liver pathology is displayed). Changes in the liver expression of these apoptotic markers in tx(J) mice compared to background mice mirrored those of Cu treated neuroblastoma cells. In contrast, few changes in apoptotic protein expression were detected in the brain between tx(J) and background mice, indicating the tx(J) mouse is a good model of hepatic, but not brain, Cu toxicity. Our results indicate that Cu-induction of neuronal apoptosis does not require de novo synthesis or degradation of apoptotic genes, and that Cu accumulation in the aged tx(J) mouse brain is insufficient to induce apoptosis.
18483695##2007-12-11##Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations.##The aim of this work was to study the mutations within ATP7B in Egyptian children with Wilson disease and to evaluate any potential correlation between genotype and phenotype in this cohort. The study consisted of 48 children with Wilson disease from 32 independent families. The 21 exons of the ATP7B gene were amplified in a thermal cycler. Direct sequencing of the amplified polymerase chain reaction (PCR) products was performed by cycle sequencing using fluorescent dye terminators in an automatic ABI sequencer. Thirty-one different mutations in 96 chromosomes were detected (19 missense, three nonsense, seven frameshift deletions, and two splice-site mutations). Of these, 12 mutations have not been previously reported. The p.N1270S, p.C703Y, IVS18-2A > G, p.R1319X, c.2304-2305insC, and p.H1069Q were present in 7.8%, 6.2%, 6.2%, 6.2%, 4.7%, and 4.7%, respectively, of studied chromosomes in independent families. One patient was homozygous for both p.N1270S and p.T1434M mutations. Frameshift and nonsense mutations were found in 50% of patients with disease onset < or =8 years compared with only 26% in patients with onset >8 years. Despite mutation heterogeneity in Egyptian children, genotype-phenotype correlation analysis seems to be promising in this population, as many patients carry homozygous mutations, a situation that mandates a larger-scale population screening to identify the carrier rate in this community.
18034201##2007-9-12##Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity.##Wilson disease (WD), an autosomal recessive disorder of copper transport, is the most common inherited liver disorder in Hong Kong Chinese. This was the first local study to elucidate the molecular basis and establish an effective DNA-based diagnostic protocol. The ATP7B genes of 65 patients were amplified by polymerase chain reaction (PCR) and sequenced. Haplotype analysis was performed using D13S301, D13S314, and D13S316. The p.L770L/p.R778L status in 660 subjects was determined to estimate WD prevalence. Allele age of p.R778L was determined by the smallest homozygosity region between D13S301 and D13S270. We identified 42 different mutations with 17 being novel. p.R778L (17.3%) was the most prevalent. Exons 2, 8, 12, 13, and 16 harbored 70% mutations. Thirty-two haplotypes were associated with WD chromosomes. The estimated prevalence rate was 1 in 5,400. Three out of 660 normal subjects had p.L770L/p.R778L. In the remaining 657 individuals, neither p.L770L nor p.R778L was found. We characterized a Hong Kong Chinese-specific ATP7B mutation spectrum with great genetic diversity. Exons 2, 8, 12, 13, and 16 should be screened first. The perfect linkage disequilibrium suggested that p.R778L and its private polymorphism p.L770L originated from a single ancestor. This East-Asian-specific mutation p.R778L/p.L770L is aged at least 5,500 years.
18277819##2008-2-19##A rare case of hemochromatosis and Wilson's disease coexisting in the same patient.##Wilson's disease and hereditary hemochromatosis are two inherited diseases with life-threatening complications. Early recognition and prompt treatment may be instrumental in reducing such complications associated with these disorders. Although both Wilson's disease and hereditary hemochromatosis are genetic in nature, the two conditions have distinct, unrelated genetic etiologies. Two distinct, separate mutations are required for simultaneous existence of the two diseases. As such, the likelihood of the two conditions coexisting is exceedingly rare. Here we report a case of a 23-year-old male with hereditary hemochromatosis with coexistent Wilson's disease. Only two reported cases exist in which this dual diagnosis was present simultaneously. In our patient, laboratory evaluation demonstrated elevated ferritin, transferrin saturation >90%, and subsequent liver biopsy demonstrated diffuse fibrotic changes. Confirmatory genetic analysis revealed the patient to be a compound heterozygous for C282Y and H63D gene mutations. Given the patient's young age and the improbability of hemochromatosis-induced hepatic damage at that age, an alternative diagnosis was sought. Further analysis revealed reduced serum ceruloplasmin along with elevated urinary copper excretion. Subsequent ophthalmologic exam revealed bilateral Kaiser Fleischer rings. In conclusion, Wilson's disease and genetic hemochromatosis both involve inherent flaws in the transportation of heavy metals and their accumulation in hepatocytes. Although both diseases arise from distinctly different genetic mutations, the coincidence of the two disorders can, in rare cases, occur.
18305288##2008-2-29##Psychiatric manifestations in Wilson's disease: a cross-sectional analysis.##Behavioral and psychiatric abnormalities in Wilson's disease (WD) have a variable frequency and spectrum. This study involved evaluation of the psychiatric comorbidities in patients of Wilson's disease, using structured clinical interview for DSM-IV Axis-I disorders (SCID). Among the 50 confirmed patients with Wilson's disease recruited for this study, 12 patients (24%) fulfilled the diagnostic criteria for syndromic psychiatric diagnosis: bipolar affective disorder (18%), major depression (4%), and dysthymia (2%). Formal assessment of psychopathology in all patients with Wilson's disease may have therapeutic significance.
18319140##2007-10-9##Non-ceruloplasmin-bound copper in routine clinical practice in different laboratories.##
18695350##2008-8-13##Acute liver failure in Lithuania.##
21423838##2011-3-23##Copper-Induced Cytotoxicity and Transcriptional Activation of Stress Genes in Human Liver Carcinoma (HepG(2)) Cells.##Copper is a naturally occurring element found as a component of many minerals. It is an essential nutrient that is normally present in a wide variety of tissues. In humans, ingestion of large quantities of copper salts may cause gastrointestinal, hepatic, and renal effects with symptoms such as severe abdominal pain, vomiting, diarrhea, hemolysis, hepatic necrosis, hematuria, proteinuria, hypotension, tachycardia, convulsions, coma, and death. The chronic toxicity of copper has been characterized in patients with Wilson's disease, a genetic disorder causing copper accumulation in tissues. Although the clinical manifestations of Wilson's disease (cirrhosis of the liver, hemolytic anemia, neurologic abnormalities, and corneal opacities) are known, the cellular and molecular events associated with copper toxicity are poorly understood. In the present study, we used human liver carcinoma (HepG(2)) cells as a model to study the cytotoxicity, and the potential mechanisms of copper-induced toxicity and carcinogenesis. We hypothesized that copper-induction of stress genes may play a role in the cellular and molecular events leading to toxicity and tumor formation in liver cells. To test this hypothesis, we performed the MTT-assay for cell viability, the CAT-Tox(L) assay for gene induction, to assess the transcriptional activation of stress genes. Data obtained from the MTT assay indicated a strong dose-response relationship with respect to copper toxicity. Upon 48 h of exposure, the chemical dose required to cause 50% reduction in cell viability (LD(50)) was computed to be 220.5 ± 23.8 μg/mL copper sulfate. The CAT-Tox (L) assay showed statistically significant inductions (p < 0.05) of a significant number of stress genes including c-fos, HMTIIA, HSP70, GRP78, RARE, GADD153, and RARE. These data support previous research indicating that copper overload is hepatotoxic. The CAT-Tox data on the other hand indicate that copper overload induces proteotoxic effects (HMTIIA, HSP70, GRP78), inflammatory reactions/oxidative stress (c-fos), and growth arrest and DNA damage (p53, GADD153). The induction of RARE points to its potential involvement in growth and development.
17981064##2007-6-29##Mitochondrial structure and function in the untreated Jackson toxic milk (tx-j) mouse, a model for Wilson disease.##Structural changes in hepatocellular mitochondria are characteristic of Wilson disease (WD). Features include variability in size and shape, increased density of matrix, discreet inclusions, and cystic dilatation of the cristae. We examined the functional basis for these mitochondrial changes in the toxic milk (tx-j) mouse model for WD. Its normal syngeic strain, C3H, served as control. Hepatic histology was near-normal in tx-j mice at 3-4-months-old and showed mild inflammation and steatosis at 6-months-old. Transmission electron microscopy showed typical mitochondrial abnormalities, specifically cystic dilatation of tips of cristae, in 3, 4, and 6-month-old tx-j mice and none in normal 3-month-old C3H mice. Citrate synthase (CS) activity was initially lower in tx-j mice than age-matched controls but increased over the first 6 months such that it was significantly greater at 5 and 6-months-old (p<0.003). No evidence for hepatic mtDNA depletion was found by long-PCR analysis. NB-PAGE showed preservation of all complexes in the oxidative-phosphorylation chain except complex IV which declined markedly from 5-months-old onwards. Hepatic complex IV activity was significantly decreased in 5-month-old tx-j mice (p<0.04). Expression of mitochondrial transfer factor A (TFAM) mRNA declined progressively in 6-8-month-old tx-j mice; immunodetectable protein levels declined in parallel. Expression of mtSSB mRNA was uniformly low in tx-j mice from 1-8-months-old. Levels of two mitochondrial antioxidant proteins capable of binding copper, thioredoxin-2 and peroxiredoxin-3, rose over the first 6 months of life. Mitochondrial changes occur early in WD and reflect complex, probably oxidative, injury.
17960799##2007-10-27##Evaluation of the Unified Wilson's Disease Rating Scale (UWDRS) in German patients with treated Wilson's disease.##Wilson's disease (WD) is an inherited autosomal-recessive disorder of copper metabolism characterized by a wide variety of neurological, hepatic, and psychiatric symptoms. The aim of the present study was the development and evaluation of a clinical rating scale, termed Unified Wilson's Disease Rating Scale (UWDRS), to assess the whole spectrum of clinical symptoms in WD. Altogether 107 patients (mean age 37.6 +/- 11.9 years; 46 male, 61 female) with treated WD participated in the study. Cronbach's alpha as a measure of the internal consistency for the entire scale was 0.92, whereas the intraclass correlation coefficient (ICC) was 0.98 (confidence interval (CI(95%)) 0.97-0.99), indicating an excellent interrater reliability as determined in 32 patients. Besides the total score was significantly correlated with the earning capacity of the patients as indicated by an estimated Spearman's rho approximately 0.54 (CI(95%) 0.40-0.69, P < 0.001). In summary, the UWDRS appears to be a promising tool to assess the disease severity in WD. Its usefulness in clinical research and drug trials should be further addressed.
17897870##2007-4-27##Neurological manifestations and ATP7B mutations in Wilson's disease.##Wilson's disease (WD) is a rare inborn metabolic error characterized by deficient biliary copper excretion secondary to ATP7B gene mutations. Neurological presentations are variable in respect to both pattern and age of onset; commonly a movement disorder presents in the second or third decade. The aim of this study was to ascertain genotype correlations with distinct neurological manifestations in 41 WD patients in a Brazilian center for WD. A total of 23 distinct mutations were detected, and the frameshift 3402delC had the highest allelic frequency (31.7%). An association between 3402delC and dysphagia was detected (p=0.01) but the limited number of patients is insufficient to allow one to draw conclusions. Both clinical studies analyzing larger cohorts and basic research on ATP7B protein function could potentially shed more light on our understanding of WD.
18054700##2007-4-3##Case of pediatric acquired chronic hepatocerebral degeneration.##Acquired chronic hepatocerebral degeneration is a central nervous system disorder secondary to several conditions related to hepatic dysfunction. Clinical features of acquired chronic hepatocerebral degeneration include a hyperkinetic extrapyramidal syndrome, neuropsychiatric symptoms, or both. We present for the first time a pediatric case of acquired chronic hepatocerebral degeneration secondary to endstage biliary disease. The pediatric phenotype of acquired chronic hepatocerebral degeneration is presented, and the differential diagnosis in regard to Wilson's disease and management alternatives are discussed.
18415754##2008-4-17##Usefulness of penicillamine-stimulated urinary copper excretion in the diagnosis of adult Wilson's disease.##
18261593##2008-2-12##Liver transplantation for Wilson's disease.##Wilson's disease is an inherited disorder of copper metabolism characterized by reduced biliary copper excretion, which results in copper accumulation in the tissues with liver injury and failure. Orthotopic liver transplantation (OLT) can be lifesaving for patients with Wilson's disease who present with fulminant liver failure and for patients' unresponsive to medical therapy. The aim of this study was to review our experience with OLT for patients with Wilson's disease. Between September 2001 and April 2007, 25 OLTs were performed in 24 patients (7 females and 17 males) with Wilson's disease of mean age 15.6 +/- 9.9 years (range, 5-51 years). Six patients underwent transplantation owing to coexistent fulminant hepatic failure and 18 with chronic advanced liver disease with (n = 8) or without (n = 10) associated neurologic manifestations. We performed 3 full-size, deceased-donor OLTs and 22 living-related donor OLTs. Eight patients had a family history of Wilson's disease. We detected a Kayser-Fleischer ring in 18 patients. All patients had a low serum ceruloplasmin level (mean, 27.8 mg/dL) and a high urinary copper excretion level (mean, 4119 mug/d) before OLT. Following successful OLT, there was a significant reduction in urinary copper excretion (median, 37.1 mug/d) in all patients. Mean follow-up was 21.7 +/- 19.8 months (range, 2-60 months). Retransplantation was required in 1 patient at 12 days after the first OLT owing to primary graft nonfunction. Five of the 24 patients died within 4 months of the surgery. The remaining 19 survivors (79%) have remained well, with normal liver function and no disease recurrence. In conclusion, OLT was a curative procedure for Wilson's disease among patients presenting with fulminant hepatic failure and others with end-stage hepatic insufficiency. After OLT, the serum ceruloplasmin level increased to the normal range, urinary copper excretion decreased, and neurologic manifestations improved.
18521802##2008-6-4##Psychopathology and personality traits in patients with treated Wilson disease grouped according to gene mutations.##Wilson disease (WD) is a recessively inherited copper storage disorder mainly affecting liver and brain. Genotype/phenotype correlations have been report ed but as yet not regarding psychic symptoms. Our aim was to investigate if a correlation might exist between genotype and phenotype concerning psychopathology and/or personality traits in patients with treated WD. Nine homozygous and three compound heterozygous Swedish patients were retrospectively investigated, representing four different mutation settings. Psychopathological symptoms were studied using the Comprehensive Psychopathological Rating Scale (CPRS), personality traits using the Karolinska Scales of Personality (KSP) and mutations were analyzed by manifold sequencing. Psychopathological symptoms: Patients with the Trp779Stop mutation had the lowest scores on the total CPRS, due to less pronounced reported CPRS items, as compared to the other three groups of patients. Compound heterozygotes for the His1069Gln/Arg1319Stop mutation showed the highest total CPRS scores. Personality traits: Patients homozygous for the Trp779Stop and the Thr977Met mutations had high scores on Psychopathy related scales whereas patients with His1069Gln/Arg1319Stop mutations had the lowest scores on these scales. Serum ceruloplasmin levels were undetectable in all patients with the Trp779Stop and Thr977Met mutations. The results show a trend towards a genotype/phenotype correlation regarding psychopathological symptoms and personality traits in treated patients with WD. If replicable, these results might contribute to the elucidation of the possible clinical importance of functionally deleterious gene mutations in WD psychopathology and personality traits.
18226344##2008-1-30##[Piggy-back liver transplantation in treating acute liver failure patients: a report of 15 cases].##
18058148##2007-12-7##[Hereditary movement disorders].##Hereditary movement disorders comprise a group of genetically defined diseases characterized by an impaired control of movements, ataxia and/or spasticity. Affected individuals are disabled, their quality of life significantly reduced and their life expectancy shortened. One or more genetic causes have been identified for many of these diseases, including Huntington's disease, Wilson's disease, spinocerebellar ataxias, recessive ataxias, hereditary spastic paraplegia and hereditary dystonias. Due to their characteristic molecular and biochemical pathogenesis, these rare diseases can often serve as models for more common disorders such as Alzheimer's disease or Parkinson's disease. The primary tasks of the German Network of Hereditary Movement Disorders (GeNeMove), funded by the German Ministry for Education and Research (BMBF), are to co-ordinate basic scientific research and clinical research into rare hereditary movement disorders and to improve the cooperation between the German centers specializing in hereditary movement disorders. For each of the diseases in its scope, GeNeMove works at creating standardized documentation of symptoms and the disease's progressive course over time; developing rating scales for clinical examinations and guidelines for therapy; improving genetic testing; fostering genetic research; and collecting samples of DNA, tissue, CSF and blood from sufferers of the disease for biobanks.
17823867##2007-6-3##Molecular pathogenesis of Wilson disease among Indians: a perspective on mutation spectrum in ATP7B gene, prevalent defects, clinical heterogeneity and implication towards diagnosis.##
18159133##2007-12-27##Down-regulation of intestinal multidrug resistance-associated protein 2 in long-evans cinnamon rats.##Wilson's disease is an inherited, autosomal recessive disorder of copper accumulation and toxicity. Lifelong chelation therapy is essential in all Wilson's disease patients. Intestinal absorption of some compounds is limited partly because they are preferentially transported in the secretory direction. Several ATP-binding cassette (ABC) transporters are expressed in the apical membrane of the small intestine and secrete various drugs into the lumen. In this study, we investigated the characteristics of the intestinal efflux ABC transporters in LEC rats. We found that the expression of multidrug resistance-associated protein 2 (Mrp2) in the jejunum of Long-Evans Cinnamon (LEC) rats, an animal model for Wilson's disease, is decreased.
18789784##2005-4-1##[The onset of psychiatric disorders and Wilson's disease].##Wilson's disease is an infrequent, autosomic recessive pathology, resulting from a loss of function of an adenosine triphosphatase (ATP7B or WDNP), secondarily to a change (more than 60 are described currently), insertion or deletion of the ATP7B gene located on the chromosome 13q14.3-q21.1, which involves a reduction or an absence of the transport of copper in the bile and its accumulation in the body, notably the brain. Wilson's disease is transmitted by an autosomic recessive gene located on the long arm of chromosome 13. The prevalence of the heterozygote is evaluated at 1/90 and the homozygote at 1/30,000. Consanguinity, frequent in the socially geographically isolated populations, increases the prevalence of the disease. The toxic quantities of copper, which accumulate in the liver since early childhood and perhaps before, remain concentrated in the body for years. Hence, cytological and histological modifications can be detected in the biopsies, before the appearance of clinical or biological symptoms of hepatic damage. The accumulation of copper in the liver is due to a defect in the biliary excretion of metal and is accompanied invariably by a deficit in ceruloplasmin; protein synthesized from a transferred ATP7B gene, which causes retention of the copper ions in the liver. The detectable cellular anomalies are of two types: hepatic lesions resulting in acute hepatic insufficiency, acute hepatitis and finally advanced cirrhosis and lesions of the central nervous system responsible for the neurological and psychiatric disorders. In approximately 40-50% of the patients, the first manifestation of Wilson's disease affects the central nervous system. Although copper diffuses in the liver towards the blood and then towards other tissues, it has disastrous consequences only in the brain. It can therefore cause either a progressive neurological disease, or psychiatric disorders. Wilson's disease begins in the form of a hepatic, neurological, or psychiatric disease in at least 90% of the patients. In some rare cases, the first manifestations of the disease can be psychiatric which, according to the literature, accounts for only 10% of the cases. The disease can be revealed by isolated behavioral problems, an irrational syndrome, a schizophrenic syndrome, or a manic-depressive syndrome. Damage to the central nervous system can be more severe, thus, several differential diagnoses have been discussed: a psychotic disorder of late appearance; a depressive state; a mental confusion disorder. The clinical syndrome is complex. Indeed, it is the polymorphism, which dominates in the description of the psychiatric demonstrations of the disease. This can lead to prejudicial diagnostic wandering, particularly since heavy sedative treatment may be required to suppress behavioral problems. Clinically, Wilson's disease generally appears between the age of 10 and 20. It rarely remains masked until after the age of 40. The first manifestations are hepatic (40% of the cases), neurological (35%) or psychiatric (10%). The inaugural disorder can finally take on a haematological, renal, or mixed form in approximately 15% of the cases. We have detailed the principal clinical elements. In approximately 40-50% of the patients, the first manifestation of the disease affects the central nervous system, where it can cause either a progressive neurological disease, or psychiatric disorders. The ophthalmologic disorder is dominated by Kayser-Fleischer's ring, representing a green or bronze colored ring on the periphery of the cornea. It occupies the higher pole of the cornea, then the lower pole, and extends to the whole circumference. It is generally only visible under examination with a slit lamp. It disappears on average within 3-5 years following copper chelating therapy. Kayser-Fleischer's ring has been described other than in Wilson's disease, in exceptional cases of prolonged cholestasis. On haematological level, the hyperhaemolysis is due to the toxicity of the ionic copper, released massively in the plasma by hepatocellular necrosis. The other manifestations can be found in the following organs: renal, osteoarticular, cardiac, endocrine, cutaneous, and in the teguments. Until 1952, the diagnosis was evoked only on clinical symptomatology. It can henceforth be marked unambiguous, even in the absence of any symptom, by the description of a ceruloplasmin plasma concentration of less than 200 ml/l, and of a Kayser-Fleischer's ring. Hepatic copper on sample is constantly increased during the disease (from 3 to 25 micromol/g of dry weight). On the other hand, the absence of a reduction in the plasma ceruloplasmin does not make it possible to exclude the diagnosis. Conversely, a reduction in ceruloplasmin can exist other than in Wilson's disease (nephritic syndrome, malabsorption syndrome, or severe hepatic insufficiency). Kayser-Fleischer's ring is quasiconstant among patients with neuropsychiatric demonstrations (thus, its absence represents a very strong argument against the diagnosis). It can on the other hand be lacking during hepatic forms, and in this case, its absence is not an argument against the diagnosis. Magnetic resonance imaging can reveal abnormal signals of the grey cores. A genetic study is conducted by liaison analysis in the event of a family history of the disease. When it is not treated, Wilson's disease induces lesions of the tissues, the outcome of which is always fatal. Treatment relies on the regulation of copper chelation, which improves the prognosis, and zinc, which captures the copper in a nontoxic form. The severe psychiatric disorders observed during Wilson's disease may require tranquilizers, but care should be taken because of potential neurological or hepatic side effects. Lithium seems an interesting treatment and remains theoretically indicated, taking into account the scarcity of the extrapyramidal symptoms and the hepatic dysfunction among patients at the stage of cirrhosis, since it is not metabolized in the liver. Although rare, it is important to approach Wilson's disease in psychiatry because the psychiatric manifestations can precede the somatic disorders and help to pose the diagnosis. We stress the importance of the early diagnosis of the pathology, the outcome of which is fatal in the absence of specific treatment.
18194128##2008-1-16##Acute renal failure in the first 100 orthotopic liver transplant patients in Southern Iran.##Postoperative acute renal failure is a frequent and serious medical complication following orthotopic liver transplant. Here, we report our experiences with liver transplant recipients who developed acute renal failure in the early period following orthotopic liver transplant. Among 100 liver transplants performed between April 1993 and January 2004, we retrospectively analyzed 91 patients (mean age, 29.9 +/- 14.0 years) who had undergone orthotopic liver transplant. The underlying causes of liver failure were cryptogenic liver cirrhosis (n=27), viral hepatitis (n= 21) (hepatitis-B-related liver cirrhosis [n=13], hepatitis-C-related liver cirrhosis [n=7], and hepatitis-B- and C-related liver cirrhosis [n=1]), autoimmune hepatitis (n=18), Wilson's disease (n=10), primary sclerosing cholangitis (n=8), biliary atresia (n=3), Budd-Chiari syndrome (n=2), and primary biliary cirrhosis (n=2). The immunosuppressive regimen included mycophenolate mofetil (azathioprine for 10 patients), cyclosporine, and steroids. Six patients received a combination of tacrolimus and steroids. Ten patients (10.9%) experienced acute renal failure, 7 (70%) were men, and none of them required renal replacement therapy and/or died. Four patients were diagnosed as having cryptogenic liver cirrhosis; 2 with hepatitis-C-related liver cirrhosis, 2 with autoimmune liver cirrhosis; 1 with primary biliary cirrhosis; and 1 hepatitis-B-related liver cirrhosis. Six patients were Child-Pugh's classification C, and the others were B. The rate of postoperative acute renal failure in our patients was relatively low when compared with other series, and our outcomes were good.
17680703##2007-8-8##Sequence variation database for the Wilson disease copper transporter, ATP7B.##Wilson disease (WND) is a disorder of copper transport resulting in copper accumulation in liver, kidney, and brain. This recessive disorder expresses variable clinical symptoms affecting liver, brain, and/or kidney. The age of onset of symptoms varies from 3 to almost 70 years, so the diagnosis for this treatable disorder is easily missed. The defective gene is a membrane P-type ATPase, with similar structure to the other metal transporting ATPases. Most patients with Wilson disease are compound heterozygotes. This report describes the database we have developed for reporting of mutations in ATP7B, the gene defective in WND. The database includes more than 518 variants (379 probable disease-causing and the remainder possible normal variants) from populations worldwide (Available at: www.medicalgenetics.med.ualberta.ca/wilson/index.php; Last accessed: 20 June 2007). The tables in this database are a valuable resource for the study of population variation and the function of the transporter, and will assist in the identification of disease and non-disease-causing sequence variants.
18000748##2007-11-15##Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins.##Copper plays an essential role in human physiology and is indispensable for normal growth and development. Enzymes that are involved in connective tissue formation, neurotransmitter biosynthesis, iron transport, and others essential physiological processes require copper as a cofactor to mediate their reactions. The biosynthetic incorporation of copper into these enzymes takes places within the secretory pathway and is critically dependent on the activity of copper-transporting ATPases ATP7A or ATP7B. In addition, ATP7A and ATP7B regulate intracellular copper concentration by removing excess copper from the cell. These two transporters belong to the family of P(1)-type ATPases, share significant sequence similarity, utilize the same general mechanism for their function, and show partial colocalization in some cells. However, the distinct biochemical characteristics and dissimilar trafficking properties of ATP7A and ATP7B in cells, in which they are co-expressed, indicate that specific functions of these two copper-transporting ATPases are not identical. Immuno-detection studies in cells and tissues have begun to suggest specific roles for ATP7A and ATP7B. These experiments also revealed technical challenges associated with quantitative detection of copper-transporting ATPases in tissues, as illustrated here by comparing the results of ATP7A and ATP7B immunodetection in mouse cerebellum.
18000558##2007-9-18##Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism.##Copper is an essential nutrient required for normal growth and development in many organisms. In humans, the disruption of normal copper absorption and excretion is associated with two severe disorders, known as Menkes disease and Wilson disease, respectively. The consequences of insufficient copper supply that is characteristic of Menkes disease have been largely linked to the inactivation of key metabolic enzymes, although other non-enzymatic processes may also be involved. In contrast, the consequences of copper accumulation in Wilson disease have been generally ascribed to copper-induced radical-mediated damage. Recent studies suggest that the cellular response to copper overload, particularly at the early stages of copper accumulation, involves more specific mechanisms and specific pathways. Genetic and metabolic characterization of animal models of Wilson disease has provided new insights into the pre-symptomatic effects of copper that is accumulated in the liver. The studies have uncovered unexpected links between copper metabolism, cell-cycle machinery, and cholesterol biosynthesis. We discuss these new findings along with the earlier reports on dietary effects of copper. Together these experiments suggest a tight link between lipid and copper metabolism and identify several candidate proteins that may mediate the cross-talk between copper status and lipid metabolism.
17994470##2007-11-13##Effect of penicillamine and zinc on iron metabolism in Wilson's disease.##
18171532##2008-1-4##[Clinical diagnosis of two fulminate Wilson disease cases].##
17910951##2007-8-28##Developmental expression of Commd1 in the liver of the Jackson toxic milk mouse.##Wilson disease (WD) is due to mutations in ATP7B, which encodes an intracellular metal-transporting P-type ATPase. In WD holoceruloplasmin production and biliary excretion of copper are decreased, leading to copper overload, oxidative stress and apoptotic cell death. Other copper-binding proteins include COMMD1, which is inactive in the Bedlington terrier hereditary copper toxicosis, and XIAP, which regulates apoptosis. We examined developmental expression of Commd1 and Xiap in the Jackson toxic milk mouse (Atp7b(tx-J), G712D missense mutation in Atp7b). Expression of Commd1 mRNA appeared unchanged by PCR but real-time PCR demonstrated 3- to 4-fold increase over the first 6 months of life. Immunodetectable Xiap dropped over the first 8 months of life and was nearly undetectable from 6 months onward. Cytosolic NF-kappaB rose then dropped precipitously at 5-6 months. In tx-j mice hepatic copper accumulation leads to decreased Xiap, increased Commd1; these responses ultimately fail to prevent progressive apoptotic cell damage.
17914724##2007-10-5##Successful treatment of tremor in Wilson's disease by thalamotomy: A case report.##Little information is available on the surgical treatment of movement disorders in Wilson's disease. We report a successful outcome of left-sided stereotactic thalamotomy in a 30-year-old man with Wilson's disease, who had severe postural-kinetic tremor of both hands. The improvement was bilateral. Our case illustrates that stereotactic thalamotomy may be considered as an option in treating severe tremor in selected patients of Wilson's disease and merit further trials.
17712859##2007-8-23##Cause of death in Wilson disease.##Before 1948, all patients with Wilson disease died shortly after diagnosis. In 1948, BAL (dimercaprol) was introduced as a possible effective treatment, to be followed by penicillamine (1955), zinc salts (1961), trientine (1969), liver transplantation (1982), and tetrathiomolybdate (1984). Despite this wide range of therapeutic options, patients still die. This article examines the cause of death in 67 patients (33 men, 34 women) out of a series of 300 seen between 1948 and 2000. Patients were classified according to their presentation as neurological, 32 patients, hepatic 11, mixed hepatic/neurological 10, hemolytic, 6, and "sibling biopsy " 8. Diagnostic failure was the principal cause of death but there were multiple other causes of which the principal was poor compliance and the development of malignant disease after 10 years of follow-up. The development of new symptoms should alert the physician to the possibility of a new pathology.
17954295##2007-1-3##D-Penicillamine-induced ANCA-associated crescentic glomerulonephritis in Wilson disease.##Several drugs, including hydralazine and propylthiouracil, can induce antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. d-Penicillamine was implicated in a few patients with rheumatoid arthritis or systemic sclerosis, but in patients with both diseases, ANCA-associated vasculitides were described in the absence of the drug. Therefore, the role of d-penicillamine treatment could not be established. We report the first case of antimyeloperoxidase antibody-associated vasculitis in a patient treated with d-penicillamine for Wilson disease. Because Wilson disease was never associated with ANCA-related nephritis, this case strongly supports that d-penicillamine can induce ANCA-vasculitis. The presentation and rapidly progressive and potentially severe outcome of this complication dramatically contrast with those of membranous and minimal change glomerulopathy, also induced by the sulfhydryl compound.
18075417##2007-12-14##The clinical value of Tc-99m TRODAT-1 SPECT for evaluating disease severity in young patients with symptomatic and asymptomatic Wilson disease.##
17587212##2007-6-26##Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease.##Wilson disease (WND), an autosomal recessive disorder of copper transport, is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic cirrhosis and neuronal degeneration are the major symptoms of WND, and mutations in the ATP7B gene are associated with WND. We have identified 28 different mutations in the ATP7B gene, including six novel variations, in 120 unrelated Korean patients with WND. Molecular defects in ATP7B were present in only 75.0% of Korean WND patients, with the most common mutation, p.Arg778Leu, having an allele frequency of 39.2%. To evaluate the functional defects of ATP7B caused by novel mutations, we used a yeast complementation system, and we used confocal microscopy to localize each mutation after transient expression in mammalian cells. Six novel variations were cloned into a yeast expression vector and two into a mammalian expression vector for confocal analysis. We found that c.2785A>G (p.Ile929Val) and c.3316G>A (p.Val1106Ile) were rare polymorphisms, whereas the others were novel variations disturbing ATP7B function.
18025747##2007-11-21##Wilson's disease presenting as isolated obsessive-compulsive disorder.##Wilson's disease (WD) is a genetic neurodegenerative disorder; it exhibits wide heterogeneity in symptoms and usually presents with liver disease and/ or neuropsychiatric manifestations. The common neurological manifestations observed are dysarthria, gait disturbance, dystonia, rigidity, tremor, dysphagia and chorea. The frequent psychiatric manifestations reported are personality and mood changes, depression, phobias, cognitive impairment, psychosis, anxiety, compulsive and impulsive behavior. Isolated obsessive-compulsive disorder (OCD) is a rare presentation of WD. Reported herein is a case of a 17-year-old boy with isolated OCD. He presented to the psychiatrist with symptoms of contamination obsessions and washing compulsions, along with compulsion of repeated feet tapping and was treated with adequate doses of fluoxetine for 6 months but did not improve. Later on, he was diagnosed as a case of WD and showed improvement with chelating and behavior therapy. This implies the importance of the occurrence of isolated psychological symptoms in WD.
17957491##2007-7-9##Epilepsy and inborn errors of metabolism in adults: a diagnostic approach.##Inborn errors of metabolism (IEMs) represent poorly known causes of epilepsy in adulthood. Although rare, these are important to recognize for several reasons: some IEMs respond to specific treatments, some antiepileptic drugs interfering with metabolic pathways may worsen the clinical condition, and specific genetic counselling can be provided. We review IEMs potentially revealed by epilepsy that can be encountered in an adult neurology department. We distinguished progressive myoclonic epilepsies (observed in some lysosomal storage diseases, respiratory chain disorders and Lafora disease), from other forms of epilepsies (observed in disorders of intermediary metabolism, including porphyrias, creatine metabolism defects, glucose transporter (GLUT-1) deficiency, Wilson disease or succinic semialdehyde dehydrogenase deficiency). We propose a diagnostic approach and point out clinical, radiological and electrophysiological features that suggest an IEM in an epileptic patient.
17804073##2007-4-20##Reversible precipitation of bovine serum albumin by metal ions and synthesis, structure and reactivity of new tetrathiometallate chelating agents.##Independent research is an important component of any undergraduate chemistry program. This article reports the findings of two of many undergraduate research projects directed by Ed Stiefel in the hopes that the results will be inspiring and useful to the scientific community. The neurological disorders associated with insufficient copper in Menkes disease and an excess of copper in Wilson's disease are well established; however, recent evidence suggests that copper may also be involved in other disorders, such as Alzheimer's, angiogenesis, and prion diseases. The exact role of copper, however, is uncertain. This study examines the role of copper and zinc in the formation of protein deposits and the chelation and removal of the metal ions to reverse the process. The bovine serum albumin (BSA) protein forms a precipitate after the addition of approximately 6 copper(II) atoms or 8 zinc(II) atoms. Other metal ions, such as Ca(II), Al(III), Ni(II), and Co(II), did not precipitate the BSA even when the metal ion to BSA ratios were in excess of 1000. The copper and zinc protein precipitates returned to solution after addition of the chelating agents, ethylenediaminetetraacetic acid (EDTA) or tetrathiometallates [(MS(4)(2-)), where M=Mo, W]. Two new choline and acetylcholine tetrathiomolybdate and tetrathiotungstate chelating agents have been synthesized and characterized. The infrared (IR) and X-ray crystal structures of the complexes revealed that the (MS(4)(2-)) cores had approximate T(d) symmetry in the choline (Ch) salts and C(2v) symmetry in the acetylcholine (AcCh) salts. The AcCh salts hydrolyzed more slowly than the ammonium or Ch salts and the tetrathiotungstate salts hydrolyzed approximately two orders of magnitude more slowly than the tetrathiomolybdate salts. The slower hydrolysis of tetrathiotungstate may make it more useful as an inorganic reagent and therapeutic agent.
17717039##2007-8-23##Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes.##The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.
17470473##2007-4-30##Ocular motility and Wilson's disease: a study on 34 patients.##
18024776##2007-11-21##The differential diagnosis of chorea.##Chorea is a hyperkinetic movement disorder characterised by excessive spontaneous movements that are irregularly timed, randomly distributed and abrupt. In this article, the authors discuss the causes of chorea, particularly Huntington's disease and the genetic syndromes that may resemble it, including HDL1-3, inherited prion disease, spinocerebellar ataxias 1, 3 and 17, neuroacanthocytosis, dentatorubro-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders, Wilson's disease, benign hereditary chorea, Friedreich's ataxia and mitochondrial disease. Acquired causes of chorea include vascular disease, post-infective autoimmune central nervous system disorders (PANDAS), drugs, systemic lupus erythematosus, antiphospholipid syndrome, thyrotoxicosis, AIDS, chorea gravidarum, and polycythaemia rubra vera. The authors suggest an approach to the clinical assessment of chorea, the value of investigations, including genetic tests (for which they offer a structured framework highlighting the importance of prior counselling), and finally briefly discuss symptomatic drug treatment of chorea.
17940926##2007-10-18##Movement disorders in pregnancy.##Movement disorders are not commonly seen during pregnancy. As a result, there are few studies on whether disease manifestations are affected by the hormonal changes that occur during pregnancy or on the teratogenicity of commonly used medications for movement disorders on the developing fetus. This article discusses movement disorders that are seen only during pregnancy (chorea gravidarum) or that may present during pregnancy (restless legs syndrome), the effect that pregnancy has on symptoms and treatment (in Parkinson's disease, essential tremor, dystonia, tic disorders, and Wilson's disease), and the role of genetic testing for movement disorders in genetic counseling for pregnant women.
17989618##2007-11-9##Successful living-donor liver transplantation for Wilson's disease with hemophagocytic syndrome.##
17876883##2007-9-19##Wilson disease: identification of two novel mutations and clinical correlation in Eastern Chinese patients.##
17972969##2007-11-2##Medical image. Hepatic Wilson's disease.##
17136311##2006-8-24##Heterozygous tx mice have an increased sensitivity to copper loading: implications for Wilson's disease carriers.##Wilson's disease carriers constitute 1% of the human population. It is unknown whether Wilson's disease carriers are at increased susceptibility to copper overload when exposed to chronically high levels of ingested copper. This study investigated the effect of chronic excess copper in drinking water on the heterozygous form of the Wilson's disease mouse model--the toxic milk (tx) mouse. Mice were provided with drinking water containing 300 mg/l copper for 4-7, 8-11, 12-15 or 16-20 months. At the completion of the study liver, spleen, kidney and brain tissue were analyzed by atomic absorption spectroscopy to determine copper concentration. Plasma ceruloplasmin oxidase activity and liver histology were also assessed. Chronic copper loading resulted in significantly increased liver copper in both tx heterozygous and tx homozygous mice, while wild type mice were resistant to the effects of copper loading. Copper loading effects were greatest in tx homozygous mice, with increased extrahepatic copper deposition in spleen and kidney - an effect absent in heterozygote and wild type mice. Although liver histology in homozygous mice was markedly abnormal, no histological differences were noted between heterozygous and wild type mice with copper loading. Tx heterozygous mice have a reduced ability to excrete excess copper, indicating that half of the normal liver Atp7b copper transporter activity is insufficient to deal with large copper intakes. Our results suggest that Wilson's disease carriers in the human population may be at increased risk of copper loading if chronically exposed to elevated copper in food or drinking water.
17410460##2006-6-20##Analysis of the T1288R mutation of the Wilson disease ATP7B gene in four generations of a family: possible genotype-phenotype correlation with hepatic onset.##Wilson disease, an autosomal recessive disorder due to mutations of the ATP7B gene, is characterized by copper accumulation and toxicity in the liver and subsequently in other organs, mainly the brain and cornea. A new missense mutation (T1288R) of the ATP7B gene has recently been discovered in a Wilson disease patient in our laboratory. The aim of the present study was to analyze clinical and genetic features of more generations of the family of the patient in which the new mutation T1288R was discovered. A total of 19 subjects were studied; in particular, four generations of the patient's family were analyzed. The ATP7B gene was analyzed by single-strand conformational polymorphism followed by direct sequencing. Two brothers presented a clinical diagnosis of Wilson disease with an hepatic phenotype and a genotype characterized by the homozygotic mutation T1288R. The heterozygotic mutation T1288R was found in seven subjects belonging to all four generations. The present study represents the first screening for a Wilson disease mutation through four generations of a nonconsanguineous family. All the patients with the homozygotic T1288R mutation in the present pedigree presented an hepatic phenotype without a neurological presentation. Consequently, a genotype-phenotype correlation could be hypothesized, although further studies are necessary to clarify this topic.
17157086##2006-7-6##Fatal liver failure following food supplements during chronic treatment with montelukast.##High aminotransferases and prolonged prothrombin time on entering our liver unit were revealing parenchymal collapse for this 45-year-old obese woman; treatment failure led her to death. Autoimmunity, paracetamol use, alcoholism, and Wilson's disease were all excluded as causes. Because of chronic asthma, she had been receiving a leukotriene receptor antagonist (montelukast) for 5 years before the current presentation; 1 week before onset she had had 1 week of treatment with two dietary supplements for weight control; one of these included Garcinia Cambogia, a possible cause of two recent cases of hepatitis in the USA; in addition, both formulas contained a citrus derivative that interferes cytochrome functions. We speculate on a causal relationship between the assumption of the additives and the fatal hepatitis and envisage a synergy between the additives and montelukast, which per se has well been studied as a hepatotoxic drug. Despite the speculative nature of this presentation, we believe the warning may serve to focus attention on the uncontrolled escalation of food additives going on in these days.
17919502##2006-7-25##Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B.##
17949296##2007-10-24##Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin.##Herein we report the results of mutation analysis of the ATP7B gene in a group of 134 Wilson disease (WD) families (268 chromosomes) prevalently of Italian origin. Using the SSCP and sequencing methods we identified 71 disease-causing mutations. Twenty-four were novel, while 19 more mutations already described, were identified in new populations in this study. A known mutation G591D showed a regional distribution, since it was only detected in 38.5% of the analyzed chromosomes in WD patients originating from Apulia, a region of South Italy. Detection of new mutations in the ATP7B gene increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.
17931203##2007-10-13##De novo autoimmune hepatitis after liver transplantation.##The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non-immune mediated liver diseases. They coined the term "de novo autoimmune hepatitis". Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres. The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1-positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP-autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value - which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur. Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo-antigens, neo-antigens in the liver, or self-antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co-stimulatory signals leading to the breaking of self-tolerance. The development of this disease in the presence of treatment with calcineurin inhibitors supports the view held by most specialists in autoimmune hepatitis that these drugs, even though effective in acute disease, are not helpful in the long-term management of autoimmune liver diseases.
17517077##2007-5-22##Genetic background of Japanese patients with adult-onset storage diseases in the liver.##In contrast to primary lysosomal diseases in young subjects, adult-onset liver storage disorders may be explained by non-lysosomal genetic defects. The aim of the present review is to summarize the genetic backgrounds of Japanese patients with hemochromatosis of unknown etiology, Wilson disease of primary copper toxicosis, and the black liver of Dubin-Johnson syndrome. Three patients with middle-age onset hemochromatosis were homozygous for mutations of HJV and two patients were homozygous for mutations of TFR2. Minor genes other than HJV and TFR2 might be involved in Japanese patients. Five of the six patients with Wilson disease were compound heterozygous, while the remaining patient was heterozygous for the mutation in ATP7B responsible for copper toxicosis. Involvement of MURR1 was not proved in the heterozygote of ATP7B. Because of ferroxidase deficiency,most patients had secondary lysosomes shared by cuprothioneins and iron complex. Six patients with Dubin-Johnson syndrome were homozygous or compound heterozygous for mutant MRP2. Despite complex metabolic disorders, the syndrome had a single genetic background. Thus, most patients with adult-onset lysosomal proliferation in the liver had genetic defects in non-lysosomal organelles, named the secondary lysosomal diseases. The proliferating lysosomes in these conditions seemed to be heterogeneous in their matrices.
17694356##2007-4-17##Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults.##Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late-onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and alpha and beta mannosidosis. Because specific treatments should be more effective at the 'psychiatric stage' before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations.
17894614##2007-9-27##Central pontine signal changes in Wilson's disease: distinct MRI morphology and sequential changes with de-coppering therapy.##
17694349##2006-8-21##Wilson's disease in two consecutive generations in a Bulgarian Roma family.##
17786364##2007-9-6##Copper efflux transporter (ATP7B) contributes to the acquisition of cisplatin-resistance in human oral squamous cell lines.##Acquired resistance to cisplatin (CDDP) is an issue in cancer chemotherapy. This resistance has been reported to be correlated with the expression of the Cu influx copper transporter 1 (CTR1) and two copper efflux transporters (ATP7A, ATP7B). We investigated the correlation between the expression of these transporters and the sensitivity to CDDP using three pairs of parent cell lines and resistant cell lines derived from various types of invasive oral squamous cell carcinoma (OSCC). Using multiple steps, each of the CDDP-resistant cell lines, HSC-4-R, OSC-19-R, HOC313-R, was selected from HSC-4 cells derived from a cancer with medium invasiveness, OSC-19 cells derived from a cancer with high invasiveness and HOC313 cells derived from a cancer with the highest invasiveness. Resistant cell lines had a stronger expression of ATP7B in conjunction with the acquisition of CDDP-resistance than parent cell lines. Furthermore, OSC-19-R cells transfected with the ATP7B siRNA had a 10.6-fold higher sensitivity to CDDP compared to OSC-19-R cells transfected with a nonsense siRNA. These results suggest that each of the resistant cell lines had acquired resistance to CDDP due to the overexpression of ATP7B. On the other hand, the expression of CTR1 was the same between sensitive cell lines and resistant cell lines and ATP7A mRNA expression was barely noted. We conclude that ATP7B is correlated with the acquisition of CDDP resistance more closely than either CTR1 or ATP7A. ATP7B may be a key determinant in the acquired resistance to CDDP in OSCC.
18033024##2007-11-23##[Treatable hereditary neuro-metabolic diseases].##Hereditary metabolic diseases may appear during adolescence or young adulthood, revealed by an apparently unexplained neurological or psychiatric disorder. Certain metabolic diseases respond to specific treatments and should be identified early, particularly in emergency situations where rapid introduction of a treatment can avoid fatal outcome or irreversible neurological damage. The main diseases leading to an acute neurological syndrome in the adult are urea cycle disorders, homocysteine metabolisms disorders and porphyria. More rarely, Wilson's disease, aminoacid diseases, organic aciduria, or pyruvate dehydrogenase deficiency, beta-oxidation disordes or biotin metabolism may be involved. Most emergency situations can be screen correctly with simple tests (serum ammonia, homocysteine, lactate, urinary prophyrines, acylcarnitine pattern, amino acid and organic acid chromatography). For chronic situations, the main treatable diseases are Wilson's disease, homocysteine, cerebrotendinous xanthomatosis, Refsum's disease, vitamin E deficiency, Gaucher's disease, Fabry's disease, and neurotransmitter metabolism disorders. We present treatable metabolic disorders as a function of the different clinical situations observed in adults.
17987735##2007-11-9##Persistent akinetic-rigid side effects of neuroleptics may indicate Wilson's disease.##Here we report two cases, where neuroleptic treatment provoked persistent akinetic-rigid symptoms resulting in the diagnosis of Wilson's disease. No liver function abnormalities suggested Wilson's disease in one of the cases. In both cases, the akinetic-rigid symptoms were originally attributed to side effects of neuroleptics, but symptoms persisted after discontinuation of treatment. In one of the cases, T2-weighted cranial MRI indicated bilateral hyperintense signals in the basal ganglia. Our cases suggest that in a subgroup of Wilson's disease, dopamine receptor antagonists may provoke akinetic-rigid neurological symptoms possibly due to the damage of dopaminergic neurons. Persistent akinetic-rigid side effects of neuroleptics in young patients thus require diagnostic tests to exclude Wilson's disease even in unsuspected cases.
17899785##2007-9-29##Extreme consumption of Beta vulgaris var. rubra can cause metal ion accumulation in the liver.##Redox homeostasis can be considered as the cumulative action of all free radical reactions and antioxidant defences in different tissues, which provide suitable conditions for life. Transition metal ions are ubiquitous in biological systems. Beta vulgaris var. rubra (table beet root) contains several bioactive agents (e.g. betain, betanin, vulgaxanthine, polyphenols, folic acid) and different metal elements (e.g. Al, B, Ba, Ca, Cu, Fe, K, Mg, Mn, Na, Zn), which act on the various physiological routes. Therefore we studied the effect of this metal rich vegetable on element content of the liver in healthy rats. Male Wistar rats (n = 7) (200 +/- 20 g) were treated with lyophilised powder of table beet root (2 g/kg b.w.) added into the rat chow for 10 days. Five healthy animals served as control. We found significant accumulation of Cu, Fe, Mg, Mn, Zn and P in the liver, which was proved by ICP-AES measurements. We suppose that the extreme consumption of table beet root can cause several disturbances not only in cases of healthy patients but, e.g. in patients suffering with metal accumulating diseases, e.g. porphyria cutanea tarda, haemochromatosis or Wilson disease-although moderate consumption may be beneficial in iron-deficiency anaemia and inflammatory bowel diseases.
17827379##2007-9-11##Wilson disease with visceral leishmaniasis: an extremely uncommon presentation.##Visceral leishmaniasis (VL), which is caused by the protozoa Leishmania donovani and transmitted by the bite of the female sand fly Phlebotomus argentipes, is common in Bihar, India. Wilson disease is an autosomal recessive disorder of copper metabolism in which copper is deposited in the brain and liver. We report a case of an extremely uncommon combination of these diseases in a patient. Treatment options for such a combination of diseases are limited and difficult.
17709362##2007-8-20##Sequential MRI changes in Wilson's disease with de-coppering therapy: a study of 50 patients.##Wilson's disease (WD) is clinically and radiologically a dynamic disorder. However, there is a paucity of studies involving sequential MRI changes in this disease with or without therapy This study looked at serial MRI changes and their clinical correlate in patients with WD The severity of MRI changes using 1.5 T MRI in 50 patients with WD was graded based on alteration in signal intensity of focal lesions and atrophy. Details of clinical manifestations, Schwab and England Activities of daily living (MSEADL) score, Neurological Symptom Score (NSS) and Chu staging were recorded. Clinical severity and disability scores were correlated with MRI scores using SPSS v10 The mean age at onset of illness and diagnosis was 12.8+/-5.6 years and 14.4+/-6.0 years, respectively. At the time of first MRI, patients had been treated for 49.0+/-77.3 months. At a follow-up of 24.2+/-12.2 months, clinically 36 patients had improved, 9 remained the same and 5 had worsened. Serial imaging revealed an improvement in MRI parameters in 35 patients, no significant changes in 10, worsening in 4 and an admixture of resolving and evolving changes in 1. The overall MRI score improved from 8.2+/-5.7 to 5.9+/-6.6. There was an improvement in measures of disability and impairment in all: Chu stage, 11.5+/-0.7 to 1.3+/-0.6; MSEADL score (%), 79.7+/-27.6 to 88.0+/-25.4; NSS, 10.6+/-11.2 to 8.0+/-11.6, with good clinico-radiological correlation. Patients with extensive changes, white-matter involvement and severe diffuse atrophy had a poor prognosis In conclusion, the majority of patients with WD showed variable improvement in clinical and MRI features when treated.
17711999##2007-8-23##Introducing single-nucleotide polymorphism markers in the diagnosis of Wilson disease.##
17634212##2007-7-18##Molecular diagnosis of Wilson disease using prevalent mutations and informative single-nucleotide polymorphism markers.##
17718866##2007-8-28##Early and severe liver disease associated with homozygosity for an exon 7 mutation, G691R, in Wilson's disease.##
17849244##2007-9-13##Significance of copper determination in late onset of Wilson's disease.##
18019719##2007-11-21##Serum selenium concentration in patients with Wilson's disease.##
17535304##2007-5-29##Serum nitric oxide levels in children with Wilson's disease.##
17882762##2007-9-21##Depression and chorea. Diagnosis: Wilson's disease.##
17925919##2007-10-11##The quality of the fragment obtained by liver biopsy for staging chronic hepatitis.##
17629589##2007-5-12##Three atypical cases of Wilson disease: assessment of the Leipzig scoring system in making a diagnosis.##
17898558##2007-9-28##Alfuzosin-induced acute liver injury.##We describe a 56-year-old man who developed an acute liver injury after taking alfuzosin for 1 month to control his newly diagnosed benign prostatic hypertrophy (BPH). There was no history of alcohol consumption or the taking herbal or traditional remedies. Viral causes, autoimmune hepatitis, and biliary tree obstruction were excluded. Other rare causes of hepatitis such as hemochromatosis, primary biliary cirrhosis and Wilson's disease were also absent in this patient. His liver test results began to improve after discontinuing the alfuzosin. Two weeks later, alfuzosin was administered again because the patient complained of dysuria. After 10 days of alfuzosin reuse, his liver test results worsened. Five months later after the complete discontinuation of the drug, his liver test results had returned to normal. This clinical sequence suggests that alfuzosin caused his acute liver injury.
17890269##2007-11-29##Liver transplantation for metabolic liver diseases in adults: indications and outcome.##Orthotopic liver transplantation is the preferred treatment for many patients with complications of end-stage liver disease. For metabolic liver diseases liver transplantation does not only replace the diseased organ, but also can potentially correct the metabolic defect. Results of liver transplantation for metabolic diseases have been encouraging. In Wilson's disease liver transplantation is considered an effective treatment for the fulminant form and for end-stage liver disease, associated with an excellent long-term outcome. However, it is still a matter of controversy whether liver transplantation should be considered in Wilson's disease patients with severe neurological impairment. Liver transplantation for hereditary haemochromatosis is relatively uncommon and is associated with a decreased post-transplantation patient survival, most likely due to infections and cardiac complications. Reduction of iron overload prior to liver transplantation in patients with hereditary haemochromatosis might be associated with a better outcome.
17889175##2007-9-25##Clinical evolution in the first 3 months of patients after liver transplantation in maintenance phase converted from mycophenolate mofetil to mycophenolate sodium due to gastrointestinal complications.##The enteric-coated mycophenolate sodium (EC-MPS) is a new formulation of mycophenolic acid with a gastro-resistant enteric coating, which releases the drug in the intestine, reducing the incidence of the gastrointestinal (GI) adverse effects. The present work provided a summary of 20 patients with liver transplantation and more than a 1 year of treatment with mycophenolate mofetil (MMF) who, after presentation of GI complications, were converted to EC-MPS. The patients were followed over a 3-month period after beginning EC-MPS treatment. The mean age of the cohort was 53 +/- 10 years and included 75% men. The reasons for transplantation were ethanol cirrhosis (70%), hepatitis C cirrhosis (30%), hepatocarcinoma (5%), and Wilson's disease (5%). At baseline, all patients were being treated with cyclosporine (CsA). CsA doses and levels were reduced during follow-up: baseline dose 179 mg/day versus 143 mg/day at 3 months; levels: 90.4 ng/mL versus 85.8 ng/mL, respectively (P = .017). The administered dose of EC-MPS was 720 mg/day in all cases. The GI complications at baseline were: diarrhea 60% (92% moderate-severe), abdominal discomfort 60% (58% moderate), abdominal pain 45% (44% moderate-severe), gas 40% (38% moderate-severe), nausea 20% (25% moderate), and dyspepsia 20% (mild). After 3 months of EC-MPS treatment, only two patients (10%) displayed moderate diarrhea. The renal evolution was favorable, serum creatinine was reduced, and 24-hour creatinine clearance significantly increased (creatinine: 1.78 +/- 1.6 mg/dL at baseline versus 1.30 +/- 0.3 mg/dL at 3 months, P = .002; creatinine clearance: 72.8 +/- 18 mL/min versus 79.6 +/- 13 mL/min, P = .001). Conversion of MMF to EC-MPS in liver transplant recipients solved the GI tolerability problems and improved renal function during the first 3 months, probably due to the concomitant reduction of anticalcineurinic dose.
17889170##2007-9-25##Liver transplantation in Wilson's disease: are its indications established?##
18254302##2008-2-8##[Epidemiological, etiological and evolutionary aspects of children cirrhosis in a developing country: experience of the pediatric department of SFAX University hospital, Tunisia].##
17969887##2007-11-1##[Effect of Gandou Decoction IV combined with short-term decoppering therapy with sodium dimercapto-sulphonate on serum indexes of hepatic fibrosis in patients with Wilson' s disease].##
17903386##2007-10-2##[A study of the liver pathology and direct sequencing of all exons of WD gene in a patient with fulminant Wilson disease].##
17609202##2007-7-3##Characterization and structure of a Zn2+ and [2Fe-2S]-containing copper chaperone from Archaeoglobus fulgidus.##Bacterial CopZ proteins deliver copper to P1B-type Cu+-ATPases that are homologous to the human Wilson and Menkes disease proteins. The genome of the hyperthermophile Archaeoglobus fulgidus encodes a putative CopZ copper chaperone that contains an unusual cysteine-rich N-terminal domain of 130 amino acids in addition to a C-terminal copper binding domain with a conserved CXXC motif. The N-terminal domain (CopZ-NT) is homologous to proteins found only in extremophiles and is the only such protein that is fused to a copper chaperone. Surprisingly, optical, electron paramagnetic resonance, and x-ray absorption spectroscopic data indicate the presence of a [2Fe-2S] cluster in CopZ-NT. The intact CopZ protein binds two copper ions, one in each domain. The 1.8 A resolution crystal structure of CopZ-NT reveals that the [2Fe-2S] cluster is housed within a novel fold and that the protein also binds a zinc ion at a four-cysteine site. CopZ can deliver Cu+ to the A. fulgidus CopA N-terminal metal binding domain and is capable of reducing Cu2+ to Cu+. This unique fusion of a redox-active domain with a CXXC-containing copper chaperone domain is relevant to the evolution of copper homeostatic mechanisms and suggests new models for copper trafficking.
17713430##2007-8-24##Live donor liver transplantation for acute liver failure.##
17573059##2007-1-9##A study on the concentrations of serum zinc, non-ceruloplasmin copper, reactive oxygen and nitrogen species in children with Wilson's disease.##
17625435##2007-7-13##Etiologies of chronic liver diseases in Hong Kong.##
17570556##2007-5-24##Non-invasive testing for Wilson disease: revisiting the d-penicillamine challenge test.##
17449133##2006-12-9##Re-evaluation of the penicillamine challenge test in the diagnosis of Wilson's disease in children.##
18021535##2007-11-21##[Curcumin attenuated the lipid peroxidation and apoptotic liver injury in copper-overloaded rats].##
17703692##2007-8-21##[Efficient diagnostics for elevated transaminases].##The diagnosis of the cause of elevated transaminases is carried out stepwise. First, a medical history is taken and a physical examination and sonography of the abdomen are performed. The second step includes laboratory tests for chronic hepatitis B and C, hereditary haemochromatosis, Wilson's disease, autoimmune hepatitis and alpha-1-antitrypsin deficiency. The third step comprises the identification of possible extrahepatic causes. Serological tests to exclude celiac disease should be first carried out when TSH and CK values do not yield an indicative finding.
17562324##2007-2-19##Biochemical basis of regulation of human copper-transporting ATPases.##Copper is essential for cell metabolism as a cofactor of key metabolic enzymes. The biosynthetic incorporation of copper into secreted and plasma membrane-bound proteins requires activity of the copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B. The Cu-ATPases also export excess copper from the cell and thus critically contribute to the homeostatic control of copper. The trafficking of Cu-ATPases from the trans-Golgi network to endocytic vesicles in response to various signals allows for the balance between the biosynthetic and copper exporting functions of these transporters. Although significant progress has been made towards understanding the biochemical characteristics of human Cu-ATPase, the mechanisms that control their function and intracellular localization remain poorly understood. In this review, we summarize current information on structural features and functional properties of ATP7A and ATP7B. We also describe sequence motifs unique for each Cu-ATPase and speculate about their role in regulating ATP7A and ATP7B activity and trafficking.
17531189##2007-2-2##Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis.##Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.
17382285##2006-12-7##XIAP: cell death regulation meets copper homeostasis.##X-linked inhibitor of apoptosis (XIAP), traditionally known as an anti-apoptotic protein, has recently been shown to be involved in copper homeostasis. XIAP promotes the ubiquitination and degradation of COMMD1, a protein that promotes the efflux of copper from the cell. Through its effects on COMMD1, XIAP can regulate copper export from the cell and potentially represents an additional intracellular sensor for copper levels. XIAP binds copper directly and undergoes a substantial conformational change in the copper-bound state. This in turn destabilizes XIAP, resulting in lowered steady-state levels of the protein. Furthermore, copper-bound XIAP is unable to inhibit caspases and cells that express this form of the protein exhibit increased rates of cell death in response to apoptotic stimuli. These events take place in the setting of excess intracellular copper accumulation as seen in copper toxicosis disorders such as Wilson's disease and establish a new relationship between copper levels and the regulation of cell death via XIAP. These findings raise important questions about the role of XIAP in the development of copper toxicosis disorders and may point to XIAP as a potential therapeutic target in these disease states.
17848726##2006-12-14##Contribution to the data on copper concentration in blood and urine in patients with Wilson's disease and in normal subjects.##Determination of copper in human tissues and body fluids may be crucial in the diagnosis of Wilson's disease. In this study we evaluated urinary copper excretion and urine and blood concentration in 14 patients in whom Wilson's disease was confirmed (group A) and in 21 subjects in whom the disease was only suspected (group B). The following values (mean +/- SD) were found: 24-h urine (microg Cu/24 h), 152 +/- 135 (A) and 31.8 +/- 10.9 (B); urine (microg Cu/ml), 0.091 +/- 0.087 (A) and 0.028 +/- 0.011 (B); and blood (microg Cu/ml), 0.62 +/- 0.25 (A) and 0.72 +/- 0.09 (B). By comparison, urine copper concentration in the group of apparently healthy subjects was 0.035 +/- 0.010 (n = 50), and blood copper concentration in autopsy cases of nonpoisoned people was 0.85 +/- 0.19 (n = 73).
17582157##2007-6-22##Sample number and denaturation time are crucial for the accuracy of capillary-based LightCyclers.##
17382611##2006-10-10##Wilson disease--a practical approach to diagnosis, treatment and follow-up.##Wilson disease is an inherited, autosomal recessive, copper accumulation and toxicity disorder that affects about 30 individuals per million. This rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase, which is important for copper excretion into bile, leading to copper accumulation in the liver. Toxic copper concentrations can also be found in the brain and kidney, and clinical phenotypes include hepatic, haemolytic, neurologic and psychiatric diseases. Diagnosis is based on the combination of clinical features and findings such as increased urinary copper excretion, reduced levels of serum ceruloplasmin, high concentrations of copper in liver tissues and Kayser-Fleischer rings. Genetic studies are also becoming available for clinical use, but the utility of direct mutation analysis is limited. Wilson disease can be treated, and early diagnosis is essential: the goal of therapy is to reduce copper accumulation either by enhancing its urinary excretion or by decreasing its intestinal absorption. Medical therapies include penicillamine, trientine, zinc and tetrathiomolibdate. Liver transplantation is a relatively successful treatment option when medical therapy fails or in case of acute liver failure, even though it is also characterized by short- and long-term complications.
17708301##2007-8-22##Split liver transplantation for acute Wilson's disease: new option for urgent recipient?##Wilson's disease is a rare metabolic disorder that may lead to fulminant hepatitis and subsequent liver failure. Herein, we present a case of split liver transplantation performed on a patient with acute Wilson's disease. A 27-year-old female with acute presentation of Wilson's disease and advanced neurological impairment, received a Right Split liver Graft (Segments: IV, V, VI, VII and VIII) transplant. The graft was obtained by an in situ splitting technique. The graft implantation was performed in a standard fashion. No acute rejection episodes of the organ occurred. The postoperative course was uneventful. The graft function, ceruloplasmine level and copper levels progressively normalized. The patient totally recovered from neurological symptoms and the Kayser-Fleischer rings disappeared within one month. At 13 months of follow-up, the patient presented with no symptoms and in good condition. The current literature reports high preoperative mortality rate in patients that underwent partial liver graft for acute hepatic failure. However, our experience indicates that in situ split technique of liver may be a feasible and effective alternative to whole graft transplantation in urgent cases. Moreover, to our knowledge, this is the first successfully case of in situ split liver transplantation for acute Wilson's disease described in literature.
17626718##2007-7-14##Validated, stability-indicated quantitative purity test for triethylenetetramine tetrachlorhydrate by automated multiple development.##There is a monography of Triethylenetetramine dichlorhydrate (Trientine) in the United States Pharmacopeia. But neither the base nor the salts di- or tetra-chlorhydrate are in the European Pharmacopeia. Triethylène tetramine tetrachlorhydrate, used by AGEPS now as matural, is more soluble then triethylene tetramine dichlorhydrate. It is administred to patients with Wilson's disease, which results from a congenital lack of the copper metabolism. A quantitative purity test of this drug by automated multiple development high-performance thin-layer chromatography is developed and validated. The validation parameters tested are specifically characterized by retention factor, linearity, limits of detection and quantitation of several nanograms, reliability, and accuracy. To determine impurities, the monography of triethylenetetramine dichlorhydrate in the American Pharmacopeia is tested. This method in classic developing tank requires two mobile phases and is not quantitative. Assays in high-performance liquid chromatography with a different column and mobile phase did not give good results for the separation of impurities. Thus, it is not possible to perform comparative validation of the separation of the impurities. Only the assay of triethylenetetramine with potentiometer detection has been validated.
17686362##2005-11-22##Wilson'S disease with neurological presentation.##A young man presented with Parkinsonism-like illness. On clinical examination and investigations, the patient showed all the features of Wilson's disease. He is being treated with Penicillamine, and has shown improvement.
17615395##2007-7-7##Function and regulation of human copper-transporting ATPases.##Copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B are evolutionarily conserved polytopic membrane proteins with essential roles in human physiology. The Cu-ATPases are expressed in most tissues, and their transport activity is crucial for central nervous system development, liver function, connective tissue formation, and many other physiological processes. The loss of ATP7A or ATP7B function is associated with severe metabolic disorders, Menkes disease, and Wilson disease. In cells, the Cu-ATPases maintain intracellular copper concentration by transporting copper from the cytosol across cellular membranes. They also contribute to protein biosynthesis by delivering copper into the lumen of the secretory pathway where metal ion is incorporated into copper-dependent enzymes. The biosynthetic and homeostatic functions of Cu-ATPases are performed in different cell compartments; targeting to these compartments and the functional activity of Cu-ATPase are both regulated by copper. In recent years, significant progress has been made in understanding the structure, function, and regulation of these essential transporters. These studies raised many new questions related to specific physiological roles of Cu-ATPases in various tissues and complex mechanisms that control the Cu-ATPase function. This review summarizes current data on the structural organization and functional properties of ATP7A and ATP7B as well as their localization and functions in various tissues, and discusses the current models of regulated trafficking of human Cu-ATPases.
17467652##2006-12-13##Ceramide: physiological and pathophysiological aspects.##Ceramide generated in the cell membrane has been shown to be central for the induction of apoptosis by death receptors and many stress stimuli such as gamma-irradiation, UV-light or infection with pathogens. Ceramide reorganizes cell membranes and forms large ceramide-enriched membrane domains that serve the spatial and temporal organization of the cellular signalosome upon activation. Thus, ceramide-enriched membrane domains mediate clustering of CD95 and DR5 to facilitate apoptosis, and they are also critically involved in apoptosis after irradiation, UV-light and infection with Pseudomonas aeruginosa. Since ceramide-enriched membrane domains amplify signals, their function is not restricted to the induction of apoptosis and it was shown that ceramide-enriched membrane domains are also involved in internalization of pathogens and the control of cytokine release from infected epithelial cells. Recent studies support the notion that changes of the ceramide metabolism are also critically involved in human diseases, for instance neurological disorders, cancer, infectious diseases and Wilson's disease.
17268820##2006-8-23##Hepatic copper-transporting ATPase ATP7B: function and inactivation at the molecular and cellular level.##Copper-transporting ATPase ATP7B (Wilson disease protein) is a member of the P-type ATPase family with characteristic domain structure and distinct ATP-binding site. ATP7B plays a central role in the regulation of copper homeostasis in the liver by delivering copper to the secretory pathway and mediating export of excess copper into the bile. The dual function of ATP7B in hepatocytes is coupled with copper-dependent intracellular relocalization of the transporter. The final destination of ATP7B in hepatocytes during the copper-induced trafficking process is still under debate. We show the results of immunocytochemistry experiments in polarized HepG2 cells that support the model in which elevated copper induces trafficking of ATP7B to sub-apical vesicles, and transiently to the canalicular membrane. In Atp7b-/- mice, an animal model of Wilson disease, both copper delivery to the trans-Golgi network and copper export into the bile are disrupted despite large accumulation of copper in the cytosol. We review the biochemical and physiological changes associated with Atp7b inactivation in mouse liver and discuss the pleiotropic consequences of the common Wilson disease mutation, His1069Gln.
17584039##2007-6-23##Perspectives for gene therapy of Wilson disease.##Wilson disease is a rare autosomal-recessive copper overload disorder due to mutations of the Wilson disease gene ATP7B. The disease typically manifests at late childhood or in young adults with hepatic and/or neurological symptoms. Being fatal without medical treatment or liver transplantation the long-term outcome of Wilson disease depends on the adherence to an effective treatment. Because current medical treatment options are not effective in all Wilson disease patients and adherence to therapy is a problem, gene therapy might represent an alternative curative future therapy. In the rat model of Wilson disease adenoviral and lentiviral gene transfer studies could prove that viral gene transfer is therapeutically effective and can reverse clinical symptoms. However, both approaches were limited by a more or less transient transgene expression. As several tactics can be used to overcome these current limitations, gene therapy approaches may become more efficient than standard medical treatment for Wilson disease in the future. This review discusses both, existing vectors and strategies and prospective developments towards liver-directed gene therapy, although there is still a long way to go until gene therapy can be used for safe treatment of Wilson disease in humans.
17660582##2007-7-31##Detection of His1069Gln mutation in Wilson disease by bidirectional PCR amplification of specific alleles (BI-PASA) test.##Wilson disease (WD) is an autosomal recessive disorder of hepatic copper metabolism caused by mutations in a gene encoding a copper-transporting P-type ATPase, ATP7B. The majority of known mutations affecting this gene are frequent in different populations, which may help to introduce rapid diagnostic procedures based on direct DNA analysis into routine clinical practise. The His1069Gln mutation in exon 14 is the most frequent one, accounting for 30-60% of all mutations in Caucasian patients. The aim of the present work was to introduce DNA-based direct analysis into routine molecular screening for the above mutation in Slovak WD patients and to assess its frequency in patients as well as in a control population. Twenty seven clinicaly diagnosed patients from twenty five families, twenty relatives of index patients and three hundred and six control DNA samples were tested using two different DNA-based methods: the earlier described amplification created restriction site (ACRS) for Alw21I in combination with nested PCR and the amplification refractory mutation system (ARMS). In 18 of 25 unrelated patients (72%), the mentioned genetic defect was present in at least one copy. In ten of them (40%), the above mutation was detected in homozygous and in eight individuals (32%) in heterozygous state. In seven WD patients (28%), this mutation was not detected. The allele frequency of His1069Gln in Slovak patients with WD was 56%, which was higher as reported in other populations. In a control group of 306 random DNA samples (612 alleles), the His1069Gln mutation was observed in 3 samples (carrier frequency 1%; allele frequency 0.49%). These frequencies correspond to figures observed in different population of European origin. Taken together, we have provided further evidence that the His1069Gln mutation is the prevalent ATP7B mutation in central-european WD patients. Although both methods used in this study worked in our hands reliably, there are in every-day use some drawbacks and limitations inherent to them (PCR reactions in two tubes, possibility of star activity or not complet digestion by restriction endonuclease, etc.). Therefore we developed a simpler, cost effective and rapid DNA diagnostic test based on bidirectional amplification of specific alleles (BI-PASA), which enables detection of homozygotes (wild and mutant) and heterozygotes, respectivelly, in one PCR reaction. The test was highly sensitive and specific, yielding no false-positive or false-negative results. Its reliability and discriminating power was tested on samples of 27 WD patients and 120 random control DNA's, previously genotyped by above mentioned methods. Comparing results of BI-PASA with ACRS and ARMS tests showed 100% concordance.
17641252##2007-7-21##Subacute sclerosing panencephalitis (SSPE): an insight into the diagnostic errors from a tertiary care university hospital.##Subacute sclerosing panencephalitis (SSPE) is a progressive disease caused by wild-type measles virus leading to premature death. Early diagnosis may help in medical interventions and counseling. The aim of this study was to ascertain diagnostic errors and their possible causes. Retrospective case record analysis of patients with subacute sclerosing panencephalitis, evaluated over a 10-year period, was performed. The following data were analyzed: initial symptoms and diagnosis, interval between onset of symptoms to diagnosis, and implications of delayed diagnosis. Among the 307 patients evaluated, initial diagnosis by various health care professionals was other than subacute sclerosing panencephalitis in 242 patients (78.8%). These included seizures, absence seizures, metachromatic leukodystrophy, Schilder's disease, cerebral palsy, hemiparkinsonism, Wilson's disease, vasculitis, spinocerebellar ataxia, motor neuron disease, nutritional amblyopia, tapetoretinal degeneration, catatonic schizophrenia, and malingering, among others. The interval between precise diagnosis and first reported symptom was 6.2 +/- 11.3 months (range, 0.2-96 months; median, 3 months). Forty-four patients (14.3%) who had symptoms for more than 1 year before the precise diagnosis had a protracted course as compared to the rest of the cohort ( P = .0001). Early and accurate diagnosis of subacute sclerosing panencephalitis needs a high index of suspicion.
17493220##2007-5-12##Frequency of urinary tract infection in pediatric liver transplantation candidates.##An increased frequency of infections has been reported in patients with chronic liver disease. The tendency of patients in this population to acquire UTI is not completely understood. We aimed at investigating the incidence of UTI in children with cirrhosis, before liver transplantation. Twenty-six children (9 girls, 17 boys; mean age, 7.66 +/- 5.73 yr) with chronic liver disease who had undergone liver transplantation between 2002 and 2004 were included. On admission for liver transplantation, patients were examined for presence of UTI. Serum biochemistry, complete blood cell count, urinalysis and culture, glomerular filtration rate, and abdominal ultrasonography were performed prior to liver transplantation. Ten of 26 patients (38.5%) were found to have symptomatic UTI. Urine cultures revealed E. coli in five (50%), Klebsiella pneumoniae in three (30%), Enterococcus faecalis in one (10%), and Enterobacter aeruginosa in one (10%) patient(s), respectively, as etiologic factors. The etiologies of chronic liver disease in our patients with UTI were BA in five, PFIC in three, Wilson's disease in one, and alpha-1 antitrypsin deficiency in one patient. We found a significantly greater number of UTIs in patients with biliary atresia than in those without biliary atresia (p < 0.05). The mean age of the patients with UTI was 2.75 +/- 3.49 yr, which was significantly lower than in those without UTI (9.75 +/- 4.86 yr, p < 0.05). Levels for white blood cells, thrombocytes, ALT, and alkaline phosphatase were significantly higher in patients with UTI than in those without UTI. There were no significant differences between the groups with regard to serum albumin, bilirubin, AST, GGT, BUN, or creatinine levels, glomerular filtration rate, duration of disease, and PELD scores. In patients with bacteriuria, renal USG revealed normal findings in all, but except one patient who had pelvicalyceal dilatation. Scintigraphic findings demonstrated acute pyelonephritis in six (60%) patients with UTI. VCUG demonstrated vesicoureteral reflux in two patients. In conclusion, symptomatic UTI is common in children with cirrhosis. It occurs more frequently in patients with biliary atresia than it does in patients with other types of chronic liver disease. In febrile children with chronic liver disease, UTI should be considered in the differential diagnosis.
17505988##2007-5-17##Hereditary iron and copper deposition: diagnostics, pathogenesis and therapeutics.##Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about 200 times higher than the prevalence of Wilson's disease. The two diseases are characterized by homozygous occurrences of mutations in the HFE gene on chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13 (Wilson's disease). Unlike most other inherited conditions, these diseases can be successfully treated, emphasizing the importance of early diagnosis. Serum ferritin values, transferrin saturation and genetic analysis are used when diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the use of urinary copper values, serum ceruloplasmin and liver biopsy. If untreated, both of these genetic diseases result in rapidly progressing multiorgan damage and early death. The key treatment for haemochromatosis is phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present treatments considerably improve the prognosis of patients, they may be inadequate in patients diagnosed so late that extensive body deposits of metal have been developed. The main research needs in this field are to further clarify molecular mechanisms of disease progression and to develop new chelators that are more effective and less toxic than those presently available.
17333204##2006-8-16##Clinical study on the effect of mineral waters containing bicarbonate on the risk of urinary stone formation in patients with multiple episodes of CaOx-urolithiasis.##Investigations in healthy persons have shown that drinking mineral water containing HCO(3) has a positive effect on urine supersaturated with calcium oxalate (SS(CaOx)). The present study evaluates in a common setting whether these effects are also relevant in patients with multiepisodic urinary stone formation. A total of 34 patients with evident multiepisodic CaOx-urolithiasis were included in the study. Patients with hyperparathyroidism, renal tubular acidosis, Wilson's disease, Cushing disease, osteoporosis and malignant diseases were excluded. In a cross-over design and double-blinded the patients received 1.5 l of a mineral water with 2.673 mg HCO(3)/l (test water) or the same amount of water with a low mineral content (98 mg HCO(3)/l) (control water) daily for 3 days. During the study period the patients diet was recorded in a protocol, but not standardised. The main target parameter was SS(CaOx )in 24 h urine. In addition, urinary pH and the most important inhibiting and promoting factors were measured in 24 h urine (Ca, Ox, Mg, Cit). Both waters tested led to a highly significant increase in 24 h urine volume without a difference between each other. In the group, drinking the water containing HCO(3) the urinary pH increased significantly and was within a range relevant for metaphylaxis of calcium oxalate stone formation (x=6.73). This change was highly significant compared to the control group. In addition, significantly increased magnesium and citrate concentration were also observed. Supersaturation with calcium oxalate decreased significantly and to a relevant extent; however, there was no difference between the waters tested. As expected, the risk of uric acid precipitation also decreased significantly under bicarbonate water intake. However, an increase of the risk of calcium phosphate stone formation was observed. It is evident that both waters tested are able to lower significantly and to a relevant extent the risk of urinary stone formation in patients with multiepisodic CaOx-urolithiasis. In addition, the bicarbonate water increases the inhibitory factors citrate and magnesium due to its content of HCO(3) and Mg. Thus, it can be recommended for metaphylaxis of calcium oxalate and uric acid urinary stones.
17510416##2007-5-19##Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer.##We and others have shown that the copper transporters ATP7A and ATP7B play a role in cellular resistance to cis-diaminedichloroplatinum (II) (CDDP). In this study, we found that ATP7A transfection of Chinese hamster ovary cells (CHO-K1) and fibroblasts isolated from Menkes disease patients enhanced resistance not only to CDDP but also to various anticancer drugs, such as vincristine, paclitaxel, 7-ethyl-10-hydroxy-camptothecin (SN-38), etoposide, doxorubicin, mitoxantron, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11). ATP7A preferentially localized doxorubicin fluorescence to the Golgi apparatus in contrast to the more intense nuclear staining of doxorubicin in the parental cells. Brefeldin A partially and monensin completely altered the distribution of doxorubicin to the nuclei in the ATP7A-expressing cells. ATP7A expression also enhanced the efflux rates of doxorubicin and SN-38 from cells and increased the uptake of SN-38 in membrane vesicles. These findings strongly suggested that ATP7A confers multidrug resistance to the cells by compartmentalizing drugs in the Golgi apparatus and by enhancing efflux of these drugs, and the trans-Golgi network has an important role of ATP7A-related drug resistance. ATP7A was expressed in 8 of 34 (23.5%) clinical colon cancer specimens but not in the adjacent normal epithelium. Using the histoculture drug response assay that is useful for the prediction of drug sensitivity of clinical cancers, ATP7A-expressing colon cancer cells were significantly more resistant to SN-38 than ATP7A-negative cells. Thus, ATP7A confers resistance to various anticancer agents on cancer cells and might be a good index of drug resistance in clinical colon cancers.
17357135##2007-3-16##Video documented follow-up of liver transplantation in Wilson's disease with predominant neurological manifestation.##Wilson's disease (WD) is a rare autosomal-recessive disorder of copper metabolism with predominantly hepatic and extrapyramidal motor symptoms. Copper chelating therapy has proven to be an effective treatment for WD. Yet, if conservative treatment fails, liver transplantation (LT) often is the only remaining therapeutic option. The indication for LT especially in patients with stable liver function but severe neurological manifestation is debated controversially. In this case report, we document the follow up of neurological symptoms in WD after LT for the first time on video.
17234160##2006-9-8##Differences in the cellular response and signaling pathways of cisplatin and BBR3464 ([[trans-PtCl(NH3)(2)]2mu-(trans-Pt(NH3)(2)(H2N(CH2)(6)-NH2)2)]4+) influenced by copper homeostasis.##[[trans-PtCl(NH(3))(2)](2)mu-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)-NH(2))(2))](4+) (BBR3464) is a cationic trinuclear platinum drug that is being evaluated in phase II clinical trials for treatment of lung and ovarian cancers. The structure and DNA binding profile of BBR3464 is different from drugs commonly used clinically. It is of great interest to evaluate the difference between the mechanisms of uptake employed by BBR3464 and cisplatin (c-DDP), as altered uptake may explain chemoresistance. Using transfected cell lines, we show that both c-DDP and BBR3464 use the copper transporter hCTR1 to enter cells and to a lesser extent, the ATP7B transporter to exit cells. Copper influenced c-DDP and BBR3464 uptake similarly; it increased the c-DDP and BBR3464 uptake in ovarian (A2780) and colorectal (HCT116) carcinoma cell lines as detected by ICP-OES. However, the effects of copper on c-DDP- and BBR3464-mediated cytotoxicity differed. Copper decreased c-DDP-induced apoptosis, caspase-3/7 activation, p53 induction and PARP cleavage in cancer cell lines. In contrast, copper increased BBR3464-induced apoptosis, and had little effect on caspase activation, PARP cleavage, and p53 induction. It was concluded that BBR3464 employs mechanisms of intracellular action distinct from c-DDP. Although these drugs use the same cellular transporters (hCTR1 and ATP7B) for influx and efflux, downstream effects are different for the two drugs. These experiments illustrate fundamental differences in the mechanisms of action between cisplatin and the novel Pt-based drug BBR3464.
17367772##2006-6-26##A kinetic method amenable to automation for ceruloplasmin estimation with inexpensive and stable reagents.##
17398272##2006-5-27##Initial clinical experience with [123I]ioflupane scintigraphy in movement disorders.##
17414838##2007-4-7##Inherited metabolic disease of the liver.##
17437607##2007-4-18##A study of clinical, MRI and multimodality evoked potentials in neurologic Wilson disease.##The aims of this study were evaluate motor, somatosensory, visual and auditory brainstem evoked potential (MEP, SEP, VEP, ABER) changes in Wilson disease (WD) and correlate these with magnetic resonance imaging (MRI) and clinical findings. Neurologic WD diagnosed on the basis of clinical, ceruloplasmin and Kayser-Fleischer ring were evaluated including pedigree charting, hepatic, renal, hematologic and osteoarticular manifestations. Blood counts, serum chemistry, MRI, MEP to tibialis anterior, tibial SEP, VEP and ABER were performed. Evoked potential (EP) changes were correlated with clinical and MRI findings. Eighteen WD patients were recruited from 17 families whose mean age was 16 years. Movement disorders were present in 14, cognitive decline in 12 and pyramidal signs in 12 patients. MRI revealed involvement of basal ganglia in 80%, thalamus in 40%, brain stem in 46.7% and subcortical white matter in 53.3%. MEP was abnormal in 35.7%, SEP in 30.8%, VEP in 57% and ABER in 61.5% patients; the latter three EP changes were subclinical. Frequency and number of EP abnormalities were higher with increasing severity of illness. SEP, VEP and ABER reveals subclinical abnormality and MEP helps in documenting both clinical and subclinical abnormalities. Number of EP abnormalities increases with increasing clinical severity of WD.
17478959##2007-5-5##Equal outcome of living-related liver transplantation for Wilson's disease from heterozygote and nonheterozygote donors: a report of a brother and sister.##
17460493##2007-4-27##Wilson disease in children: serum aminotransferases and urinary copper on triethylene tetramine dihydrochloride (trientine) treatment.##
17430491##2007-4-14##Bowel obstruction due to diaphragmatic hernia in an elder child after pediatric liver transplantation.##A 10-yr-old boy with end-stage liver cirrhosis due to Wilson's disease received a living donor liver transplantation (LDLT) at our institution. The donor was his father and the graft was a left lateral segment. The liver transplantation procedure and the postoperative course were uneventful. Two months after the procedure, he developed a first episode of bowel obstruction that was treated with conservative therapy. During a second episode of bowel obstruction, he also presented respiratory distress. A plain chest X-ray revealed the presence of small intestine loops in the right thoracic cavity and bowel obstruction due to diaphragmatic hernia was diagnosed. Repair of the diaphragmatic hernia was performed and the patient has been doing well after the surgery. Diaphragmatic hernia after LDLT is rare but should be recognized as a possible complication when a left lobe or a left lateral segment graft is used.
17430479##2007-4-14##Pediatric liver transplantation in Iran: evaluation of the first 50 cases.##LT is nowadays accepted as the definitive therapy for end-stage liver disease. We report our experiences with pediatric LT using grafts from living related and DD. From April 1999 to March 2006, 50 infants and children who underwent LT were studied for pretransplantation status, medical and surgical complications and survival rate. There were 33 (66%) boys and 17 (34%) girls. The mean age of patients was 9.9 +/- 4.8 yr (range: 0.9-17.7) with a mean weight of 33.4 +/- 18.4 kg (range: 7.5-80). The main indications were cryptogenic cirrhosis (30%), autoimmune cirrhosis (24%), followed by biliary atresia (22%), Wilson disease (14%), progressive familial intrahepatic cholestasis (4%), fulminant hepatitis (4%) and tyrosinemia (2%). We used living-related donor in 14 (28%) and split liver in 5 (10%) cases and other patients received whole liver from DD. The mean follow-up of patients was 24.7 +/- 22.6 months (range: 1-72). The main postoperative complications were acute cellular rejection (44%) and infections (30%), whereas chronic rejection was seen in 26% of cases. The mortality rate was 24%. Overall mean survival (76% alive) was 63.5 +/- 5.7, 95% CI: 52.3-74.6. Our results demonstrate that pediatric LT is a feasible undertaking in Iran. Organ shortage in our area led to liberal use of living related and split liver techniques. The overall results of the pediatric LT in Iran are encouraging.
17466925##2006-8-18##Antitumor and antiinflammatory effects of tetrathiotungstate in comparison with tetrathiomolybdate.##Tetrathiomolybdate (TM) is an anticopper drug under development for treating Wilson's disease. Its mechanism of action involves forming a tight tripartite complex in the blood with serum albumin and available copper. When available copper levels are lowered in animals with TM, strong antiangiogenic and antitumor effects are observed. Similarly, TM has excellent efficacy in animal models of fibrotic, inflammatory, and autoimmune diseases, and it protects against heart damage from doxorubicin (DXR) and liver damage from acetaminophen, carbon tetrachloride, and concanavalin A. Tetrathiotungstate (TT) also forms a similar tripartite complex in the blood and has similar effects to TM on copper. In this article, whether TT had similar antitumor effects, and similar effects in protecting the heart against DXR toxicity, as TM was evaluated. It was found that the 2 drugs were comparable in their effects when doses were used that lowered copper availability to the same extent.
17524919##2007-5-26##Pediatric liver transplantation for acute liver failure.##The only proven therapy for patients unlikely to recover from acute liver failure (ALF) is liver transplantation. Correct diagnosis of these individuals and rapid referral to a transplant center are crucial. We evaluated 12 pediatric patients with ALF who underwent liver transplantation (LT) at our institution during a 3-year period. The reasons for transplantation were hepatitis A (3 patients); non-A, non-E hepatitis (3); autoimmune hepatitis (1); fulminant Wilson's disease (3); Amanita phalloides (mushroom) poisoning (1); and hepatitis B and toxic hepatitis with leflunomide treatment (1). Seven of the participants were female and five were male (mean age, 9.1 +/- 4.2 years). Three received right liver-lobe grafts, one received a whole liver graft, and the remainder received left or left-lateral liver lobe grafts. All patients recovered from hepatic coma the second postoperative day. Two patients died at postoperative days 57 and 71 due to adult respiratory distress syndrome and sepsis with multiorgan failure, respectively. One patient required retransplantation because of chronic rejection 7 months after the initial transplantation. That patient died 10 days after retransplantation because of sepsis. Nine patients were healthy at follow-up (range, 2-46 months). LT is the only treatment option for ALF in patients in countries with low organ-donation rates. In this scenario, donor preparation in a limited time frame is difficult. We have been able to decrease the duration of donor preparation to approximately 4 hours (including biopsy of the donated liver tissue).
17715636##2007-8-25##Acute liver failure--practical management.##The three most important components of the management of Acute Liver Failure are:- 1) Identification of causes requiring specific treatment including hepatic lymphoma, the Budd-Chiari syndrome, ischaemic hepatic necrosis, fulminating septicaemia, Wilson's disease and reactivation of HBV in chronic carriers. 2) Institution of early monitoring and optimal intensive care for multi-organ involvement to improve chances of spontaneous recovery or of transplantation. Deteriorating encephalopathy with cerebral oedema is related to a systemic inflammatory response and infections need to be treated aggressively. 3) Assessment of the need for transplantation based on strong positive predictive values provided by the King's or Clichy criteria. A significant percentage of those not fulfilling criteria also progress. The MARS liver support device has corrective effects on the disturbed pathophysiology of ALF and may be used to enhance spontaneous recovery or as a bridge to transplant, although the latter is not yet proven by controlled clinical trial.
17519831##2007-5-24##What is the reason of elevated alanine aminotransferase level in HBeAg negative patients with low viremia: NAFLD or chronic hepatitis?##
17333351##2006-5-14##Wilson's disease: what lies beneath.##
17433323##2006-10-20##Late-onset Wilson's disease.##
17591069##2007-6-27##Urgent adult-to-adult right lobe living donor liver transplantation for acute liver failure; a single center experience from Turkey.##
16740400##2006-1-14##Wilson's disease with myoclonus and white matter lesions.##White matter lesions (WML) and epilepsy have been occasionally seen in Wilson's disease. No cases of generalized myoclonus have been reported so far. We present a patient with psychiatric symptoms starting at age 16, followed by tremor, generalized dystonia and severe generalized myoclonus. In addition to classical findings, the MRI showed also extensive WML in temporal, parietal and frontal regions, preserving interhemispheric fibers. Necropsy revealed marked alterations of white matter, cortex and basal ganglia. We subsequently review the literature concerning WML and myoclonus in Wilson's disease.
17390257##2007-3-29##Wilson's Disease.##Wilson's disease is an autosomal-recessive disorder caused by mutation in the ATP7B gene, with resultant impairment of biliary excretion of copper. Subsequent copper accumulation, first in the liver but ultimately in the brain and other tissues, produces protean clinical manifestations that may include hepatic, neurological, psychiatric, ophthalmological, and other derangements. Genetic testing is impractical because of the multitude of mutations that have been identified, so accurate diagnosis relies on judicious use of a battery of laboratory and other diagnostic tests. Lifelong palliative treatment with a growing stable of medications, or with liver transplantation if needed, can successfully ameliorate or prevent the progressive deterioration and eventual death that would otherwise inevitably ensue. This article discusses the epidemiology, genetics, pathophysiology, clinical features, diagnostic testing, and treatment of Wilson's disease.
17907522##2007-10-3##Hepatitis A super infection as a cause of liver failure in a child with Wilson's disease.##Infection with hepatitis A virus can cause severe or even fatal illness in patients with chronic liver disease. Here we describe a seven-year-old girl who presented as acute liver failure and was diagnosed with Wilson's disease and later with coexistent hepatitis A infection. Wilson's disease was demonstrated on the basis of low ceruloplasmin, high urinary copper excretion, histological evidence of cirrhosis, and high biochemical estimation of liver copper concentration. Hepatitis A was diagnosed serologically. Our case suggests that acute hepatitis A may play a part in the acute decompensation seen in some cases of unrecognized Wilson's disease. We also emphasize the importance of prevention measures of hepatitis A infection in patients with chronic liver disease.
17303181##2006-6-9##Abnormal hepatobiliary and circulating lipid metabolism in the Long-Evans Cinnamon rat model of Wilson's disease.##Long-Evans Cinnamon (LEC) rats exhibit a genetic defect in Atp7b gene, which is homologous to the human Wilson's disease gene, resulting in an inability to mobilize copper from the liver. This study was undertaken to gain insight into the relationship between liver copper accumulation and plasma lipid profile, circulating lipoprotein composition, hepatic sterol metabolism and biliary lipid secretion rates in 12-week-old LEC rats compared to control Long-Evans rats. Concomitant with hepatic copper deposition, LEC rats displayed increased content of triglycerides (TGs), free cholesterol (FC) and cholesteryl ester (CE) in the liver. Hepatic concentrations of malondialdehyde (MDA), an index of lipid peroxidation were also significantly elevated in LEC rats (50%). This steatosis was associated with aberrant microsomal apolipoprotein (apo) B-100 and microsomal triglyceride transfer protein (MTP) content, hypotriglyceridemia, hypocholesterolemia and abnormalities in both circulating lipoprotein composition and size. Atypical hepatobiliary sterol metabolism was established by the assessment of the activity of key intracellular enzymes for cholesterol homeostasis, which demonstrated, with respect to controls, a 40% reduction in 3-hydroxy-3-methylglutaryl coenzyme A reductase, a 30% reduction in cholesterol 7alpha-hydroxylase, and a 54% reduction in acyl CoA:cholesterol acyltransferase. During a 6-h biliary drainage, a decline in the bile acid output was recorded and might be linked to the low protein expression of the bile salt export pump (BSEP or ABCB11). Our data emphasize the crucial role of copper balance in hepatic sterol homeostasis and lipoprotein metabolism in LEC rats. Additional studies are needed to delineate the mechanisms of these disorders.
17229731##2007-1-17##Cu(I) binding and transfer by the N terminus of the Wilson disease protein.##Wilson and Menkes diseases are genetic disorders of copper metabolism caused by mutations in the Wilson (WND) and Menkes (MNK) copper-transporting P1B-type ATPases. The N termini of these ATPases consist of six metal binding domains (MBDs). The MBDs interact with the copper chaperone Atox1 and are believed to play roles in catalysis and in copper-mediated cellular relocalization of WND and MNK. Although all six MBDs have similar folds and bind one Cu(I) ion via a conserved CXXC motif, biochemical and genetic data suggest that they have distinct functions. Most studies aimed at characterizing the MBDs have employed smaller polypeptides consisting of one or two domains. The role of each MBD is probably defined by its environment within the six-domain N terminus, however. To study the properties of the individual domains within the context of the intact Wilson N terminus (N-WND), a series of variants in which five of the six metal binding CXXC motifs are mutated to SXXS was generated. For each variant, the Cu(I) binding affinity and the ability to exchange Cu(I) with Atox1 were investigated. The results indicate that Atox1 can deliver Cu(I) to and remove Cu(I) from each MBD, that each MBD has stronger Cu(I) retention properties than Atox1, and that all of the MBDs as well as Atox1 have similar K(Cu) values of (2.2-6.3) x 10(10) m(-1). Therefore, the specific role of each MBD is not conferred by its position within the intact N-WND but may be related to interactions with other domains and partner proteins.
17461475##2007-4-28##Diagnostic criteria for acute liver failure due to Wilson disease.##
17368143##2007-3-21##Wilson's disease.##
17368142##2007-3-21##Wilson's disease.##
17368141##2007-3-21##Wilson's disease.##
17205981##2007-1-7##High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease.##Copper is essential for human physiology, but in excess it causes the severe metabolic disorder Wilson disease. Elevated copper is thought to induce pathological changes in tissues by stimulating the production of reactive oxygen species that damage multiple cell targets. To better understand the molecular basis of this disease, we performed genome-wide mRNA profiling as well as protein and metabolite analysis for Atp7b-/- mice, an animal model of Wilson disease. We found that at the presymptomatic stages of the disease, copper-induced changes are inconsistent with widespread radical-mediated damage, which is likely due to the sequestration of cytosolic copper by metallothioneins that are markedly up-regulated in Atp7b-/- livers. Instead, copper selectively up-regulates molecular machinery associated with the cell cycle and chromatin structure and down-regulates lipid metabolism, particularly cholesterol biosynthesis. Specific changes in the transcriptome are accompanied by distinct metabolic changes. Biochemical and mass spectroscopy measurements revealed a 3.6-fold decrease of very low density lipoprotein cholesterol in serum and a 33% decrease of liver cholesterol, indicative of a marked decrease in cholesterol biosynthesis. Consistent with low cholesterol levels, the amount of activated sterol regulatory-binding protein 2 (SREBP-2) is increased in Atp7b-/- nuclei. However, the SREBP-2 target genes are dysregulated suggesting that elevated copper alters SREBP-2 function rather than its processing or re-localization. Thus, in Atp7b-/- mice elevated copper affects specific cellular targets at the transcription and/or translation levels and has distinct effects on liver metabolic function, prior to appearance of histopathological changes. The identification of the network of specific copper-responsive targets facilitates further mechanistic analysis of human disorders of copper misbalance.
17290463##2007-2-10##Constantin von Economo's contribution to the understanding of movement disorders.##Constantin von Economo's (CvE) main scientific achievements were his studies on the cytoarchitectonics of the cerebral cortex, sleep, and encephalitis lethargica (EL). He found a close relationship between motor symptoms and psychiatric and behavioral disorders in EL and postencephalitic Parkinsonism and identified the underlying neuropathology in the diencephalon and the brainstem. In agreement with Tretiakoff's findings in Parkinson's disease, CvE related postencephalitic Parkinsonism to neuronal loss in the substantia nigra. Several of CvE's early, less well-known publications also deal with the basal ganglia and movement disorders. He demonstrated in rabbits that the substantia nigra modulates automatization, coordination, and succession of masticatory movements and swallowing. In a study on the effects of experimental lesions of the cerebral peduncle in cats and monkeys, CvE hypothesized a corticotegmental pathway that maintains motor functions after pyramidal tract lesions. Recent studies have identified this pathway, which ends in the pedunculopontine nucleus. In a study on posthemiplegic chorea, CvE discussed various pathophysiological hypotheses that partly resemble modern concepts of chorea. In a clinicopathological study on Wilson's disease, CvE traced the striofugal fibers and visualized the basal ganglia outflow pathways. CvE was an outstanding multidisciplinary movement disorder specialist who contributed substantially to modern basal ganglia research.
17300224##2007-2-16##Differential regulation of the Menkes and Wilson disease copper transporters by hormones: an integrated model of metal transport in the placenta.##Copper (Cu) plays a critical role in the developing foetus, but virtually nothing is known concerning the regulation of its uptake and metabolism in the placenta. In this issue of the Biochemical Journal, Hardman and colleagues, using a model of placental trophoblasts in culture, identify differential hormonal regulation of two copper-transporting ATPases; namely, those responsible for Menkes disease (ATP7A; MNK) and Wilson disease (ATP7B; WND). Insulin and oestrogen, which are essential during gestation, up-regulate MNK and this leads to trafficking of the MNK protein from the Golgi to the basolateral membrane, resulting in increased Cu efflux. At the same time, insulin decreased WND levels, and this leads to intracellular sequestration of the protein to a perinuclear region that reduces apical Cu release. As such, this results in a concerted flux of Cu from the basolateral surface of the trophoblast that would potentially be used by the developing foetus. An integrated model of vectorized Cu transport is proposed, which involves co-ordinated expression of transporters, organelle interactions and probable protein-protein interactions. The findings have wider implications for considering general models of intracellular metal transport.
17109627##2006-11-18##Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells.##Copper deficiency during pregnancy results in early embryonic death and foetal structural abnormalities including skeletal, pulmonary and cardiovascular defects. During pregnancy, copper is transported from the maternal circulation to the foetus by mechanisms which have not been clearly elucidated. Two copper-transporting ATPases, Menkes (ATP7A; MNK) and Wilson (ATP7B; WND), are expressed in the placenta and both are involved in placental copper transport, as copper accumulates in the placenta in both Menkes and Wilson disease. The regulatory mechanisms of MNK and WND and their exact role in the placenta are unknown. Using a differentiated polarized Jeg-3 cell culture model of placental trophoblasts, MNK and WND were shown to be expressed within these cells. Distinct roles for MNK and WND are suggested on the basis of their opposing responses to insulin. Insulin and oestrogen increased both MNK mRNA and protein levels, altered the localization of MNK towards the basolateral membrane in a copper-independent manner, and increased the transport of copper across this membrane. In contrast, levels of WND were decreased in response to insulin, and the protein was located in a tight perinuclear region, with a corresponding decrease in copper efflux across the apical membrane. These results are consistent with a model of copper transport in the placenta in which MNK delivers copper to the foetus and WND returns excess copper to the maternal circulation. Insulin and oestrogen stimulate copper transport to the foetus by increasing the expression of MNK and reducing the expression of WND. These data show for the first time that MNK and WND are differentially regulated by the hormones insulin and oestrogen in human placental cells.
17318448##2007-2-24##The roles of copper transporters in cisplatin resistance.##Platinum-based antitumor agents have been effective in the treatments of many human malignancies but the ultimate success of these agents is often compromised by development of drug resistance. One mechanism associated with resistance to platinum drugs is reduced intracellular accumulation owing to impaired drug intake, enhanced outward transport, or both. Mechanisms for transporting platinum drugs were not known until recent demonstrations that import and export transporters involved in maintenance copper homeostasis are also involved in the transport of these drugs. Ctr1, the major copper influx transporter, has been convincingly demonstrated to transport cisplatin and its analogues, carboplatin, and oxaliplatin. Evidence also suggests that the two copper efflux transporters ATP7A and ATP7B regulate the efflux of cisplatin. These observations are intriguing, because conventional thinking of the inorganic physiologic chemistry of cisplatin and copper is quite different. Hence, understanding the underlying mechanistic aspects of these transporters is critically important. While the mechanisms by which hCtr1, ATP7A and ATP7B transport copper ions have been studied extensively, very little is known about the mechanisms by which these transporters shuffle platinum-based antitumor agents. This review discusses the identification of copper transporters as platinum drug transporters, the structural-functional and mechanistic aspects of these transporters, the mechanisms that regulate their expression, and future research directions that may eventually lead to improved efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporters' activities.
17306619##2006-9-1##Fulminant hepatitis in dengue haemorrhagic fever.##Dengue virus is estimated to cause over 100 million infections throughout the world annually. While dengue infections can have a wide range of infections, atypical manifestations have been described. These involve the central nervous system, cardiac alterations and hepatitis. Here, we highlight a case of dengue haemorrhagic fever (DHF) with fulminant hepatitis. A 55-year-old male was admitted for 16 days, developing severe thrombocytopenia as low as 6x10(9)/L, haematocrit of 48% with transaminitis: ALT: 3,515 U/L, AST: 12,541 U/L, GGT: 1,094 U/L. Subsequent investigations excluded any occult liver lesions, hepatitis A, B and C, Wilson's disease, Epstein-Barr virus and Cytomegalo virus as possible causes. His dengue PCR was positive. His condition subsequently improved with supportive treatment. Liver injury from dengue virus is mediated by its direct infection of hepatocytes and kupffer cells. While mild to moderate elevations of serum aminotransferases (ALT and AST<5X normal) are common in dengue virus infection, liver failure rarely dominate the clinical picture. Liver dysfunction was commoner in DHF, with case reports indicating that severe hepatic dysfunction (ALT and AST>10X normal) was seen with DHF associated with spontaneous bleeding tendencies. Overall prognosis depends on age and other concomitant co-morbidities. We seek to review the literature on dengue infections with hepatitis and discuss issues pertaining to pathophysiology of liver impairment in dengue, the frequency of transaminitis associated with DHF and the overall prognosis.
17410957##2007-4-7##What's your diagnosis? Wilson disease (hepatolenticular degeneration) with Keyser-Fleischer ring.##
17325640##2005-10-3##Screening for mutations in ATP7B gene using conformation-sensitive gel electrophoresis in a family with Wilson's disease.##
17435591##2007-4-17##Wilson disease: description of 282 patients evaluated over 3 decades.##The clinical manifestations of Wilson disease (WD) are varied and challenging. We conducted the current study to present the phenotypic characteristics and follow-up for a large cohort of patients with WD. We reviewed the medical records of 282 cases of WD (male:female ratio, 196:86) for clinical features, investigations, treatment, and outcome data. The clinical presentations were as follows: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and "presymptomatic," 15 (5.3%). Mean age was 15.9 years. Presymptomatic patients and those with the hepatic form of WD were younger and patients with osseomuscular and psychiatric forms were older than neurologic patients. The mean duration of illness at the time of diagnosis was 28 months. Predominant neurologic features were as follows: parkinsonism, 62.3%; dystonia, 35.4%; cerebellar, 28%; pyramidal signs, 16%; chorea, 9%; athetosis, 2.2%; myoclonus, 3.4%; and behavioral abnormalities, 16%. Kayser-Fleischer (KF) rings were seen as follows: neurologic patients, 100%; hepatic patients, 86%; and presymptomatic patients, 59%. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24-hour urinary copper excretion was increased in 70% of patients. Neuroimaging (computed tomography/magnetic resonance imaging) and electrophysiologic abnormalities were seen in many patients. Overall, 195 patients were on D-penicillamine therapy and 182 on zinc sulphate. Follow-up data, available for 225 patients, for a mean duration of 46 months, revealed improvement in 176, no change in 20, and deterioration in 6. Twenty-three patients died. To conclude, despite increased awareness and recognition and significant inroads into therapeutic frontiers, follow-up remains poor in developing countries and a return to previous level of functioning is not universal.
16737839##2006-3-6##Three sisters with very-late-onset major depression and parkinsonism.##Familiar Parkinson's disease has an age of onset from the second to the sixth decade, whereas Wilson's disease (WD) usually presents in the first decade of life. We studied three sisters with a form of very-late-onset major depression and parkinsonism with probable linkage to ATP7B gene. Molecular studies demonstrated a nucleotide deletion at the 5'UTR region in a single allele of ATP7B gene. They did not have a family history of WD, or markers indicative for copper deposition in peripheral tissues. We suggest that single allele mutations of ATP7B gene may confer a susceptibility for late-onset major depression and parkinsonism.
17300494##2007-2-16##Neurological complications of liver transplantation in pediatric patients: a single center experience.##Neurologic complications (NCs) are a significant cause of morbidity and mortality in patients who undergo liver transplantation (LT). The aim of this study was to evaluate the incidence and type of NCs and associated factors in pediatric LT patients. We retrospectively reviewed NCs in the medical records of 40 consecutive infants, children, and adolescents who underwent LT at our institution. The subjects consisted of 23 boys and 17 girls (median age, 8.5 +/- 0.85 yr; range, 11 months to 17 yr). The indications for LT were Wilson's disease in 10 patients, fulminant hepatic failure (FHF) in nine, and other types of chronic liver disease in 21. NCs were found in 14 patients (35%). Those 14 individuals experienced a total of 16 episodes of NCs (two separate episodes in two of the patients). The most common NCs were seizure (seven episodes in six patients) and posterior leukoencephalopathy syndrome (PLES; five episodes in four patients). Seizure was the presenting symptom in three episodes of PLES. Two episodes of diffuse encephalopathy were observed in two patients, and two episodes of psychiatric symptoms occurred in two patients. We also noted one episode of tremor in one patient, one episode of acute dystonic reaction in one patient, and one episode of headache in one patient. Patients with Wilson's disease had a higher incidence of NCs (60%) than did patients without Wilson's disease (26.7%); however, this difference was not significant. The incidence of NCs was 44% in patients with FHF and 35% in those without FHF. That difference also was not significant. Immunosuppressive agents were the primary cause of 13 of the 16 episodes of NC. Uremia with hypertension, hypoxia, and hypomagnesemia caused one neurologic episode each. NCs, which are frequent in the first 30 days after pediatric LT, did not affect survival in this group. NCs were reversed by the discontinuation or reduction of immunosuppressive agents in 12 episodes, correction of hypomagnesemia and the reduction of immunosuppressive agents in one episode, and the correction of uremia and hypertension in one episode. Refractory epilepsy developed in one patient, and death unrelated to NCs occurred in one. The mortality rate was 7.1% (n = 1) in patients with NCs and 15.4% (n = 4) in those without NCs (p = 0.64). NCs are an important complication after LT. It is essential that each transplantation team collaborate with pediatric neurologists to ensure the rapid and accurate diagnosis of NCs in infants, children, and adolescents after LT and to prevent the delay of appropriate treatment.
17718054##2007-8-28##[Whipple's triad as a clinical manifestation of hepatolenticular degeneration].##Hepatolenticular degeneration (Wilson's disease) is a rare condition characterised by a defect in biliary excretion of copper resulting in excessive copper accumulation and toxicity. To the most frequent symptoms of this disorder belong liver, neurological or psychiatric disturbances, although other less common clinical features may sometimes be present. Since the clinical presentation of the disease is highly heterogeneous, it may mimic the symptoms of many various disorders. Diagnosis of the condition depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Early detection and treatment protect patients from devastating organ damage. We describe an atypical case of Wilson's disease in a 23-year-old woman, whose clinical presentation suggested the presence of an insulin-secreting tumour. After the diagnosis was established and zinc sulphate treatment implemented, her clinical status improved remarkably. The presented case suggests that hepatolenticular degeneration should be taken into consideration in a differential diagnosis of hypoglycaemia of an unknown origin.
17301931##2007-2-15##[Cerebral imaging for Wilson disease].##Wilson disease is an autosomal recessive inherited copper metabolic disorder that is characterized by diminished biliary excretion of copper and a raised serum level of free copper. This leads to a toxic copper accumulation, particularly in the liver and the brain. Therefore, clinical symptoms are dominated by hepatic and extrapyramidal symptoms. Untreated Wilson disease has an unfavorable outcome. Cerebral changes are depicted most sensitively by magnetic resonance tomography. Pathological findings mainly focus on the basal ganglia, the midbrain and the brainstem. Depending on the therapy and the severity of the neurological symptoms, signal increase as well as signal decrease may be observed in T1-weighted (T1w) and T2-weighted (T2w) images and can be reversible when using an appropriate therapy. Hyperintense areas in T2-weighted images are induced by edema, gliosis, demyelinisation or cystic degeneration. Signal increase in T1-weighted images are found in patients with hepatic insufficiency and are probably due to manganese deposits. Signal decrease in T2-weighted images is probably caused by the paramagnetic effect of the copper accumulation. Furthermore, recent studies show a correlation between the clinical severity and changes in diffusion-weighted sequences. Although cross-section imaging plays a rather subordinate role in the primary diagnostics of Wilson disease, the described cerebral changes in patients with extrapyramidal disturbances should include Wilson disease in the differential. Persistent or progressive hyperintense lesions in T2-weighted images reflect therapy failure, and clinical recovery correlates to an improvement in MR images. Therefore, repeat MR imaging can be used to monitor medical therapy.
17313472##2007-2-23##Cure of ventriculitis and central nervous system shunt infection by Staphylococcus epidermidis with vancomycin by intraventricular injection in a liver transplant recipient.##A 19-year-old female underwent orthotopic liver transplantation for acute hepatic failure because of fulminant Wilson's disease. Three months post transplantation she developed systemic fungal meningoencephalitis and obstructive hydrocephalus that required cerebrospinal fluid (CSF) shunting by a ventriculo-atrial shunt. Subsequently, she contracted Staphylococcus epidermidis bacteremia, ventriculitis, and shunt infection. Treatment with vancomycin either by conventional intravenous (i.v.) or continuous i.v. injection proved ineffective because of insufficient drug concentrations in the CSF. Eradication of S. epidermidis from CSF and cure of chronic ventriculitis and shunt infection was readily achieved by delivering vancomycin by intraventricular injection (5 mg/24 h) via an extraventricular drain together with continuous i.v. infusion (4 g/24 h) over a period of 18 days. This treatment was well tolerated and free of untoward side effects despite the patient's chronic immunosuppression subsequent to liver transplantation. Intraventricular injection of vancomycin is an effective and safe procedure to eradicate S. epidermidis from the central nervous system when i.v. vancomycin treatment fails.
17276780##2007-2-6##Wilson's disease.##Progressive hepatolenticular degeneration, or Wilson's disease, is a genetic disorder of copper metabolism. Knowledge of the clinical presentations and treatment of the disease are important both to the generalist and to specialists in gastroenterology and hepatology, neurology, psychiatry, and paediatrics. Wilson's disease invariably results in severe disability and death if untreated. The diagnosis is easily overlooked but if discovered early, effective treatments are available that will prevent or reverse many manifestations of this disorder. Studies have identified the role of copper in disease pathogenesis and clinical, biochemical, and genetic markers that can be useful in diagnosis. There are several chelating agents and zinc salts for medical therapy. Liver transplantation corrects the underlying pathophysiology and can be lifesaving. The discovery of the Wilson's disease gene has opened up a new molecular diagnostic approach, and could form the basis of future gene therapy.
17108057##2006-11-15##Triethylenetetramine and metabolites: levels in relation to copper and zinc excretion in urine of healthy volunteers and type 2 diabetic patients.##Triethylenetetramine (TETA), a selective Cu(II)-chelator used in the treatment of Wilson's disease, is now undergoing clinical trials for the treatment of heart failure in diabetes. Despite decades of clinical use, knowledge of its pharmacology in human subjects remains incomplete. Here, we first used liquid chromatography-mass spectrometry (LC-MS) to detect and identify major metabolites of TETA in human plasma and urine, and then used this method to measure concentrations of TETA and its metabolites in the urine of healthy and diabetic subjects who were administered increasing doses (300, 600, 1200, and 2400 mg) of TETA orally. Twenty-four-hour urine collections were performed before and after dosing participants. Two major metabolites of TETA were detected in human urine, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine, the latter being novel. Both metabolites were verified with synthetic standards by LC-MS. The proportion of unchanged TETA excreted as a fraction of total urinary drug-derived molecules was significantly higher in healthy than in matched diabetic subjects, consistent with a higher rate of TETA metabolism in the latter. TETA-evoked increases in urinary Cu excretion in nondiabetic subjects were more closely correlated with parent drug concentrations than in diabetic subjects, whereas, by contrast, urinary Cu was more closely associated with the sum of TETA and MAT. These findings are consistent with the hypothesis that MAT could play a significant role in the molecular mechanism by which TETA extracts Cu(II) from the systemic compartment in diabetic subjects.
17272994##2007-2-3##Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease.##
17272992##2007-2-3##Wilson's disease: an old disease keeps its old secrets.##Wilson's disease is a rare condition characterized by a defect in biliary excretion of copper, due to a mutation of both alleles of "Wilson's disease" gene (ATP7b gene). Many different mutations have been identified in affected patients. Since the clinical presentation of the disease is highly heterogeneous, it has been suspected that this variability could be related to different phenotypes. In this paper, Folhoffer et al. report a series of 109 Hungarian patients with Wilson's disease. The authors identified 8 novel, previously unreported, mutations of ATP7b gene in their population. However, 17% of patients with an established diagnosis of Wilson's disease still did not have any identifiable mutation. Since not all exons were analyzed, more studies are needed to identify the corresponding mutations. Overall, the authors failed to document any genotype-phenotype correlation suggesting that non genetical factors are involved in the clinical variability of the disease.
17438623##2007-4-18##Gene symbol: ATP7B.##
17438598##2007-4-18##Gene symbol: ATP7B.##
17438596##2007-4-18##Gene symbol: ATP7B.##
17285615##2007-2-8##Therapeutic plasmapheresis as a bridge to liver transplantation in fulminant Wilson disease.##Wilson disease is an autosomal recessive disorder of copper metabolism that leads to the accumulation of copper mainly in the liver, cornea, brain, and kidney. Rarely, Wilson disease can present as fulminant hepatic failure with direct antiglobulin test-negative hemolytic anemia and renal failure. In the absence of liver transplantation, this disease is uniformly fatal because medical therapy is ineffective. This report describes the successful use of plasmapheresis for a patient with fulminant Wilson disease as a bridge to transplantation. Five daily therapeutic plasmapheresis procedures using fresh frozen plasma as a replacement fluid were performed over 6 days. Serum copper, urinary copper excretion, and hemolysis were significantly reduced and renal function improved. The patient's clinical status improved and she remained clinically stable until a liver transplant was possible. Plasmapheresis can be a successful medical treatment in fulminant Wilson disease and should be considered as a therapeutic measure to stabilize a patient by decreasing serum copper, reducing hemolysis, and helping to prevent renal tubular injury from copper and copper complexes until liver transplantation is possible.
17286794##2007-2-9##Discontinuation of penicillamine in the absence of alternative orphan drugs (trientine-zinc): a case of decompensated liver cirrhosis in Wilson's disease.##
17295864##2007-2-14##Mild zinc deficiency and dietary phytic acid accelerates the development of fulminant hepatitis in LEC rats.##
16736232##2005-10-28##The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice.##In MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-hydroxydopamine induced dopaminergic neurotoxicity and Parkinson's disease iron accumulates in substantia nigra pars compacta which has been suggested to participate in oxidative stress induced neurodegeneration. Pretreatment with iron chelators desferal, clioquinol, VK-28 and M30 are neuroprotective in both models. To determine the specificity of chelation neuroprotective activity we have examined the effect of D-penicillamine, a relatively specific copper chelator, in the mice model of MPTP-induced dopamine depletion. Our studies show that D-penicillamine, employed for removal of copper in Wilson disease is relatively weak in preventing dopaminergic neurotoxicity induced by MPTP, as compared to iron chelators previously studied. The results indicate that for prevention of MPTP-induced dopamine depletion and dopamine neurodegeneration, iron rather than copper chelation may be more effective and specific.
17259995##2006-11-03##Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.##Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.
17295181##2007-2-14##Hepatocellular carcinoma associated with an atypical presentation of Wilson's disease.##
17083099##2006-11-4##Patient with late-onset Wilson's disease: deterioration with penicillamine.##
17107946##2006-11-14##A cadmium-transporting P1B-type ATPase in yeast Saccharomyces cerevisiae.##Detoxification and homeostatic acquisition of metal ions are vital for all living organisms. We have identified PCA1 in yeast Saccharomyces cerevisiae as an overexpression suppressor of copper toxicity. PCA1 possesses signatures of a P1B-type heavy metal-transporting ATPase that is widely distributed from bacteria to humans. Copper resistance conferred by PCA1 is not dependent on catalytic activity, but it appears that a cysteine-rich region located in the N terminus sequesters copper. Unexpectedly, when compared with two independent natural isolates and an industrial S. cerevisiae strain, the PCA1 allele of the common laboratory strains we have examined possesses a missense mutation in a predicted ATP-binding residue conserved in P1B-type ATPases. Consistent with a previous report that identifies an equivalent mutation in a copper-transporting P1B-type ATPase of a Wilson disease patient, the PCA1 allele found in laboratory yeast strains is nonfunctional. Overexpression or deletion of the functional allele in yeast demonstrates that PCA1 is a cadmium efflux pump. Cadmium as well as copper and silver, but not other metals examined, dramatically increase PCA1 protein expression through post-transcriptional regulation and promote subcellular localization to the plasma membrane. Our study has revealed a novel metal detoxification mechanism in yeast mediated by a P1B-type ATPase that is unique in structure, substrate specificity, and mode of regulation.
18039017##2007-11-28##Palmar erythema.##Palmar erythema (PE), an often overlooked physical finding, is due to several physiologic or systemic pathologic states. PE can exist as a primary physiologic finding or as a secondary marker of systemic pathology. Primary or physiologic PE can be due to heredity, occurs in at least 30% of pregnant women as a result of associated alterations in the function of the skin and its microvasculature, or may be a diagnosis of exclusion (i.e. idiopathic PE). Secondary PE from systemic pathology encompasses a wide range of disease states. Twenty-three percent of patients with liver cirrhosis, from varying causes, can manifest PE as a result of abnormal serum estradiol levels. Patients with a rare neonatal liver disease such as Wilson disease and hereditary hemochromatosis may exhibit PE along with the other systemic manifestations of the genodermatoses. PE has been reported to occur in >60% of patients with rheumatoid arthritis and is associated with a favorable prognosis. Up to 18% of patients with thyrotoxicosis and 4.1% of patients with diabetes mellitus can have PE. This cutaneous manifestation of diabetes occurs more often than the more classic diseases such as necrobiosis lipoidica diabeticorum (0.6%). PE can be seen in early gestational syphilis and among patients with human T-lymphotrophic virus-1-associated myelopathy. Drug-induced PE with hepatic damage has been documented with use of amiodarone, gemfibrozil, and cholestyramine, while topiramate and albuterol (salbutamol) have been reported to cause PE in the setting of normal liver function. Fifteen percent of patients with both metastatic and primary brain neoplasms may have PE. Increased levels of angiogenic factors and estrogens from solid tumors have been postulated as the cause of PE in such cases. Erythema ab igne can mimic PE, and patients with atopic diathesis are more likely to have PE than matched control subjects. Smoking and chronic mercury poisoning are environmental causes of PE.No treatment of primary PE is indicated. If medication is the cause of PE, the drug responsible should be discontinued if possible. Identification of PE related to underlying disorders should be followed by treatment of the underlying condition. In light of the numerous etiologies of PE, this article reviews the current literature and provides a framework to help guide the clinician in determining the cause of PE in patients presenting with this finding.
16939419##2006-8-31##Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B).##The Wilson protein (ATP7B) is a copper-translocating P-type ATPase that mediates the excretion of excess copper from hepatocytes into bile. Excess copper causes the protein to traffic from the TGN (trans-Golgi network) to subapical vesicles. Using site-directed mutagenesis, mutations known or predicted to abrogate catalytic activity (copper translocation) were introduced into ATP7B and the effect of these mutations on the intracellular trafficking of the protein was investigated. Mutation of the critical aspartic acid residue in the phosphorylation domain (DKTGTIT) blocked copper-induced redistribution of ATP7B from the TGN, whereas mutation of the phosphatase domain [TGE (Thr-Gly-Glu)] trapped ATP7B at cytosolic vesicular compartments. Our findings demonstrate that ATP7B trafficking is regulated with its copper-translocation cycle, with cytosolic vesicular localization associated with the acyl-phosphate intermediate. In addition, mutation of the six N-terminal metal-binding sites and/or the trans-membrane CPC (Cys-Pro-Cys) motif did not suppress the constitutive vesicular localization of the ATP7B phosphatase domain mutant. These results suggested that copper co-ordination by these sites is not essential for trafficking. Importantly, copper-chelation studies with these mutants clearly demonstrated a requirement for copper in ATP7B trafficking, suggesting the presence of an additional copper-binding site(s) within the protein. The results presented in this report significantly advance our understanding of the regulatory mechanism that links copper-translocation activity with copper-induced intracellular trafficking of ATP7B, which is central to hepatic and hence systemic copper homoeostasis.
16904856##2006-6-7##Reply to T.U. Hoogenraad's paper published last April. Zinc therapy in Wilson's disease.##
17975309##2007-10-30##Distinct functional roles for the Menkes and Wilson copper translocating P-type ATPases in human placental cells.##
17727313##2007-8-31##Clinical significance of the laboratory determination of low serum copper in adults.##
16545904##2005-7-21##Different neurological outcome of liver transplantation for Wilson's disease in two homozygotic twins.##Wilson's disease is a genetic disorder characterized by accumulation of copper in many organs and tissues. Phenotypic manifestations are wide-ranging from neuropsychiatric disorders, to severe liver disease requiring liver transplantation. Clinical presentation is not often related to the genetic defect and siblings may have different type of disease. Liver transplantation is indicated for all patients with Wilson's disease and decompensated liver cirrhosis unresponsive to medical therapy, but its efficacy in resolving the neurological symptoms is still controversial, because as far now, very different outcomes have been reported. We describe here on the exceptional case of two homozygotic twins, both with liver cirrhosis due to Wilson's disease, one of them with severe neuropsychiatric involvement, who both underwent liver transplantation and subsequently had very different outcome despite same genetic background. The presence of neurological clinical manifestations in Wilson's disease should recommend caution indicating liver transplantation, because irreversible brain damage may exist.
17539347##2007-6-2##[Hepatolenticular degeneration: yesterday, today, tomorrow].##
17161572##2006-10-8##Liver imaging findings of Wilson's disease.##Wilson's disease is a rare, autosomal-recessive inherited disorder of copper metabolism resulting in accumulation of copper in liver. The form of liver disease varies, depending on the severity of the disease at the time of diagnosis and pathological findings include fatty changes, acute hepatitis, chronic active hepatitis, cirrhosis and occasionally fulminant hepatic necrosis. Liver imaging findings reflect a wide range of physiopathological processes of the disease and also demonstrate the associated findings of cirrhosis in cases with advanced disease.
17179709##2006-4-12##Wilson's disease: a great masquerader.##
21960773##2011-10-1##Diagnosis and long-term management of Wilson disease.##
18286826##2008-2-22##Ethnic specific background of mutations in Bulgarian patients with Wilson disease.##
16709660##2006-5-18##Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study.##
17300695##2007-2-16##Clinical and molecular characterization of Wilson disease in Spanish patients.##Wilson disease (WD) results when specific mutations occur at the ATP7B gene. The presence of mutations in the ATP7B gene was studied in the coding region and the intron-exon boundaries in 15 WD Spanish patients, and their first-degree relatives when possible. A total of 20 nucleotide sequence changes were detected, 18 missense and two splicing mutations. Six of these variants were classified as disease-causing mutations, five missense, and one splicing; four of them have been previously described (M645R, A1065P, H1069Q, and 3060 + 5G > T), whereas two were novel (P768L and A990P). No mutation was clearly prevalent, although the H1069Q mutation predominated, nor did a good phenotype-genotype correlation exist. The two new mutations described were manifested as an asymptomatic increase in serum transaminases. The remaining 14 changes were classified as polymorphisms and their potential effects on protein function are discussed. The identification of mutations in the ATP7B gene has allowed a conclusive diagnosis to be made of WD in patients presenting neurological phenotype or neurological of hepatic phenotype, who would otherwise not have been diagnosed using classical criteria. WD patients could start chelating treatment earlier on and possibly modify the natural progression of the disease.
17401235##2007-4-3##Recurrent limb weakness as initial presentation of Wilson's disease.##A 28-year-old normotensive euthyroid man presented with recurrent lower motor neuron type of weakness without sensory or autonomic involvement, with preserved reflexes. Systemic examination was significant for mild hepatosplenomegaly. Investigations revealed persistent hypokalemic, hyperchloremic, normal-anion-gap metabolic acidosis with deranged liver functions. Urine pH was 6.0 even after oral ammonium-chloride loading test. Type I renal tubular acidosis was diagnosed. A search for the etiology revealed bilateral Kayser-Fleischer ring, with low serum ceruloplasmin levels and high urinary copper, confirming it to be Wilson's disease.
17346443##2007-3-10##Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities.##Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes.
17880018##2007-9-21##Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson disease.##Wilsonian crisis is fatal unless copper removal is initiated early and liver transplantation is performed for patients that fulfill criteria for a poor outcome. We report a patient presenting with severe hemolysis and impending acute liver failure that made a rapid recovery with prompt initiation of plasmapheresis and chelation therapy. Rapid copper removal by plasmapheresis alleviated hemolysis and liver injury. A review of the literature was performed examining the use of plasmapheresis and albumin dialysis with continuous veno-venous hemodialysis or molecular adsorbents and recirculating system.
17317524##2006-4-12##Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene.##Wilson disease (WD) is an autosomal recessive disorder of copper biliary excretion caused by an impaired function of ATP7B, a metal-transporting P-type ATPase encoded by WD gene. It results in copper accumulation, mostly in liver and brain tissues. Mutation analysis was carried out on 11 WD French unrelated patients presenting a predominant neurological form of this illness. SSCP and dHPLC analysis followed by sequencing of the 21 exons and their flanking introns were performed. Thirteen different mutations in a total of 17, and, among them, 10 novel variants were evidenced. Two deletions (c.654_655delCC and c.1745_1746delTA), 4 missense mutations (p.F763Y, p.G843R, p.D918A and p.L979Q), 1 nonsense mutation (p.Q1200X), 1 splice site mutation (c.1947-1G>C) and 2 intronic silent substitutions (c.2448-25G>T and c.3412+13T>A) were detected. These data extend the mutational spectrum of the disease, already known to be a very heterogeneous genetic disorder. As compared to hepatic manifestations, the phenotypes associated to these mutations confirm that neurological presentations associated with other mutations than p.H1069Q are also often late in their onset. Most of these neurological forms probably correspond to an attenuated impairment of copper metabolism, as compared to hepatic forms of the disease, mostly diagnosed earlier.
17154398##2006-12-13##Revised King's College score for liver transplantation in adult patients with Wilson's disease.##Fulminant Wilson's disease (WD) is almost invariably fatal, and liver transplantation is the only life-saving treatment. Decompensated chronic WD usually responds to chelation therapy. Our aim was to validate 3 published scoring systems for deciding between chelation treatment and liver transplantation in patients with chronic decompensated and fulminant WD. Model for end-stage liver disease (MELD) score, as well as WD prognostic index (WPI) and its recently revised version (RWPI) were evaluated as predictors of the safety for chelation therapy. A group of 14 adult patients with decompensated chronic WD who improved on penicillamine treatment were compared with 21 patients with fulminant WD. The diagnosis of WD was based on increased urinary copper excretion and confirmed by elevated liver copper content and/or mutation analysis of the WD gene. The MELD score, WPI, and RWPI were calculated for all patients with WD. The accuracy of the MELD score, WPI, and RWPI for prediction of response to chelation therapy in patients with decompensated chronic WD was 0.968, 0.980, and 0.993, respectively. None of the decompensated chronic WD patients had a MELD score >30, RWPI >11, or WPI >7. RWPI showed the highest accuracy and the lowest false negativity compared with WPI and MELD. In conclusion, our data indicate that RWPI, originally proposed for pediatric patients, is also useful for adults.
17160357##2005-9-1##Analysis of most common mutations R778G, R778L, R778W, I1102T and H1069Q in Indian Wilson disease patients: correlation between genotype/phenotype/copper ATPase activity.##The present study was intended to estimate the frequencies of the most common mutations (R778L, R778W, R778G, I1102T and H1069Q) of ATP7B in Indian Wilson disease (WD) population and to explore the correlation between genotype/phenotype and copper ATPase activity. A total of 33 WD patients and their family members from North West states of India were examined. The H1069Q, R778W and R778L mutations were absent in these WD patients. R778W and I1102T mutations were present in 36% of WD patients. Family analysis for these mutations using PCR-RFLP documented 5 carriers and 2 asymptomatic WD patients. The copper ATPase activity in WD patients was significantly reduced (50%) than that of control individuals. No significant difference was observed in copper stimulated ATPase activity between homozygous (R778W/R778W, I1102T/I1102T) and compound heterozygous (R778W/unknown mutation, I1102T/unknown mutation) WD patients. Serum ceruloplasmin, serum copper levels were significantly lower in homozygous WD patients than that of compound heterozygous. However, no significant difference was observed in liver copper contents between heterozygous and homozygous patients. In conclusion, the data suggest that R778W and I1102T are most common mutations and provide the basis of genetic (PCR-RFLP) diagnostic tool for Indian WD patients as well as in siblings/parents where biochemical parameters are ambiguous.
17344776##2007-3-9##Wilson's disease with hepatic presentation in childhood.##Diagnosis of Wilson's disease with hepatic presentation in childhood using clinical and common laboratory parameters is still challenging and is often missed or delayed. The aim of the study was to document the clinical and laboratory parameters of hepatic presentation of Wilson's disease in children. The study was conducted at a tertiary-care hospital in a developing country. Clinical and common laboratory parameters were recorded in 32 Wilson's disease children with hepatic presentation. The diagnosis was based on positive family history, Kayser-Fleischer ring, low serum ceruloplasmin level, elevated basal urinary copper excretion and favorable response to therapy with D-penicillamine. Mean age+/-SD at presentation was 9+/-2.97 years and 21 (65.6%) were boys. Chronic liver disease (21; 65.6%) followed by fulminant hepatic failure 1(6; 18.8%) were the commonest presentation. In the whole group, Kayser-Fleischer ring was found in 21 (65.6%), low serum ceruloplasmin in 16 (50%) and elevated basal urinary copper excretion in all 32 (100%) children. Diagnosis of Wilson's disease was made at presentation on the basis of i) Kayser-Fleischer ring, low serum ceruloplasmin, elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 11 (34.4%), ii) Kayser-Fleischer ring, elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 10 (31.2%), iii) elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 6 (18.8%) and iv) low ceruloplasmin, elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 5 (15.6%) children. Wilson's disease can not be excluded in children presenting with hepatic involvement using the commonly practiced clinical and laboratory parameters. A combination of various clinical and laboratory parameters were used for the diagnosis of Wilson's disease in the studied children with hepatic presentation.
17272918##2007-2-3##Coexistence of Wilson's disease and neurofibromatosis type 1 in a 14-year-old boy.##
17330175##2007-3-3##Unified Wilson's Disease Rating Scale - a proposal for the neurological scoring of Wilson's disease patients.##
17221826##2007-1-16##[Wilson's disease].##Wilson's disease is a rare autosomal recessive disorder of hepatic copper transport leading to a biliary excretion inhibition of copper. Overload of the metal mainly in liver and basal ganglia leads to hepatic but also to extrapyramidal motor as well as psychiatric clinical symptoms. Diagnosis is based on clinical suspicion, parameters of copper metabolism, ophthalmic examination and a liver biopsy. A radiocopper test is able to identify patients even with inconsistent laboratory results. For initial assessment and follow-up neurophysiological investigation and MRI are recommended additionally. Genetic analysis can be helpful to detect asymptomatic relatives of the index patient. Dependent on the stage of the disease for therapy chelating drugs and zinc are possible but must be given lifelong without longer interruptions. With early diagnosis and consequent treatment the prognosis of Wilson's disease is excellent and usually the need for liver transplantation can be prevented.
17189043##2006-3-8##Transcranial brain parenchyma sonography in movement disorders: state of the art.##The present paper summarizes recommendations on transcranial sonography (TCS) application in neurodegenerative diseases, resulting from a consensus meeting of the European Society of Neurosonology and Cerebral Hemodynamics. TCS of distinct infra- and supratentorial brain structures detects characteristic changes in several movement disorders, such as abnormal hyperechogenicity of substantia nigra (SN) in Parkinson's disease and of lenticular nucleus in dystonia, Wilson's disease and atypical Parkinsonian disorders. In healthy adults, the TCS finding of marked SN hyperechogenicity indicates a subclinical functional impairment of the nigrostriatal dopaminergic system. The finding of marked SN hyperechogenicity in combination with normal lenticular-nucleus echogenicity discriminates idiopathic Parkinson's disease from multiple-system atrophy and progressive supranuclear palsy with a positive predictive value of more than 90%. As TCS is a quick and noninvasive method, using the same duplex-ultrasound machines as for investigation of intracranial vessels, applicable even in agitated patients, this method has a great potential to be more widely used.
17190918##2006-12-28##Optimizing therapy of seizures in patients with renal or hepatic dysfunction.##Patients with epilepsy may suffer from renal or hepatic diseases that interfere with their antiepileptic drug (AED) treatment. Furthermore, such diseases may themselves cause seizures. Reduced renal function and hypoalbuminemia lead to accumulation of renally excreted AEDs, such as gabapentin, vigabatrin, topiramate, levetiracetam, and phenytoin. Valproate, lamotrigine, and benzodiazepines are less affected. Low protein-bound AEDs are extensively removed by hemodialysis and supplemental doses are required for dialysis patients. Uremia and related conditions, including intracranial hemorrhage, glucose and electrolyte imbalances, and concomitant drug use, can cause seizures, as can dialysis encephalopathy, primary cerebral lymphoma, fungal infections, and immunosuppressant toxicity in renal transplant recipients. Hepatic dysfunction reduces enzymatic metabolism of AEDs and causes hypoalbuminemia. Gabapentin, topiramate, and levetiracetam are preferred in these conditions, whereas conversely valproate and felbamate are potentially hepatotoxic and should be avoided. Seizures related to hepatic encephalopathy are controlled by oral lactulose or neomycin. Porphyria sufferers may benefit from gabapentin, oxcarbazepine, or levetiracetam. Seizures in Wilson's disease may derive from d-penicillamine-induced pyridoxine deficiency. Effective treatment of seizures in renal and hepatic diseases requires attention to changes in AED pharmacokinetics and adequate care of the underlying illnesses. Monitoring of free drug concentrations is a valuable aid to therapy.
17171802##2006-12-16##Expression of ATP7B in human gastric cardiac carcinomas in comparison with distal gastric carcinomas.##
17313814##2007-2-23##[Living related liver transplantation for Wilson's disease: clinical study of 32 cases].##
17225847##2007-1-18##Two unusual cases with Wilson's disease: hepatoma and fulminant hepatitis treated with plasma exchange.##We report two atypical cases of Wilson's disease. The first case is a 22-year-old male patient with a history of disease for 15 years and diagnosed as Wilson's disease upon investigations. Alpha-fetoprotein level was found elevated and computed tomography showed a 3.5-cm liver mass. Hepatocellular carcinoma was diagnosed. Radiofrequency ablation and liver transplantation were performed successfully. The second case is a 24-year-old female patient who presented with fulminant hepatitis. Urinary copper excretion and ceruloplasmin levels were suggestive of Wilson's disease. Despite chelation therapy, no improvement was observed. Plasma exchange therapy was performed for seven days. Her clinical status improved, and transplantation was no longer needed. To conclude, although hepatoma is rarely seen in Wilson's disease, patients should be examined regularly to diagnose it in a treatable stage. Removal of copper and toxic metabolites with plasma exchange therapy may be a way of treatment for fulminant hepatitis associated with Wilson's disease.
18156766##2007-12-25##[A korean family with Wilson disease occurred in two consecutive generations.].##Wilson disease (WD) is one of the most common inborn errors of metabolism characterized by degenerative changes in the brain, liver and kidney dysfunction, and Kayser-Fleischer rings due to toxic accumulation of copper. We investigated a Korean family with WD occurred in two consecutive generations. The proband, a 14-yr-old girl, was noticed to have abnormal liver function on a routine health examination at school and was diagnosed of having WD by further laboratory tests and liver biopsy. Molecular genetic analysis of ATP7B gene demonstrated that she was homozygous for Ala-874Val mutation, one of the three common mutations in Korean patients with WD. Further study for her family members revealed that the proband's father, a paternal uncle, and the youngest sister were compound heterozygous for Ala874Val and Asn1270Ser mutations of the ATP7B gene. In addition, the proband's mother and a younger sister were heterozygous carriers of Ala874Val mutation. Therefore, WD occurred in two consecutive generations due to a WD father and a heterozygous mother. Actually, abnormal results on liver function tests were found in the proband's father and a paternal uncle a few years ago but a diagnosis of WD has not been made. Therefore, although WD has been thought to be uncommon in Korea, it should be considered in a differential diagnosis of patients exhibiting abnormal liver function with unknown cause.
17078070##2006-11-2##Neurological manifestations in Wilson's disease: Report of 119 cases.##We describe the neurological manifestations of 119 patients with WD (93 index cases and 26 affected family members) seen between 1963 and 2004. The mean age at symptoms onset was 19.6 years (range, 7-37 years). Medical records were reviewed for the patient's first neurological examination. The most frequent neurological manifestations observed were dysarthria (91%), gait disturbance (75%), risus sardonicus (72%), dystonia (69%), rigidity (66%), tremor (60%), and dysphagia (50%). Less frequent manifestations were chorea (16%) and athetosis (14%). Rare neurological presentations were seizures (4.2%), and pyramidal signs (3%).
17044091##2006-10-18##Wilson's disease tremor is associated with magnetic resonance imaging lesions in basal ganglia structures.##Wilson's disease (WD) is an inherited disorder of copper metabolism yielding marked motor deficits, including a severely disabling tremor. As a structural correlate of the disease, a variety of cerebral abnormalities has been revealed. However, the relationship between motor deficits and cerebral lesions has remained largely unknown. Here, we investigated correlation between WD tremor and cerebral magnetic resonance imaging (MRI) findings. Cerebral MRI abnormalities in 6 symptomatic WD patients were compared to findings in 6 asymptomatic WD patients and 10 healthy controls. All patients were treated with long-term copper chelating therapy. Motor symptoms including tremor were determined by Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). MRI findings in symptomatic WD patients revealed significant symmetric T2*-weighted hypointense signal alterations of globus pallidus, head of the caudate nucleus, and substantia nigra. In contrast, MRI of asymptomatic WD patients did not differ from healthy controls. Correlation analysis revealed a significant positive correlation between MRI basal ganglia lesions and UPDRS action tremor score. Our results demonstrate for the first time that Wilson's disease tremor is associated with lesions of the globus pallidus, the head of the caudate nucleus, and the substantia nigra.
17109711##2006-11-18##Wilson's disease associated with delusional disorder.##Wilson's disease (WD), or hepatolenticular degeneration, is a genetic neurodegenerative disorder of copper metabolism. It is an uncommon medical condition that produces psychiatric symptoms during the early phase in approximately 50% of patients. Reported herein is a case of WD in a young man presenting persistent delusional disorder of organic etiology, which resolved entirely after 4 months of combined pharmacotherapy. The present case demonstrates the importance of considering the occurrence of psychotic symptoms in WD patients given that psychiatric manifestations in WD are known to be uncommon as well as inhomogeneous. It also supports the hypothesis that psychopathologic features in WD have an organic foundation.
17162252##2006-3-17##Comparison of lowering copper levels with tetrathiomolybdate and zinc on mouse tumor and doxorubicin models.##Tetrathiomolybdate (TM), presumably by lowering copper levels and availability, has shown excellent efficacy in animal models of cancer and models of injury that produce fibrotic or inflammatory damage in lung, heart, and liver. Trials in human patients are underway. If the efficacy of TM is indeed through lowering copper levels, other anticopper drugs should be equally efficacious. Zinc is an anticopper drug, with proven efficacy in Wilson's disease, a disease of copper toxicity. In this study, the efficacy of zinc is compared with TM on a mouse tumor model and on the doxorubicin model of heart damage, and it is hypothesized that when copper availability is lowered to an equivalent extent, the 2 drugs would show equivalent efficacy. No effect is found of zinc on inhibiting growth of a tumor that is markedly inhibited by TM, and zinc is found to be less effective than TM in inhibiting cardiac damage from doxorubicin. This study shows that TM's mechanism of action in protecting against doxorubicin toxicity is because of its anticopper effects, as copper supplementation eliminated the protective effect of TM. It is also hypothesized that the differences between TM and zinc may be caused by TM's mechanism of action in which it binds copper already in the body, whereas zinc does not.
17175351##2006-6-14##The role of plasmapheresis therapy for perioperative management in ABO-incompatible adult living donor liver transplantation.##
17175346##2006-7-27##Pediatric liver transplant with Campath 1H induction--Preliminary report.##
17196137##2007-1-2##[Direct sequencing and analysis of exons of Wilson' disease gene with the most mutations: a study in Hunan Han patients].##
16967214##2006-9-13##Contribution of transjugular liver biopsy in patients with the clinical presentation of acute liver failure.##
17100729##2006-11-15##Effect of living donor liver transplantation on outcome of children with inherited liver disease and hepatocellular carcinoma.##We described six children with heritable liver disease and hepatocellular carcinoma treated with living-related liver transplantation. Underlying liver diseases were type-1 tyrosinemia (three patients), progressive familial intrahepatic cholestasis type II (two patients), and Wilson's disease (one patient). Two of the tumors were found incidentally during liver transplantation. Number of nodules was 12, 15, 3, 2, and 1 (in two patients). Three patients were treated with chemotherapy before the procedure. Chemotherapy was not given to any patient after liver transplantation. The mean follow-up was 17.7 +/- 6 months (range: 7-24). All patients are tumor recurrence free. Both graft and patient survival rates are 100% at a median of 18.5 months follow-up. Physicians in charge of treating children with heritable liver disease should screen them periodically for the development of hepatocellular carcinoma. Liver transplantation may offer these children better survival rates.
17129551##2006-11-30##[Wilson's disease: forms of presentation in childhood].##Wilson's disease can manifest with symptoms of liver disease or neuropsychiatric disorders in children and adults. This autosomal recessive disorder is caused by a copper metabolism disorder due to a mutation in the ATP7B transporter. Excessive amounts of copper accumulate in the body due to inhibition of the release of copper into bile. Because effective treatment is available, recognizing this disease in presymptomatic or early stages, when it can be reversed, is highly important. Diagnosis is often easy but the available tests (measurement of ceruloplasmin, and blood, urinary and liver copper levels) can be misleading. There is no single test with 100% sensitivity in screening nor do any of the tests, when used alone, provide 100% specificity. Diagnosis is currently based on the combination of clinical findings and the results of laboratory tests. Genetic study, with a finding of mutations in the two alleles of the ATP7B gene, is still not a rapid and easily available alternative and the absence of these mutations does not rule out the possible presence of other mutations not yet described.
17179586##2006-12-21##[Basal ganglia calcification: clinical manifestations and diagnostic evaluation].##Physiological intracranial calcification occurs in about 0,3-1,5% of cases. It is asymptomatic and is detected incidentally by neuroimaging. Pathological basal ganglia calcification is due to various causes, such as: metabolic disorders, infectious and genetic diseases and other. Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification. Besides tetany and seizures this condition is presented by parkinsonism and dementia. Such parkinsonism doesn't respond to drugs containing levodopha. Infections (toxoplasmosis, rubella, cytomegalovirus, cysticercosis, AIDS) give multiple and asymmetric intracranial calcification. Inherited and neurodegenerative diseases cause symmetrical, bilateral basal ganglia calcification which is not related to metabolic disorders (blood calcium level and other), those are: Cockayne syndrome, tuberous sclerosis, Fahr's syndrome, Down syndrome and other. We observed some cases of basal ganglia calcification and studied clinical manifestations and treatment tolerance of this pathological condition. Since adequate treatment of hypoparathyroidism may lead to marked clinical improvement, serum concentration of calcium, phosphorus, and parathyreoid hormone is suggested to be determined in all individuals with calcification of the basal ganglia to rule out hypoparathyroidism. Basal ganglia calcification in young patient with acute hepatitis may be result of Wilson disease.
17264425##2007-2-1##ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients.##
17249260##2007-1-26##Wilson's disease presenting as status epilepticus.##A patient of Wilson's disease having neurological as well as psychiatric manifestations who presented with status epilepticus is being reported. The diagnosis was confirmed by biochemical investigations and 'face of giant panda' sign was present on MRI brain.
17063115##2006-10-26##Diagnosis and management of Wilson's disease: results of a single center experience.##
17052424##2005-11-18##The spectrum of neurodegeneration in children.##
17173260##2006-12-19##Membranoproliferative glomerulonephritis in a patient with Wilson's disease.##Wilson's disease is an autosomal recessive disorder of hepatobiliary copper metabolism. Glomerular diseases can ensue during the course of Wilson's disease and membranous nephropathy is the eventual pathology in the majority of these cases. Membranoproliferative glomerulonephritis (MPGN) has rarely been reported in patients with Wilson's disease. Further, in this report, we present a patient with Wilson's disease who had developed MPGN during follow-up due to D-penicillamine therapy. This case is presented to draw attention to the rare association of Wilson's disease and MPGN and to discuss the possible underlying causes.
16991150##2006-9-23##Synchronized brain network underlying postural tremor in Wilson's disease.##Common neurological manifestation of Wilson's disease (WD) is a postural tremor of the upper extremities. Recently, the primary sensorimotor cortex (S1/M1) has been shown to be involved in WD postural tremor generation. However, neuropathological changes in WD are mostly observed in subcortical structures. We therefore aimed to investigate whether S1/M1 may be functionally interconnected with other brain areas. In five WD patients, we used magnetoencephalography and surface electromyography (EMG) to record simultaneously cerebral neuronal activity and muscular activity during sustained posture of the right forearm. As demonstrated previously, the strongest coupling to tremor EMG was observed in the contralateral S1/M1. This area was taken as reference in order to identify and localize cerebro-cerebral coherence at tremor frequency and its first harmonic. The analysis revealed significant coherence within an oscillatory network including S1/M1, higher cortical motor areas (premotor cortex, PM; supplementary motor area, SMA), posterior parietal cortex (PPC) and thalamus contralateral as well as the cerebellum ipsilateral to the tremor forearm. Flow of information was mainly of bidirectional nature. Taken together, our results indicate that WD postural tremor is generated within a synchronized cerebello-thalamo-cortical network, comprising S1/M1, higher cortical motor areas (SMA, PM), and PPC.
16991142##2006-9-23##Adverse reaction after tetrathiomolybdate treatment for Wilson's disease: a case report.##
17182432##2006-12-22##Copper- and iron-rich matrices in hepatocellular lipofuscin particles of a young male patient: diagnostic ultrastructures for Wilson disease.##A 17-year-old male patient appeared with the biochemical liver damage associated with hypoceruloplasminemia and mild iron overload. Genetic analysis identified a compound heterozygosity of ATP7B responsible for the primary copper toxicosis of Wilson disease without mutations in HFE. A liver specimen consisted of cirrhotic nodules of large-sized hepatocytes with fatty change and those of fat-free small-sized hepatocytes. Histochemically, iron was distributed diffusely in the small-sized hepatocytes, while copper grains appeared in a few of the hepatocytes near the fibrous bands. X-ray microanalysis on the liver tissue fixed with a 0.1% osmium tetroxide solution and embedded in epoxy resin disclosed (1) complex formation of copper with sulfur, and iron with phosphorus in the hepatocyte lipofuscin particles, (2) intraparticle localization of the cuprothionein in the less dense matrix and ferric proteins in the dense matrix, and (3) high affinity of the cuprothionein to lead staining. Considering the fact that ceruloplasmin is the major ferroxidase essential for iron efflux, iron deposits in the hypoceruloplasminemic patients with Wilson disease are not a complication, but a natural event. This study disclosed for the first time the diagnostic ultrastructures of Wilson disease, which might represent different detoxification processes to the reactive metals of copper and iron.
16970921##2006-8-10##Effects of copper metabolism on neurological functions in Wistar and Wilson's disease model rats.##Behavioral functions of Wistar and Long-Evans Cinnamon (LEC) rats, Wilson's disease animal model, were compared by measuring the open-field, acoustic startle reflex and prepulse inhibition (PPI), and shuttle-box avoidance learning tests with or without oral supplementation with copper or D-penicillamine, copper chelator. All of the LEC rats, irrespective of the treatment, exhibited higher locomotor activity, a decreased habituation to startle response or a lower PPI, compared with Wistar rats. The copper content of all brain regions examined, except for the medulla oblongata of LEC rats, was significantly lower than those in Wistar rats. Besides, in the region of the striatum and the nucleus accumbens of the LEC rats, lower content of norepinephrine, and higher content of dopamine and serotonin were observed compared with Wistar rats. Although copper supplementation did not affect the brain copper content, it reduced the PPI in both Wistar and LEC rats. In contrast, D-penicillamine supplementation decreased both the brain copper content and locomotor activity, and enhanced the startle amplitude only in Wistar rats. These findings suggest that an imbalance in copper homeostasis affects monoamine metabolism and behavioral functions.
16676348##2006-5-6##A new hepatocytic isoform of PLZF lacking the BTB domain interacts with ATP7B, the Wilson disease protein, and positively regulates ERK signal transduction.##The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of the BTB-domain/zinc-finger family, and shown to regulate the expression of Hox genes during embryogenesis and the expression of cyclin A in the cell cycle progression. Here, a 45-kDa isoform of PLZF without a BTB domain was identified via yeast two-hybrid screening using the C-terminal region of ATP7B as bait in our determination of the biological roles of the Wilson disease protein outside of its copper-binding domain. Our immunoprecipitation experiments showed that the hepatocytic isoform of PLZF could specifically interact with the C-terminal region of ATP7B. The immunostaining of HepG2 cells revealed that the ATP7B and PLZF proteins were apparently colocalized into the trans-Golgi complexes. It was also determined that disruption of PLZF expression in the HepG2 cells affected an attenuation of ERK activity in a dose-dependent manner. The hepatocytic activities of ERK kinase were found to be enhanced as the result of PLZF or ATP7B expression, but this enhancement was abrogated by the deletion of the C-terminal region of ATP7B. Furthermore, a transgenic Drosophila strain that ectopically expressed the hepatocytic deltaBTB-PLZF exhibited phenotypic changes in eye and wing development, and these alterations were fully recovered as the result of ATP7B expression, indicating the obvious in vivo interaction between the two proteins. Those PLZF-induced abnormalities were attributed to the enhancement of ERK signaling, as was shown by phenotypic reversions with loss-of-function mutations in ERK signal transduction in Drosophila. These data suggest the existence of a mechanism that regulates ERK signaling via the C-terminus of ATP7B and the ATP7B-interacting hepatocytic PLZF.
16741141##2006-6-1##Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization.##Milk copper (Cu) concentration declines and directly reflects the stage of lactation. Three Cu-specific transporters (Ctr1, Atp7A, Atp7B) have been identified in the mammary gland; however, the integrated role they play in milk Cu secretion is not understood. Whereas the regulation of milk composition by the lactogenic hormone prolactin (PRL) has been documented, the specific contribution of PRL to this process is largely unknown. Using the lactating rat as a model, we determined that the normal decline in milk Cu concentration parallels declining Cu availability to the mammary gland and is associated with decreased Atp7B protein levels. Mammary gland Cu transport was highest during early lactation and was stimulated by suckling and hyperprolactinemia, which was associated with Ctr1 and Atp7A localization at the plasma membrane. Using cultured mammary epithelial cells (HC11), we demonstrated that Ctr1 stains in association with intracellular vesicles that partially colocalize with transferrin receptor (recycling endosome marker). Atp7A was primarily colocalized with mannose 6-phosphate receptor (M6PR; late endosome marker), whereas Atp7B was partially colocalized with protein disulfide isomerase (endoplasmic reticulum marker), TGN38 (trans-Golgi network marker) and M6PR. Prolactin stimulated Cu transport as a result of increased Ctr1 and Atp7A abundance at the plasma membrane. Although the molecular mechanisms responsible for these posttranslational changes are not understood, transient changes in prolactin signaling play a role in the regulation of mammary gland Cu secretion during lactation.
16937262##2005-9-20##Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading.##The toxic milk (tx) mouse is a rodent model for Wilson disease, an inherited disorder of copper overload. Here we assessed the effect of copper accumulation in the tx mouse on zinc and iron metabolism. Copper, zinc and iron concentrations were determined in the liver, kidney, spleen and brain of control and copper-loaded animals by atomic absorption spectroscopy. Copper concentration increased dramatically in the liver, and was also significantly higher in the spleen, kidney and brain of control tx mice in the first few months of life compared with normal DL mice. Hepatic zinc was increased with age in the tx mouse, but zinc concentrations in the other organs were normal. Liver and kidney iron concentrations were significantly lower at birth in tx mice, but increased quickly to be comparable with control mice by 2 months of age. Iron concentration in the spleen was significantly higher in tx mice, but was lower in 5 day old tx pups. Copper-loading studies showed that normal DL mice ingesting 300 mg/l copper in their diet for 3 months maintained normal liver, kidney and brain copper, zinc and iron levels. Copper-loading of tx mice did not increase the already high liver copper concentrations, but spleen and brain copper concentrations were increased. Despite a significant elevation of copper in the brain of the copper-loaded tx mice no behavioural changes were observed. The livers of copper-loaded tx mice had a lower zinc concentration than control tx mice, whilst the kidney had double the concentration of iron suggesting that there was increased erythrocyte hemolysis in the copper-loaded mutants.
17090957##2006-11-9##Accumulation of copper induces DNA strand breaks in brain cells of Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson Disease.##Copper accumulation and induction of DNA strand breaks were investigated in the brain of Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson disease that is a heritable disease of copper accumulation and copper toxicity in the liver, kidney and brain. Copper contents in the brain of LEC rats increased from 20 weeks of age and were approximately 3.5 to 6 folds higher than those in the brain of WKAH rats at 24 weeks of age. Hepatic copper contents in LEC rats increased from 4 to 12 weeks of age in an age-dependent manner, and then decreased from 16 to 20 weeks of age. Thus, we consider that copper accumulated in the liver was released from severely damaged hepatocytes and deposited in the brain, although copper contents in the brain were 1/20-fold lower than those in the liver. We also evaluated the amounts of DNA single-strand breaks (SSBs) in the brain by comet analysis. The proportions of nuclei in the cerebrum and cerebellum without DNA damage decreased, and nuclei with severe DNA damage appeared in LEC rats at 24 weeks of age. The comet scores of cerebrum and cerebellum cells significantly increased in LEC rats and were significantly higher than those in WKAH rats at 24 weeks of age. The results show that SSBs in LEC rat brain cells are induced at a lower concentration of copper than are SSBs in hepatic cells.
16586257##2006-1-2##[Correlation of clinical aspects as well as genotype and phenotype in Wilson's disease on the basis of epidemiologic, clinical and cranial MRI findings].##Wilson's disease, a rare autosomal recessive disorder of hepatic copper transport, is characterized by a varying pattern of hepatic, neurologic and psychiatric symptoms. Currently, about 250 causative mutations of the ATP 7B gene are known. However, a correlation between genotype and phenotype according to these mutations is not yet clear. To elucidate a possible correlation in this study 39 patients with Wilson's disease were subdivided into three groups according to the underlying mutation in group I for homocygote respectively group II for compound heterocygote mutation in H1069Q and group III for other mutations. Clinical subtype and extent of neurologic disturbance as well as epidemiologic aspects, presence of psychiatric symptoms, results of acustically evoked potentials (Wave III, interpeak latency III-V) and findings of cranial MRI were considered. While psychopathological symptoms, the results of acustically evoked potentials and cranial MRI show a correlation to the clinical subtype of Wilson's disease there was no genotype-phenotype correlation on the basis of the mutation in H1069Q. The qualitative and quantitative pattern of results do not show any significant differences in the three groups of genotype. Thus, the time of treatment onset still has most influence on the extent of clinical manifestation and reversibility of the toxic copper accumulation.
16987733##2006-9-22##Treatment of dystonia.##Dystonia, defined as a neurological syndrome characterised by involuntary, patterned, sustained, or repetitive muscle contractions of opposing muscles, causing twisting movements and abnormal postures, is one of the most disabling movement disorders. Although gene mutations and other causes are increasingly recognised, most patients have primary dystonia without a specific cause. Although pathogenesis-targeted treatment is still elusive, the currently available symptomatic treatment strategies are quite effective for some types of dystonia in relieving involuntary movements, correcting abnormal posture, preventing contractures, reducing pain, and improving function and quality of life. A small portion of patients have a known cause and respond to specific treatments, such as levodopa in dopa-responsive dystonia or drugs that prevent copper accumulation in Wilson's disease. Therapeutic options must be tailored to the needs of individual patients and include chemodenervation with botulinum toxin injections for patients with focal or segmental dystonia, and medical treatments or deep brain stimulation for patients with generalised dystonia.
16941464##2006-8-31##Prevalence of the H1069Q mutation in ATP7B in discordant pairs with early-onset Parkinson's disease.##
16996405##2005-11-29##Psychological presentations without hepatic involvement in Wilson disease.##Wilson disease is an autosomal recessive inborn error of copper metabolism that leads to neurologic symptoms and variable degrees of hepatic damage. The most common characteristic signs clinically are liver disease, psychiatric disease, neurologic disease, or a combination of these. Early recognition by means of clinical signs and an early initiation of therapy using chelators or zinc-salts are essential for a good outcome and prognosis. This report describes a male suffering from Wilson disease who exhibited an unusual presentation that included psychological manifestations without hepatic involvement. He was initially treated for attention-deficit hyperactivity disorder and a seizure disorder until brain imaging established the diagnosis of Wilson disease.
16940238##2006-8-28##Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress.##The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper that generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic antioxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5), and fulminant hepatic failure (group III, n = 5) and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in group II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-dependent superoxide dismutase (CuZn-SOD), and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase (GPx) activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD, and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.
17066601##2006-10-28##[Indications of urgent plasma exchange and cytapheresis therapies--a review based on literature data and personal experience].##Emergency plasma exchange therapy is life saving in many cases. Therefore, clinicians must be aware of the indications at which any delay in initiating therapy may prove to be fatal. Different hematological (Moschkowitz-, hyperviscosity- and catastrophic antiphospholipid syndrome; massive haemolysis [e.g Wilson's disease]), neurological (myasthenic), endocrine (thyrotoxicosis) and nephrological (rapidly progressive glomerulonephritis) crisis situations and for prevention of them; certain poisonings, fulminant liver failure, severe pancreatitis due to chylomicronaemia, meningococcus sepsis and iatrogenic or suicidal drug-overdose. In this latter, it is of fundamental importance that the protein binding of the drug should be high (>80%), whereas the volume of its distribution should be relatively low (<0,2 l/kg body weight) and the endogenous clearance of it should be less, than 500 ml/min. Urgent leukocytapheresis should be performed above 50.000 blasts/microl, in acute or chronic myeloid leukemia if symptoms of leukostasis are present (if blasts are above 100.000/microl, cytoreduction is mandatory even without symptoms). Similarly, urgent thrombocytapheresis should be administered above platelet numbers 1000 G/l, when there is concomitant thrombophilia or clinical symptoms of thrombostasis are present.
16884690##2006-7-7##Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases.##The P-type ATPases affected in Menkes and Wilson diseases, ATP7A and ATP7B, respectively, are key copper transporters that regulate copper homeostasis. The N termini of these proteins are critical in regulating their function and activity, and contain six copper-binding motifs MxCxxC. In this study, we describe the identification of glutaredoxin (GRX1) as an interacting partner of both ATP7A and ATP7B, confirmed by yeast two-hybrid technology and by co-immunoprecipitation from mammalian cells. The interaction required the presence of copper and intact metal-binding motifs. In addition, the interaction was related to the number of metal-binding domains available. GRX1 catalyses the reduction of disulphide bridges and reverses the glutathionylation of proteins to regulate and/or protect protein activity. We propose that GRX1 is essential for ATPase function and catalyses either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport.
16966556##2006-9-13##Subcortical white matter abnormalities related to drug resistance in Wilson disease.##Wilson disease (WD) produces typical lesions in the brain, which can aid in diagnosis and therapy. The authors present a drug-resistant WD case with atypical cerebral lesions with marked involvement of white matter as visualized on MRI scans. The diagnosis was confirmed by identification of mutations in the ATP7B gene. The case demonstrates an uncommon pathology-related cerebral copper accumulation and emphasizes the importance of genetic screening in the diagnosis of WD.
16814495##2006-3-9##Inhibition of delayed rectifier K+ currents by copper in acutely dissociated rat hippocampal CA1 neurons.##A growing number of research results demonstrate that copper is an important trace element to life. In this study, whole-cell recording made from acutely dissociated rat hippocampal CA1 neurons was employed to investigate the actions of copper (Cu(2+)) on the delayed rectifier K(+) currents (I(K)). External application of various concentrations of Cu(2+) (1-1000microM) reduced the amplitude of I(K) in a dose-dependent manner with an IC(50) value of 100microM and a Hill coefficient of 0.4. 300microM of Cu(2+) depolarized the I(K) activation curves by 12.5mV and hyperpolarized the I(K) state-inactivation curves by 17.4mV, respectively. At this concentration, Cu(2+) also significantly increased the value of the fast decay time constant (tau(1)), but had no effect on the I(K) recovery from inactivation. These results suggest that relevant concentrations of copper at physiological and pathological level can influence the neuronal excitability of rat hippocampal CA1 neurons by voltage-gated delayed rectifier K(+) channels, and such actions are likely involved in the pathophysiology of Cu-related Wilson's disease.
16950693##2006-9-5##Regression of nodular liver lesions in Wilson's disease.##Long-term follow-up abdominal imaging studies have not been reported previously in patients with the hepatic form of Wilson's disease (WD). This paper reports the case of a 35-year-old woman with symptoms dating back several months and with multiple, nodular liver lesions. The lesions were hyperdense on non-enhanced computed tomography and hypointense on T2-weighted magnetic resonance (MR) images. A diagnosis of WD was established several weeks after her admission to hospital, and chelating treatment was commenced promptly. No abnormalities were found on follow-up MR examinations of the abdomen and brain 4.5 years later. These imaging features suggest that so long as WD is diagnosed in the initial stages, liver nodules can regress with time and complete healing can be achieved with continuous decoppering treatment.
16942668##2006-9-1##Nonalcoholic Fatty Liver Disease (NAFLD): Approach in the Adolescent Patient.##Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver disease whose hallmark is the accumulation of large-droplet fat in hepatocytes. This metabolic disorder occurs mainly in overweight or obese individuals. The disease mechanism involves hyperinsulinemia and hepatic insulin resistance, not ethanol abuse. NAFLD may be the hepatic manifestation of the "metabolic syndrome" classically associated with type 2 diabetes mellitus and cardiovascular disease. NAFLD ranges from simple steatosis, which is the least rapidly progressing disorder, to nonalcoholic steatohepatitis to cirrhosis, which can evolve to chronic liver failure. The high prevalence of NAFLD in children has been recognized only in the past 5 to 10 years, as rates of childhood obesity have soared. Accordingly, the best strategies for diagnosis and treatment of childhood NAFLD are a work in progress and remain controversial. Weight reduction through a healthy diet and regular medium-intensity exercise is the mainstay of current treatment. Few research data are available to guide pharmacologic therapy. Certain points regarding management of childhood NAFLD require emphasis: It is a serious liver disease that requires detailed clinical investigation. Other liver diseases causing fatty liver and/or abnormal liver tests, notably Wilson disease and chronic viral hepatitis, need to be excluded. Liver biopsy can provide critical diagnostic and staging information. Associated genetic or endocrine disorders need to be identified. Treatment should begin with a low-glycemic index diet that provides adequate nutrients but is low in harmful fats and eliminates foods causing postprandial hyperglycemia. Initially, this can target two to three problem foods so that it is easy for the adolescent to follow. Regular exercise suited to the capabilities and interests of the teenager should be added to the daily routine. Where possible, a team approach, including a dietician and psychologist, should be utilized, as adolescents do better in a supportive atmosphere. Optimal drug treatment requires further research: current front-runners are vitamin E and metformin. The roles of drugs that alter appetite and bariatric surgery for adolescents with NAFLD have not been determined.
16791614##2006-4-18##Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing.##Wilson disease is an autosomal recessive inherited disorder of copper metabolism. The Wilson disease gene codes for a copper transporting P-type ATPase (ATP7B). Molecular genetic analysis reveals at least 300 distinct mutations. While most reported mutations occur in single families, a few are more common. The most common mutation in patients from Central, Eastern, and Northern Europe is the point mutation H1069Q (exon 14). About 50-80% of Wilson disease (WD) patients from these countries carry at least one allele with this mutation with an allele frequency ranging between 30 and 70%. Other common mutations in Central and Eastern Europe are located on exon 8 (2299insC, G710S), exon 15 (3400delC) and exon 13 (R969Q). The allele frequency of these mutations is lower than 10%. In Mediterranean countries there is a wide range of mutations, the frequency of each of them varies considerably from country to country. In Sardinia, a unique deletion in the 5' UTR (-441/-427 del) is very frequent. In mainland Spain the missense mutation M645R in exon 6 is particularly common. Data from non-European countries are scarce. Most data from Asia are from Far Eastern areas (China, South Korea and Japan) where the R778L missense mutation in exon 8 is found with an allele frequency of 14-49%. In summary, given the constant improvement of analytic tools genetic testing will become an integral part for the diagnosis of WD. Knowledge of the differences in the worldwide distribution of particular mutations will help to design shortcuts for genetic diagnosis of WD.
16940686##2006-8-31##Pros and cons of immunochemical and enzymatic method in the diagnosis of Wilson's disease.##
16998287##2006-9-26##[Wilson disease: an update].##Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin (<20 mg/dL), high 24 hour urine copper (>100 microgram), high hepatic copper content (>250 microgram/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.
16998622##2006-4-17##Compound overload of copper and iron in patients with Wilson's disease.##This review of the copper-iron interaction in Wilson's disease was mainly based on ten patients (three females and seven males) studied in our institutes because the genetic tests of ATP7B for Wilson's disease of primary copper toxicosis and HFE for hemochromatosis, the biochemical parameters of copper and iron, and morphological studies on biopsied liver specimens were complete. All patients had hypoceruloplasminemia and hepatic lesions compatible with Wilson's disease. One patient was homozygous and nine patients were compound heterozygous for the mutations in ATP7B, and all patients were free from the major mutation, C282Y, of HFE. The biochemical parameters of iron metabolism were not specific, except for serum ferritin concentration. Judging from the traditional criteria, seven patients had hyperferritinemia. Histochemical iron was stained in the livers of seven patients and histochemical copper was found in nine patients. Microanalysis was more sensitive than histochemistry, detecting copper and iron accumulation in the hepatocellular lipofuscin particles of all patients. Using an improved fixative, intralipofuscin distribution was found to be different between cuprothionein and iron complexes. Iron overload in Wilson's disease might be worsened after treatment because of the close relation to hypoceruloplasminemia, in which the iron efflux from the liver to the circulation is disturbed.
16644258##2006-2-22##Retrospective determination of ceruloplasmin in newborn screening blood spots of patients with Wilson disease.##Wilson disease is an autosomal recessive disorder of copper transport, caused by the reduced or absent function of the Wilson disease gene ATP7B on chromosome 13. The disease is characterized by reduced incorporation of copper into the ceruloplasmin protein and reduced excretion of copper into the bile. Wilson disease is effectively treated if detected early. Our study goals were to determine the feasibility of a population screening for Wilson disease using dried blood spots and to characterize the base-line ceruloplasmin concentration in newborn blood spots of patients with Wilson disease. Ceruloplasmin was analyzed in dried blood spots obtained from 353 Mayo Clinic pediatric volunteers aged from 3 months to 18 years and from 1045 anonymous newborn screening specimens using a sandwich enzyme-linked immunosorbent assay. The original newborn screening blood spots were retrieved from two patients with Wilson disease along with age-matched controls for ceruloplasmin determination. The mean (+/-SD) concentration of ceruloplasmin in the pediatric blood spots was 40.0+/-14.4 mg/dL (range 13.1 to >60 mg/dL) and newborn blood spots was 47.2+/-15.5mg/dL (range 6.5 to >60 mg/dL). Ceruloplasmin in the newborn blood spots from two Wilson disease patients were 2.6 and 2.8 mg/dL, respectively. The newborns affected with Wilson disease had significantly lower ceruloplasmin levels in blood spots than unaffected newborns. These findings support that presymptomatic screening for Wilson disease using dried blood spots could be possible, even in the newborn period.
16763975##2006-6-10##Extrapyramidal symptoms in Wilson's disease are associated with olfactory dysfunction.##Wilson's disease is a rare autosomal recessive disorder characterized by the accumulation of copper, mainly in the liver and the brain. As copper accumulation in the brain leads to disturbances in basal ganglia function, neurological-type patients typically present with hypo- and hyperkinetic extrapyramidal symptoms, with Parkinsonism being very common. Although there are numerous reports on olfactory deficits in primary neurodegenerative disorders, olfactory function has not been investigated in metabolic disorders presenting with extrapyramidal features. Twenty-four patients with Wilson's disease participated in the investigation. All patients were treated pharmacologically. They comprised patients with liver disease alone (including mild enzyme elevation in asymptomatic individuals; n = 11) and/or neurological symptoms (n = 13) at the time of testing. Twenty-one patients underwent both [18F]fluoro-2-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and magnetic resonance imaging (MRI). The severity of extrapyramidal symptoms was judged using a clinical score system ranging from 0 (no symptoms) to 3 (severe symptoms). In all patients, psychophysical testing was performed using the Sniffin' Sticks, which involved tests for odor threshold, discrimination, and identification. Results from the present study revealed that Wilson's disease patients with neurological symptoms show a significant olfactory dysfunction compared to hepatic-type patients. Individuals who are more severely neurologically affected also present with a more pronounced olfactory deficit. Of interest, there was no significant effect of long-term treatment with penicillamine on olfactory function. Olfactory function did not correlate significantly with the presence of MRI visible lesions in the basal ganglia or with any regional glucose metabolism as measured by [18]F-FDG-PET. In conclusion, these findings indicate that the underlying pathological alterations with degeneration in the basal ganglia and neuronal loss in association with a marked increase of the copper content in this brain region play a role in the olfactory deficit.
16932613##2006-3-05##Wilson's disease: an update.##Wilson's disease (WD) is an inborn error of copper metabolism caused by a mutation to the copper-transporting gene ATP7B. The disease has an autosomal recessive mode of inheritance, and is characterized by excessive copper deposition, predominantly in the liver and brain. Diagnosis of the condition depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring, and a new diagnostic scoring system has recently been proposed. Mutations in ATP7B can occur anywhere along the entire 21 exons, which makes the identification of gene defects particularly challenging. Identification of carriers and presymptomatic family members of affected individuals is achieved by polymerase-chain-reaction-based marker analysis. The traditional treatment for WD is based on copper chelation with agents such as D-penicillamine, but use of this drug has been questioned because of reported side effects. The use of agents such as trientine and ammonium tetrathiomolybdate has been advocated, although results of long-term trials are awaited. In selected cases, orthotropic hepatic transplantation can reverse the basic metabolic abnormality in WD and improve both hepatic and neurological symptoms. Studies of the underlying defects in ATP7B and its suspected modifiers ATOX1 and COMMD1 are expected to unravel the disease's genotype-phenotype correlation, and should lead to the design of improved drugs for ameliorating the suffering of patients.
16752136##2006-2-22##Wilson's disease: cranial MRI observations and clinical correlation.##
16842975##2006-5-10##Plasma copper, iron, ceruloplasmin and ferroxidase activity in schizophrenia.##As ceruloplasmin and copper abnormalities have been implicated in schizophrenia, we investigated the role of a second copper-containing non-ceruloplasmin protein, the iron oxidase ferroxidase II, in a prospective study of ten inpatients with schizophrenia and a comparison group. Ferroxidase II is a protein known to reciprocally regulate with ceruloplasmin in Wilson's disease, an illness characterized by psychotic symptoms, decreased ceruloplasmin, and increased copper deposition in tissues. Ferroxidase II plays a key role in the maintenance of near-normal iron metabolism in Wilson's disease, but its role in schizophrenia has never been studied. In this study, we assayed ceruloplasmin by two enzymatic assays, a standard clinical laboratory p-phenylenediamine oxidation assay and a second assay based on the rate of the oxidation and incorporation of iron (Fe3+) into transferrin; we assayed ferroxidase II activity using this second iron oxidation assay. We found that ceruloplasmin levels as measured by both enzymatic methods, but not ferroxidase II, were elevated in schizophrenia. The increased ceruloplasmin also correlated with elevated serum copper as assayed by atomic absorption spectrophotometry, which was unsurprising as the majority of copper in blood is bound to ceruloplasmin. It has been proposed that copper, as a component of several enzymes linked to dopamine synthesis, may play a role in schizophrenia by exacerbating or perpetuating dopaminergic dysregulation. Our study suggests that the ceruloplasmin elevation in schizophrenia is specific, and not simply an elevation of plasma copper-containing oxidative enzymes. Increases in ceruloplasmin may result in increased levels of copper, which ultimately proves deleterious in schizophrenia.
16790037##2006-6-22##Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation.##Immunosuppression is currently the treatment of choice for severe inflammatory bowel disease (IBD). Thus, it was anticipated that the course of preexisting IBD should improve after orthotopic liver transplantation (OLT). Despite sufficient allograft immunosuppressive therapy, however, exacerbation of IBD or the development of de novo IBD after OLT were described in some cases, primarily in patients transplanted for end-stage primary sclerosing cholangitis (PSC). In addition, the development of de novo IBD in patients undergoing OLT for indications other than PSC was described. Evaluating our collective of 314 liver transplanted patients we found five patients transplanted for various indications other than PSC (autoimmune hepatitis [AIH], acute-on-chronic hepatitis B, Wilson's disease, and cryptogenic cirrhosis) who developed de novo IBD after OLT despite sufficient immunosuppressive therapy with tacrolimus or cyclosporine. PSC was widely excluded in these patients by clinical and histological examinations and there was no sign of an enteric infection. It was remarkable that all patients were suspected to have an autoimmune background. Four of our patients were women and almost all patients showed histologically typical signs of an ulcerative colitis (UC). To prevent allograft rejection, three of five patients were treated with cyclosporine and the other two with tacrolimus. After diagnosis, treatment with aminosalicylates and corticosteroids led to complete clinical and histological remission. However, relapses occurred frequently after termination of specific therapy. In combination with previous reports, our cases indicate an immune dysregulation leading to the development of de novo IBD after OLT under immunosuppressive therapy. Reviewing the literature, it should be considered that apart from the autoimmune background, immunosuppressive therapy may itself play a major role in the development of de novo IBD. From the clinical point of view, it is of critical importance to detect this phenomenon, since diarrhea is an important cause of morbidity and mortality in transplanted patients and therapy for this disorder completely differs from the treatment for other causes of diarrhea. Aminosalicylates and courses of corticosteroids offer an effective treatment.
16873303##2006-7-29##Simple and effective strategies for detection of allele dropout in PCR-based diagnosis of Wilson disease.##
16793346##2006-6-21##Resolution of decompensated cirrhosis from Wilson's disease with zinc monotherapy: a potential therapeutic option?##
16737843##2006-3-2##Iron removal by phlebotomy for the prophylaxis of fulminant hepatitis in a Wilson disease model of Long-Evans Cinnamon Rats.##Long-Evans Cinnamon rats are an animal model of Wilson disease with a compound load of copper and iron. However, the mechanisms of the high mortality rate from fulminant hepatitis in the rats remain undetermined. In this study, phlebotomy as an alternative for an iron-deficient diet was investigated to modify hepatitis in the rats. One group of female rats was treated with phlebotomy twice a week, and the other group received blood tests only every 2 weeks. Liver specimens were examined for biochemical non-heme iron and copper, and histochemical trivalent iron. Although all rats examined had icteric hepatitis around the age of 20 weeks, the mortality of fulminant hepatitis was lower in phlebotomized rats than in control rats (1/18 versus 8/20, p<0.05). Phlebotomy not only ameliorated the severity of hepatitis, but also reduced serum malondialdehyde. Non-heme iron in the liver was the greatest in victims of fulminant hepatitis in the control group. There was no difference in the hepatic copper content between the two groups. The prognosis of hepatitis in the rats with Wilson disease was hepatic non-heme iron-dependent, and iron removal by phlebotomy was an effective prophylaxis against fulminant hepatitis.
16607473##2005-10-15##Profound midbrain atrophy in patients with Wilson's disease and neurological symptoms?##Wilson's disease (WD) is characterized by impaired hepatic copper secretion and subsequent copper accumulation in many organs predominantly liver and brain, secondary to loss of function mutations in the copper transport protein ATP7B. If the disease is recognized too late or treatment is not adequate, brain copper accumulation leads to progressive neurodegeneration with a variety of clinical symptoms. The nigrostriatal dopaminergic system seems rather vulnerable. Midbrain atrophy, however, has not been recognized as one of the prime features of patients with WD. Here we report quantification of midbrain diameter in 41 patients with WD. Data were correlated to the severity of neurological symptoms and the integrity of dopaminergic neurons measured via dopamine transporter binding. For control, we measured midbrain diameter in 18 patients with no evidence for brainstem dysfunction and 5 patients with progressive supranuclear palsy (PSP). Patients with WD had a reduced midbrain diameter (15.5 +/- 0.4 mm) compared to controls (18.5 +/- 0.2 mm). WD patients without neurological symptoms had midbrain diameter that were not different from controls (18.0 +/- 0.3 mm), while patients with neurological symptoms showed midbrain atrophy similar to patients with PSP (14.4 +/- 0.3 mm versus 14.1 +/- 0.3). There was a strong and significant correlation between midbrain atrophy and the severity of neurological symptoms (r= -0.68, p < 0.001) while midbrain atrophy and dopamine transporter binding correlated significantly but was less pronounced (r=0.46, p < 0.001). In summary, we were able to show, that midbrain diameter is an easy to perform quantification of neurodegeneration induced by brain copper accumulation and that other structures than substantia nigra dopaminergic neurons seem to contribute to midbrain atrophy in WD.
16857005##2006-7-22##Hepatocellular carcinoma in Wilson's disease: a rare association in childhood.##Wilson's disease is a hereditary disorder of copper metabolism that results in the accumulation of copper in the body, primarily in the liver, brain, and cornea. Hepatocellular carcinoma, in contrast to other causes of cirrhosis, is seldom associated with Wilson's disease. We present a 12-yr-old boy with Wilson's disease in whom hepatocellular carcinoma was incidentally diagnosed in the pathologic specimen examined after liver transplantation.
16803697##2006-6-29##Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats: an animal model for Wilson disease.##
17355091##2007-3-16##Hepatitic inherited metabolic disorders.##Primary metabolic disorders are a disparate group of diseases that may or may not be accompanied by hepatic manifestations. Those with liver involvement may show a range of histopathologic changes. Proper histologic diagnosis requires correlation with clinical and laboratory data, including evaluation for mutations either via serum protein electrophoresis or through formal genetic analysis. This article is a review of the three most common inherited metabolic disorders which may present with a hepatitic pattern. In alpha1-antitrypsin disorder, there is a broad range of clinical presentations, age at presentation, and histological features ranging from "neonatal hepatitis" to a chronic progressive hepatitis in later childhood and adulthood. Hence, this disorder must be in the differential diagnosis of liver disease of the very young, and in older children and adults, with or without coexistent overt pulmonary symptoms. In Wilson disease, presentation tends to be in older childhood or the adult, with a progressive chronic hepatitis. Cystic fibrosis may feature a characteristic obstructive biliary syndrome, coexisting with the many extrahepatic manifestations of this debilitating disease. Lastly, the progressive familial intrahepatic cholestasis (PFIC) syndromes are given as examples of inherited metabolic conditions in which relentlessly progressive cholestatic liver disease eventuates over years in end-stage cholestatic liver disease with cirrhosis. Distinguishing features include absence of elevated serum gamma-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, and elevated GGT in PFIC-3. However, molecular studies are required for a confident diagnosis of the rare PFIC syndromes.
16815276##2005-8-25##Corneal copper deposition associated with chronic lymphocytic leukemia.##
16831968##2006-7-13##Influence of homozygosity for methionine at codon 129 of the human prion gene on the onset of neurological and hepatic symptoms in Wilson disease.##
16944016##2006-9-1##Successful plasma exchange treatment in hemolytic crisis of Wilson's disease preventing liver transplantation.##
16799059##2006-6-27##Retinal localization and copper-dependent relocalization of the Wilson and Menkes disease proteins.##
16269182##2005-9-19##Acute fulminant hepatitis B in a patient with diabetic nephropathy treated successfully with concomitant lamivudine and molecular adsorbents recirculating system.##A 36-year-old man with type 2 diabetes and diabetic nephropathy treated with hemodialysis developed hepatitis B virus (HBV)-induced acute fulminant hepatic failure (FHF). Despite supportive treatment, the condition rapidly progressed as manifested by severe jaundice, coagulopathy and hepatic coma. He was placed on the waiting list for liver transplantation and was treated with lamivudine and extracoporeal liver support with the molecular adsorbent recirculating system (MARS). After three 8-h sessions of MARS treatment in 1 week, he had remarkable improvement in clinical symptoms and serum biochemistry. On the 14th hospital day, surface antigen seroconversion was noted with undetectable hepatitis B virus surface antigen (HBs Ag) and low titre of anti-HBs antibody, indicating a complete recovery from acute fulminant hepatitis B. MARS treatment has been reported to benefit patients with liver failure from different causes including acute exacerbation of chronic hepatitis B, poisoning, post transplantation and Wilson's disease. The present case suggests its potential benefit when combined with lamivudine in treating uremic patients with acute fulminant hepatitis B.
16696937##2006-4-18##Mutation analysis of Taiwanese Wilson disease patients.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, which is caused by mutation in copper-transporting ATPase (ATP7B). In the present study, we report a molecular diagnosis method to screen the WD chromosome in patients or in heterozygotic carriers in Taiwan. Exons 8, 11, 12, 13, 16, 17, and 18 of ATP7B are selected for the screening of mutations. The most common mutation, Arg778Leu or Arg778Gln, was first screened by PCR-RFLP then we combined single-stranded conformation polymorphism (SSCP) analysis followed by direct DNA sequencing on the DNA fragments with mobility shift on SSCP analysis. The diagnostic rate was compared with standard ATP7B whole gene sequencing analysis. Ten different mutations were identified among 29 WD patients; among them four were novel (Ala1168Pro, Thr1178Ala, Ala1193Pro, and Pro1273Gln). The false positive rates were tested against 100 normal individuals and listed as follows: exon 8: 5%; exon 11: 4%; exon 12: 6%; exon 13: 5%; exon 16: 5%; exon 17: 3%; exon 18: 4%. The Arg778Leu mutation exhibited the highest allelic frequency (43.1%). The detection rate of WD chromosomes is 65.52%, which is as sensitive as whole gene sequencing scanning. According to our results, WD chromosomes in Taiwan are predominantely located at exons 8, 11, 12, 13, 16, 17, and 18. The standard sequencing analysis on the entire gene is time consuming. We recommend screening these 7 exons first on those individuals who have a higher risk in having WD, before whole gene and promoter sequencing analysis in Taiwan.
16563643##2005-6-17##Free radical-mediated neurotoxicity may be caused by inhibition of mitochondrial dehydrogenases in vitro and in vivo.##We previously demonstrated that copper facilitated the formation of reactive oxygen species, and inhibited pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in vitro and in animal models of Wilson's disease in vivo. However, direct Cu(2+) toxicity has only been demonstrated for Wilson's disease. We now hypothesize that inhibition of these mitochondrial dehydrogenases might also contribute to many other injuries and disorders that are reactive oxygen species-mediated. We have modeled reactive oxygen species-mediated injuries using inducers of reactive oxygen species such as hydrogen peroxide, ethacrynic acid or menadione, or another redox active metal (Cd(2+)). Here we demonstrated that these toxic exposures were accompanied by an early marked reduction in both pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase activities, followed by a decrease in neuronal mitochondrial transmembrane potential and ATP, prior to murine cortical neuronal death. Thiamine (6 mM), and dihydrolipoic acid (50 microM), required cofactors for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (thiamine as thiamine pyrophosphate), attenuated the reactive oxygen species-induced reductions in these enzyme activities, as well as subsequent loss of mitochondrial transmembrane potential and ATP, and neuronal death. We next tested the effect of thiamine supplementation on an in vivo model of reactive oxygen species-mediated injury, transient middle cerebral artery occlusion, and reperfusion in rats. Oral or i.p. thiamine administration reduced the middle cerebral artery occlusion-induced infarct. These data suggest that reactive oxygen species-induced neuronal death may be caused in part by reactive oxygen species-mediated inhibition of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in vitro and in vivo, and that thiamine or dihydrolipoic acid may constitute potential therapeutic agents not just against Cu(2+) neurotoxicity, but may reduce neuronal degeneration in the broader range of diseases mediated by free radical stress.
16865855##2006-7-27##[Antioxidant therapy in chronic liver diseases].##In chronic liver diseases with inflammatory reactions (chronic viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, chemicals and drug induced hepatitis, Wilson disease, haemochromatosis) the oxidative stress, the cell alteration induced by free radicals is an important part of the pathogeneis beside the aetiological factors. In this paper the development of free radicals and their physiological role are demonstrated. The factors, which are influenced by the free radicals and antioxidants, as well as the pathological effects caused by oxidative stress in biological systems are discussed in details. The authors demonstrate the free radical processes as key factors in alcoholic liver diseases and non-acoholic steatohepatitis, furthermore the possible treatment modalities in the inhibition of these alterations. Also the free radical processes in chronic viral hepatitis and autoimmune hepatitis are discussed as well. The oxidative stress is able to enhance the progression of chronic inflammatory liver disease independently from the aetiological factor or with it together. That is why the antioxidant drugs could be applied also in the treatment of chronic liver diseases beside the therapy based on the aetiological factors.
16775300##2006-6-16##MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation.##
16632204##2005-7-1##Copper transfer studies between the N-terminal copper binding domains one and four of human Wilson protein.##Human Wilson protein functions in the secretory pathway to insert copper ultimately into the multicopper oxidase ceruloplasmin and also plays a role in the excretion of excess copper to the bile. This copper-transporting P-type ATPase possesses six N-terminal cytosolic copper-binding domains contained within an approximately 72 amino acid consensus motif and the first four of these domains, denoted WLN1-4, are implicated in copper acquisition from the metallochaperone HAH1, whereas the domains closest to the membrane portion of the enzyme, WLN5-6, are essential for copper transport across the membrane. In order to test our hypothesis that copper transfer occurs between domains in the N-terminus of Wilson protein, we expressed and purified to homogeneity copper-binding domains 1, 3, 4, 5-6, and 6, denoted by WLN1, WLN3, WLN4, WLN5-6, and WLN6, respectively. Since we determined WLN1 and WLN4 to have the highest and lowest isoelectric points (6.77 and 3.85, respectively) and thus are readily separated via ion exchange chromatography, we developed a copper transfer assay between these domains. We anaerobically incubated either Cu(I)-WLN1 with apo-WLN4 or apo-WLN1 with Cu(I)-WLN4, then separated these domains and quantified the amount of copper that migrates from one domain to another by ICP-MS. Regardless of whether we start with Cu(I)-WLN1 or Cu(I)-WLN4 as the initial copper donor, we demonstrate facile copper transfer between WLN1 and WLN4, thereby demonstrating the feasibility of copper transfer between these domains in vivo.
16868807##2005-11-21##The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease.##
16723212##2006-5-24##PET imaging of the basal ganglia.##The present chapter reviews PET imaging in basal ganglia disorders; Parkinson's disease is used as a model of these disorders because the neurochemical pathobiology of this disease is well known and great advances in the imaging area have been achieved. Other basal ganglia disorders including Tourette's syndrome, dystonia, Huntington's chorea and Wilson's disease are also dealt with. With PET and SPECT techniques, the whole integrative dopaminergic network of neurons can be studied, which plays an important role in differential diagnostics. Furthermore, pharmacological effects of medication can be visualized and the role of stereotaxic neurosurgery can be evaluated. Finally, functional imaging gives clues about the prognosis and rehabilitation aspects of the basal ganglia disorders.
16768127##2006-6-14##[NASH in children].##It has long been recognized that hepatic steatosis (fatty liver) occurs in obese children as in adults. Steatosis of any etiology can be associated with the development of necro-inflammation and fibrosis, so called steatohepatitis, and even cirrhosis. Nonalcoholic steatohepatitis (NASH) has been proposed as a component of insulin resistant syndrome and exists in pediatric population. The other etiology of NASH in children has not been clearly understood. In addition to obesity, adipose tissue distribution also appears to influence metabolic complications. Subjects with visceral fat adiposity appear to be at risk for fatty liver because of their ability to transport free fatty acids directly into the portal vein for conversion to triglycerides within the liver. A stronger relationship of serum ALT to visceral adiposity than BMI was demonstrated. Many metabolic diseases such as Wilson's disease, NICCD, OTC deficiency, carnitine deficiency have steatohepatitis and cirrhosis. It may play the important role to reveal the mechanism of progress to NASH.
16768116##2006-6-14##[Drug-induced NASH].##Steatohepatitis is pathologically characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Alcoholic hepatitis is a prototype of this syndrome, but a variety of diseases such as obesity, diabetes mellitus, Wilson disease and hepatitis C could reveal very similar pathological changes in some occasions. Therefore, well defined diseases need to be excluded in the process of differential diagnosis of steatohepatitis. Pathways possibly involved in the development of drug-induced steatohepatitis were categorized into four and outlines of the possible mechanisms involved in the development of this syndrome were proposed in this article.
16804509##2006-6-29##Psychosis and Wilson's disease: a case report.##In this article we present a case of a 26-year-old woman with clinical picture of acute psychosis, as the first and main manifestation of Wilson's disease, who developed abnormal involuntary choreoathetoid limb movements, few days after initiation of neuroleptic therapy. At the first movement neurological symptoms were misinterpreted as side effect of haloperidol, but consulted neurologist suggested additional diagnostic procedure which confirmed Wilson's disease. Psychiatric symptomatology and abnormal involuntary movements were the clinical manifestation of this disease, which improved with neuroleptic and chelating treatment. Interdisciplinary approach with good collaboration of psychiatrists and neurologists is crucial for Wilson's disease, because early diagnosis and treatment without delay is critical to the prognosis. This case serves as a reminder that involuntary movements can be side effect of antipsychotics but also the clinical manifestation of some illnesses, for example Wilson's, Huntington's and Fuhr's diseases.
16840991##2006-7-15##[Wilson disease].##Wilson disease is an autosomal recessive disorder of copper overload. A principal characteristic of this disease is its wide phenotypic and genotypic variability. Its results from mutations of the ATP 7B gene located on chromosome 13, that encodes a hepatic copper transport protein. More than 300 mutations of this gene have been identified. This protein ensures the transport of copper in the hepatocyte, its incorporation with the apoceruloplasmin and its biliary excretion. The clinical manifestations are heterogeneous as well in their presentation, dominated by the neuropsychiatric and hepatic symptoms, as in the age of the first symptoms. Early recognition and initiation of therapy with chelators or zinc are essential for prognosis. Liver transplantation is indicated in cases with fulminant hepatitis, end-stage liver cirrhosis and should be considered in the therapy resistant neurological forms. A regular follow-up with monitoring of adverse effects of treatment and compliance is essential. Any discontinuation of treatments will involve, within a very variable time, but in constant manner, a reappearance or a reaggravation of the signs. Such relapses are often brutal and can be extremely serious, especially since response to subsequent treatment is often poor.
16554302##2006-3-22##Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A.##The P-type ATPase affected in Wilson disease, ATP7B, is a key liver protein required to regulate and maintain copper homeostasis. When hepatocytes are exposed to elevated copper levels, ATP7B traffics from the trans-Golgi network toward the biliary canalicular membrane to excrete excess copper into bile. The N-terminal region of ATP7B contains six metal-binding sites (MBS), each with the copper-binding motif MXCXXC. These sites are required for the activity and copper-regulated intracellular redistribution of ATP7B. Two proteins are known to interact with the ATP7B N-terminal region: the copper chaperone ATOX1 that delivers copper to ATP7B, and COMMD1 (MURR1) that is potentially involved in vesicular copper sequestration. To identify additional proteins that interact with ATP7B and hence are involved in copper homeostasis, a yeast two-hybrid approach was employed to screen a human liver cDNA library. The dynactin subunit p62 (dynactin 4; DCTN4) was identified as an interacting partner, and this interaction was confirmed by co-immunoprecipitation from mammalian cells. The dynactin complex binds cargo, such as vesicles and organelles, to cytoplasmic dynein for retrograde microtubule-mediated trafficking and could feasibly be involved in the copper-regulated trafficking of ATP7B. The ATP7B/p62 interaction required copper, the metal-binding CXXC motifs, and the region between MBS 4 and MBS 6 of ATP7B. The p62 subunit did not interact with the related copper ATPase, ATP7A. We propose that the ATP7B interaction with p62 is a key component of the copper-induced trafficking pathway that delivers ATP7B to subapical vesicles of hepatocytes for the removal of excess copper into bile.
16687536##2006-5-12##1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy.##
16734296##2006-6-1##A 32-year-old patient with hemolytic anemia and fulminant hepatic failure.##Wilson's disease presenting as acute hemolytic anemia and fulminant hepatic failure is a rare and poorly recognized disorder. We report a patient who developed hemolytic anemia and fulminant hepatic failure as the initial manifestations of Wilson's disease. The diagnosis was established by the findings of low serum ceruloplasmin, elevated urinary copper and elevated hepatic copper concentration. Liver transplantation is the only effective means of treatment in patients presenting with Wilsonian fulminant hepatic failure. Despite intensive medical therapy our patient had a fatal outcome before transplantation could be undertaken. The objective of this report is to discuss the clues to diagnosis in this form of Wilson's disease, as delay in diagnosis seems to be responsible for the high mortality.
16550035##2006-3-22##Inherited metabolic liver disease.##
16550033##2006-3-22##Hepatobiliary pathology.##
16321443##2005-8-9##The use of tetrathiomolybdate in treating fibrotic, inflammatory, and autoimmune diseases, including the non-obese diabetic mouse model.##Tetrathiomolybdate was originally developed for use in Wilson's disease. However, lowering copper levels to below normal levels with tetrathiomolybdate has been found to have efficacy in cancer, probably by turning down signaling by angiogenic cytokines. More recently, we have shown in animals models that tetrathiomolybdate dramatically inhibits pulmonary and liver fibrosis. In other animal models, we have shown that the drug also inhibits liver damage from concanavalin A and acetaminophen, and heart damage from doxorubicin. These studies are briefly reviewed, and we then present data on tetrathiomolybdate's partially protective effect against diabetes in non-obese diabetic mice, an autoimmune model of type I diabetes. Possible mechanisms of tetrathiomolybdate's protective effect are briefly considered.
16649058##2005-8-29##Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease.##Wilson disease (WD) is the most common disorder resulting in hepatic copper overload. A similar form of copper-associated cirrhosis caused by mutations of the canine copper toxicosis MURR1 gene is also observed in Bedlington terriers. Recent studies indicate that MURR1 might influence human copper metabolism and the clinical presentations of WD. However, the correlation between the MURR1 gene and the Chinese patients with WD has not been reported. In the present study, all three exons of the MURR1 gene including the intron-exon boundaries were directly sequenced in 120 unrelated healthy Chinese and 218 unrelated Chinese patients with WD. No mutations were detected in coding and splice site sequence in the human MURR1 gene. A novel polymorphism 3'+119T-->A in the 3' untranslated region (UTR) was identified in three healthy individuals and four patients with two disease-causing mutations in the ATP7B gene and a great diversity of clinical presentations. Of the ATP7B mutations reported here, Gly1268Arg is a novel one. Also, the previously described nucleotide change IVS2+63C-->G was detected in 31.66% of normal chromosomes and 26.15% of WD chromosomes. The results have indicated that there is no correlation between MURR1 and WD in the Chinese population.
16495228##2006-2-22##Structure of the ATP binding domain from the Archaeoglobus fulgidus Cu+-ATPase.##The P-type ATPases translocate cations across membranes using the energy provided by ATP hydrolysis. CopA from Archaeoglobus fulgidus is a hyperthermophilic ATPase responsible for the cellular export of Cu+ and is a member of the heavy metal P1B-type ATPase subfamily, which includes the related Wilson and Menkes diseases proteins. The Cu+-ATPases are distinct from their P-type counter-parts in ion binding sequences, membrane topology, and the presence of cytoplasmic metal binding domains, suggesting that they employ alternate forms of regulation and novel mechanisms of ion transport. To gain insight into Cu+-ATPase function, the structure of the CopA ATP binding domain (ATPBD) was determined to 2.3 A resolution. Similar to other P-type ATPases, the ATPBD includes nucleotide binding (N-domain) and phosphorylation (P-domain) domains. The ATPBD adopts a closed conformation similar to the nucleotide-bound forms of the Ca2+-ATPase. The CopA ATPBD is much smaller and more compact, however, revealing the minimal elements required for ATP binding, hydrolysis, and enzyme phosphorylation. Structural comparisons to the AMP-PMP-bound form of the Escherichia coli K+-transporting Kdp-ATPase and to the Wilson disease protein N-domain indicate that the five conserved N-domain residues found in P1B-type ATPases, but not in the other families, most likely participate in ATP binding. By contrast, the P-domain includes several residues conserved among all P-type ATPases. Finally, the CopA ATPBD structure provides a basis for understanding the likely structural and functional effects of various mutations that lead to Wilson and Menkes diseases.
16532467##2006-3-15##Genotype-phenotype correlation of the Wilson disease ATP7B gene.##
16610028##2006-4-13##Copper toxicosis gene MURR1 is not changed in Wilson disease patients with normal blood ceruloplasmin levels.##
16571664##2006-3-29##Structure of human Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake.##Human Wilson protein is a copper-transporting ATPase located in the secretory pathway possessing six N-terminal metal-binding domains. Here we focus on the function of the metal-binding domains closest to the vesicular portion of the copper pump, i.e., domain 4 (WLN4), and a construct of domains 5 and 6 (WLN5-6). For comparison purposes, some experiments were also performed with domain 2 (WLN2). The solution structure of apoWLN5-6 consists of two ferredoxin folds connected by a short linker, and (15)N relaxation rate measurements show that it behaves as a unit in solution. An NMR titration of apoWLN5-6 with the metallochaperone Cu(I)HAH1 reveals no complex formation and no copper exchange between the two proteins, whereas titration of Cu(I)HAH1 with WLN4 shows the formation of an adduct that is in fast exchange on the NMR time scale with the isolated protein species as confirmed by (15)N relaxation data. A similar interaction is also observed between Cu(I)HAH1 and WLN2; however, the relative amount of the adduct in the protein mixture is lower. An NMR titration of apoWLN5-6 with Cu(I)WLN4 shows copper transfer, first to WLN6 then to WLN5, without the formation of an adduct. Therefore, we suggest that WLN4 and WLN2 are two acceptors of Cu(I) from HAH1, which then somehow route copper to WLN5-6, before the ATP-driven transport of copper across the vesicular membrane.
16487486##2006-1-5##Development of liver regenerative therapy using glycoside-modified bone marrow cells.##Several recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency at which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase efficiently. We tried to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor and desialylated BMCs. Desialylated BMCs were produced with treatment of neuraminidase. Desialylated BMCs that expressed green fluorescent protein (GFP) were injected into Long Evans Cinnamon (LEC) rats, a human Wilson's disease model, intravenously. At 3 and 5 months after transplantation, GFP-expressing hepatocyte nodules appeared in the liver of these BMC-transplanted LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated by the direct accumulation of BMCs and that this strategy is new BMC therapy for liver regeneration.
16567646##2006-3-27##Solution structure of the N-domain of Wilson disease protein: distinct nucleotide-binding environment and effects of disease mutations.##Wilson disease protein (ATP7B) is a copper-transporting P(1B)-type ATPase that regulates copper homeostasis and biosynthesis of copper-containing enzymes in human tissues. Inactivation of ATP7B or related ATP7A leads to severe neurodegenerative disorders, whereas their overexpression contributes to cancer cell resistance to chemotherapeutics. Copper-transporting ATPases differ from other P-type ATPases in their topology and the sequence of their nucleotide-binding domain (N-domain). To gain insight into the structural basis of ATP7B function, we have solved the structure of the ATP7B N-domain in the presence of ATP by using heteronuclear multidimensional NMR spectroscopy. The N-domain consists of a six-stranded beta-sheet with two adjacent alpha-helical hairpins and, unexpectedly, shows higher similarity to the bacterial K(+)-transporting ATPase KdpB than to the mammalian Ca(2+)-ATPase or Na(+),K(+)-ATPase. The common core structure of P-type ATPases is retained in the 3D fold of the N-domain; however, the nucleotide coordination environment of ATP7B within this fold is different. The residues H1069, G1099, G1101, I1102, G1149, and N1150 conserved in the P(1B)-ATPase subfamily contribute to ATP binding. Analysis of the frequent disease mutation H1069Q demonstrates that this mutation does not significantly affect the structure of the N-domain but prevents tight binding of ATP. The structure of the N-domain accounts for the disruptive effects of >30 known Wilson disease mutations. The unique features of the N-domain provide a structural basis for the development of specific inhibitors and regulators of ATP7B.
16543824##2006-3-18##Prion protein gene codon 129 modulates clinical course of neurological Wilson disease.##The polymorphism in the human prion protein gene at codon 129 (PRNP 129) determines susceptibility to prion disease, and has been associated with early onset and a more severe course of other neurodegenerative disorders. Here, we tested the hypothesis that PRNP is a disease-modifying gene in clinical Wilson disease with a neurological phenotype. Allele frequencies in patients with clinical Wilson disease were not different from those of a healthy German control population, and PRNP 129 genotypes did not result in different serum copper, serum ceruloplasmin, or copper in 24-h urine concentrations. PRNP 129 methionine homozygosity, however, led to significantly more severe neurological symptoms in elderly patients, particularly tremor, supporting the notion that PRNP 129 homozygosity contributes to neuronal vulnerability.
16606763##2006-4-12##Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease.##
16466879##2004-10-26##Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice.##Zinc therapy has replaced penicillamine as first-line therapy for Wilson's disease. New guidelines reflect the paradigm shift in treatment that has occurred in recent years. In the old paradigm, Wilson's disease was seen as genetic disorder associated with the accumulation of copper in the liver and in other organs once the liver had become overloaded with copper. When left untreated, the disease was regarded as uniformly fatal. The old treatment guidelines advised, 'decoppering' with penicillamine because this chelating agent was considered effective in restoring most patients to health. Before the start of treatment, patients were warned that their symptoms could worsen during the first weeks or months of therapy, so as to prevent them from abandoning penicillamine therapy in dismay. In the new paradigm, Wilson's disease is seen as a hereditary disorder associated with copper intoxication. The essence of symptomatic Wilson's disease is poisoning by free copper in the blood, that is, by copper that is not bound to ceruloplasmin. This form of copper is toxic, whereas accumulated copper and copper that is bound to ceruloplasmin or metallothionein is not. The treatment of symptomatic Wilson's disease is no longer aimed at 'decoppering', the removal of accumulated copper, but at the normalization of the free copper concentration in blood, to reverse the copper poisoning. This can be achieved safely and effectively with zinc therapy. Zinc induces metallothionein, a highly effective detoxification protein that binds copper. Oral zinc therapy leads to storage of metallothionein-bound copper in the mucosa of the gut and to the excretion of copper via the stools. New treatment guidelines advise against the use of chelating agents as initial treatment because they may aggravate copper intoxication and cause iatrogenic deterioration.
16705248##2006-5-18##Treatment of toxic liver damage by antihepatocytotoxic serum.##Acute liver failure (ALF) is a broad term that refers to both fulminant hepatic failure (FHF) and subfulminant hepatic failure (or late-onset hepatic failure). The latter term is reserved for patients with liver disease for up to 26 weeks prior to the development of hepatic encephalopathy. Some patients with previously unrecognized chronic liver disease decompensate and present with liver failure; although this technically is not FHF, discerning this at the time of presentation may not be possible (eg, Wilson disease). The objective of present research was to define suitable method for the treatment of toxic damage of the liver. We consider that liver changes occurred in the case of toxic damage can be reversed by administration of antihepatocytotoxic serum which has been developed by us. For this purpose we are going to induce liver toxic damage in the Wister line and investigate the liver regeneration cellular mechanisms after administration of antihepatocytotoxic serum. Experimental investigations were performed on Wister line male rats, animals were divided into four equal groups. In I and II groups we were modelling acute liver failure by injections of hepatotoxic agent CCL4 (I) and performing 70% hepatectomy (II), III group was served as control group, and IV group served as donors for HPCs. The main aspect of our study was to stimulate liver reparative regeneration and by this help to organ function restoration. Performed studies have shown hypertrophy and moderate hyperplasia of hepatocyte organelles. Oval shaped HPCs were also observed, Performed investigations had shown effectiveness of our ALF treatment method in terms of damaged liver function restoration, normalization of morphological picture and biochemical measurements and we hope that administration of antihepatocytotoxic serum developed by us can give a chance to patients with acute liver failure.
16603785##2006-4-11##Wilson's disease: a patient undiagnosed for 18 years.##Wilson's disease, an autosomal recessive disorder of copper metabolism, is the most common inherited hepatic disease in Hong Kong. Diagnosis is based on the presence of Kayser-Fleischer rings, typical neurological symptoms, and/or a low serum ceruloplasmin concentration (<0.20 g/L). Early detection and treatment protect patients and their presymptomatic siblings from devastating organ damage. The diagnosis of Wilson's disease may nonetheless be overlooked if only established clinical and laboratory tests are used as diagnostic criteria. We report diagnosis of the disorder using genetic analysis of ATP7B in a presymptomatic sibling who escaped diagnosis during family screening 18 years previously. The patient was 11 months old when family screening was performed following diagnosis of Wilson's disease in an elder sister. The boy was considered to be unaffected on the basis of laboratory results in the expected range: serum copper level, 4.6 micromol/L; serum ceruloplasmin level, 0.16 g/L; and 24-hour urinary copper excretion, 0.14 micromol/day. Molecular analysis of ATP7B was performed; it revealed that the two siblings shared the same compound heterozygous mutations (G943D and 2299delC). We recommend that molecular diagnosis is the only definitive means of diagnosing Wilson's disease in children younger than 1 year.
17230654##2007-1-19##Gene symbol: ATP7B. Disease: Wilson disease.##
17230652##2007-1-19##Gene symbol: ATP7B. Disease: Wilson disease.##
17230650##2007-1-19##Gene symbol: ATP7B. Disease: Wilson disease.##
17230645##2007-1-19##Gene symbol: ATP7B. Disease: Wilson disease.##
16825709##2006-7-11##[Cryptogenic hepatic cirrhosis in a 14 years old boy].##Alcoholism is the main etiological factor of hepatic cirrhosis among adults whereas among children the following pathologies lead to hepatic cirrhosis: bile ducts disease (atresia or hypoplasia of bile ducts, progressive familial intrahepatic cholestasis), metabolic disorders (tyrosinemia, hemochromatosis, galactosemia, alpha1 - antitrypsin deficiency, Wilson's disease), chronic viral hepatitis B, delta, C, autoimmune hepatitis. Despite the availability of modern diagnostic methods scanty clinical symptomatology may be a cause of late diagnosis, often in the stage of complications. Presented case of a 14 years old boy is an example of late diagnosis of cryptogenic hepatic cirrhosis.
16416415##2006-1-18##Painless legs moving toes in a patient with Wilson's disease.##We describe and present a video of a 20-year-old woman with Wilson's disease (WD) who developed the painless variant of painful legs and moving toes (PLMT) syndrome. The symptoms appeared during a subsequent minor exacerbation of her extrapyramidal symptomatology, only to gradually disappear 3 to 4 months later. We suggest that, in our case, a structural central nervous system lesion caused by WD may have been associated with the development of PLMT.
16637558##2006-4-28##Nonalcoholic fatty liver disease.##NAFLD likely is the most common liver disease in children and is responsible for significant progression to cirrhosis, portal hypertension, and the need for liver transplantation in adults and even in some adolescents. Early diagnosis and lifestyle interventions appear to be our best hope for controlling progression of disease. The pediatrician is responsible for screening all obese children with measurement of aminotransferases. Those with elevated enzymes (particularly ALT) for longer than 3 months, in the absence of markers of hepatitis B or C, autoimmune chronic active hepatitis, Wilson's disease, hemochromatosis, or alpha-1-antitrypsin deficiency, should follow up with an abdominal ultrasound. In patients with a BMI in the morbidly obese range, an ultrasound to search for a diffusely echogenic liver should be performed even if the liver enzymes are normal. Findings suggestive of NAFLD should prompt the institution of appropriate dietary and exercise regimens. If these are unsuccessful after a 3-month trial, the patient should be referred to a pediatric gastroenterologist and hepatologist for further work-up and treatment, preferably in the context of a controlled therapeutic trial. Only by aggressively engaging this current epidemic will we be able to decrease the mounting human cost of NAFLD.
16549536##2006-3-22##Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia.##Wilson disease (WD) is an autosomal recessive disorder due to the defect in ATP7B gene characterized by excessive accumulation of copper in the liver with progressive hepatic damage and subsequent redistribution to various extrahepatic tissues including the brain, kidneys, and cornea. Strikingly, the total serum copper concentration is always low in WD, even though the non-ceruloplasmin copper level is still expected to be high. To assess the role of free radical reactions catalyzed by non-ceruloplasmin copper, we investigated erythrocyte metabolism and oxidative stress as a mechanism for hemolysis in eight WD patients during episodes of acute hemolysis and compared them with eight follow-up cases of WD on d-penicillamine therapy and eight healthy, age-matched children. Elevated levels of non-ceruloplasmin copper were found in all the WD patients during an episode of hemolytic anemia. There was marked inhibition in erythrocyte enzymes, namely, hexokinase, total adenosine triphosphatase (ATPase), and glucose-6-phosphate dehydrogenase (G-6-PD) from WD patients compared with patients on penicillamine and healthy children, indicating altered erythrocyte metabolism during a hemolytic crisis. Antioxidant status was also found to be compromised as is evident from decreased glutathione (GSH) levels, decreased antioxidant enzymes (namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), increased lipid peroxidation, and deranged plasma antioxidants. Uric acid showed maximum decrease followed by ascorbic acid. These findings suggest that the free radical production by elevated non-ceruloplasmin copper through transition metal catalyzed reactions leads to oxidative injury resulting in altered erythrocyte metabolism and severely compromised antioxidant status of WD patients during hemolytic anemia.
16533893##2006-3-13##Sydenham's chorea in western Pennsylvania.##
17802941##2007-9-7##Pregnancy and liver disease.##Liver dysfunction can appear at any point of pregnancy and causes great anxiety to the patient, her family and sometimes her medical attendants. This review concentrates on conditions specific to pregnancy (hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, toxemia of pregnancy, HELLP syndrome) and provides a guide in diagnosis and management of hepatobiliary conditions that are probably related to pregnancy (e.g., gallstones, Budd-Chiari syndrome) or that are not specific to pregnancy (e.g., acute viral hepatitis), and also the situations in which pregnancy occurs during pre-existing liver disease (e.g., chronic active hepatitis, cirrhosis, Dubin-Johnson syndrome, Wilson's disease).
16635921##2006-4-26##Morbus Wilson: Case report of a two-year-old child as first manifestation.##Morbus Wilson, or Wilson's disease, is a genetic disease of copper metabolism. Usually the disease is detected when the first clinical symptoms appear, generally not before 5 years of age. This case report shows that the disease can be detected much earlier if abnormal laboratory findings in the patient's history prompt further investigations.
16480686##2006-1-18##Reactive oxygen species modify oligosaccharides of glycoproteins in vivo: a study of a spontaneous acute hepatitis model rat (LEC rat).##The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, spontaneously develops hepatitis as the result of abnormal copper accumulation in liver. The findings of this study show that copper, hydrogen peroxide, and lipid peroxides accumulate to drastically high levels in LEC rat serum in acute hepatitis but not chronic hepatitis. The effect of these reactive oxygen species (ROS) on oligosaccharides of glycoproteins in the LEC rat serum was examined. Lectin blot and lectin ELISA analyses showed that sialic acid and galactose residues of serum glycoproteins including transferrin were decreased in acute hepatitis. Further analyses of oligosaccharide structures of transferrin demonstrated that di-sialylated and asialo-agalacto biantennary sugar chains, but not tri-sialylated sugar chain, exist on transferrin in the acute hepatitis rats. In addition, treatment of non-hepatitis rat serum with copper ions and hydrogen peroxide decreased tri-sialylated sugar chain of the normal transferrin and increased di-sialylated and asialo-agalacto biantennary sugar chains. This is the first evidence to show that ROS result in the cleavage of oligosaccharides of glycoproteins in vivo, and indicate this cleavage of oligosaccharides may contribute the development of acute hepatitis.
16543147##2005-4-19##XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.##X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis. Here, we describe a role for XIAP in copper metabolism. We find that XIAP levels are greatly reduced by intracellular copper accumulation in Wilson's disease and other copper toxicosis disorders and in cells cultured under high copper conditions. Elevated copper levels result in a profound, reversible conformational change in XIAP due to the direct binding of copper to XIAP, which accelerates its degradation and significantly decreases its ability to inhibit caspase-3. This results in a lowering of the apoptotic threshold, sensitizing the cell to apoptosis. These data provide an unsuspected link between copper homeostasis and the regulation of cell death through XIAP and may contribute to the pathophysiology of copper toxicosis disorders.
16729535##2006-5-30##[Wilson's disease].##Wilson's disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene chromosome 13. The discovery of the gene allowed a better understanding of cytosolic copper trafficking its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This disease can be efficiently treated by chelation and zinc therapy. Liver transplantation is the therapy to patients with hepatic fulminant course, or in those with relentless progression of hepatic dysfunction in spite of medical therapy.
16684691##2006-5-11##Familial gene analysis for Wilson disease from north-west Indian patients.##
16494700##2006-2-24##Dengue virus infection: a major cause of acute hepatic failure in Thai children.##
15657943##2005-1-20##Effect of D-penicillamine on rat lung elastin cross-linking during the perinatal period.##This study was designed to clarify the effects of D-penicillamine (DPA), a drug used for treatment of various pathological events, on lung elastin formation and maturation of the newborn in the perinatal period. The investigation was conducted on 20 newborn rats bred from 40 female and six male rats. DPA doses 400 mg kg(-1) day(-1) and physiological saline were given intraperitoneally (i.p) to experimental and control groups. To assess newborn maturation, their body and lung weights were determined. Serum Cu levels were measured by atomic absorption spectroscopy and ceruloplasmin (Cp) activities were measured spectrophotometrically. Newborn lung tissue elastin, desmosine (DES) and isodesmosine (IDES) levels were measured by HPLC. The results showed that DPA treatment caused loss of skin elasticity and reduction in body and lung weight in newborns of the experimental group. The serum Cu levels and Cp activity were found to be significantly lower in both maternal and newborn of the experimental groups compared with the control group. The lung DES, IDES and elastin values of newborns in the experimental group were decreased compared with the control group. In conclusion, our results indicate that 400 mg kg(-1) day(-1) DPA, a dose that is used in the treatment of Wilson's disease, rheumatoid arthritis and cystinuria, caused the retardation of newborn maturation, a decrease in DES-IDES cross-links and levels of lung elastin of offspring in the perinatal period. Another conclusion to be drawn from this study is that even low levels of Cu depletion due to DPA administration induces a change in cross-linking in lung elastin during the perinatal period.
16510432##2006-3-3##Allele dropout in PCR-based diagnosis of Wilson disease: mechanisms and solutions.##
16461012##2005-10-19##Wilson's disease and benign epilepsy of childhood with centrotemporal (rolandic) spikes.##Cases with a clinical and electroencephalographic phenotype of benign epilepsy of childhood with centrotemporal spikes (BECTS) in association with a proven organic brain lesion have rarely been reported. To our knowledge, we herein describe for the first time a patient with Wilson's disease who subsequently manifested BECTS. Our case bolsters the argument that in at least some cases, BECTS is associated with organic brain disease.
16453085##2005-6-18##A short history of neurosciences in Austria.##Based on internal medicine and psychiatry and in close connection with pathology, the neurosciences in Austria began to develop in the 18(th) century, e.g. with the description of inflammation of the central nervous system by J. P. Franck (1745-1823) and the "phrenology" by F. J. Gall (1745-1823). Under the influence of the great pathologist C. Rokitansky (1804-1878), the tripode of the Vienna neurology - L. Türck (1810-1868), as initiator, Th. v. Meynert (1833-1892) the activator, and H. Obersteiner (1847-1922) as the founder of the Vienna Neurological Institute, presented basic contributions to the morphology and pathology of the nervous system. At the end of the 19(th) and in the early 20(th) century, they were followed by important publications by S. Fred (aphasia), C. Redlich (tabes dorsalis), F. Sträussler (CNS syphilis), A. Spitzer (fiber anatomy of the brain), P. Schilder (diffuse sclerosis), R. Barany (Nobel price for physiology and medicine 1914), J. Wagner v. Jauregg (Nobel price for medicine, 1927), O. Loewi (Nobel Price for Physiology and Medicine together with Sir H. Dale, 1936), A. Schüller (histiocytosis X), C. v. Economo (encephalitis lethargica and cytoarchitectonics of the human cerebral cortex), E. Pollak (Wilson disease), E. Gamper (mesencephalic subject), J. Gerstmann (Gerstmann-Sträussler-Scheinker syndrome and Gerstmann parietal syndrome), H. Hoff with L. Schönbauer (brain tumors and surgery), and others. Major research institutions were the departments of psychiatry I and II at the University of Vienna School of Medicine (foundation 1870), unification 1911, separation into departments of neurology, psychiatry and neuropsychiatry of children and adolescents in 1971), the Obersteiner Institute in Vienna (foundation 1882, separation 1993), the university departments at Graz and Innsbruck, both founded in 1891, and other laboratories, where renouned clinicans and neuroscientists, like O. Marburg, H. Hoff, O. Pötzl, O. Kauders, F. Seitelberger, H. Tschabitscher, K. Weingarten, H. Reisner,W. Birkmayer, H. Petsche, F. Gerstenbrand, H. Bernheimer, H. W. Heiss, H. Lassmann, W. Poewe, L. Deecke, and many of their associates produced important contributions to wide areas of modern neurosciences. Important for the future are the foundation of the Institute of Brain Research at Vienna Medical University and of the Austrian Society of Neurology which will give further impact for the future progress of neuroscience research in Austria and its integration into the international science community.
16679666##2006-5-9##CNS demyelination due to hypocupremia in Wilson's disease from overzealous treatment.##
16573616##2006-4-1##Feasibility of duct-to-duct biliary reconstruction in pediatric living related liver transplantation: report of three cases.##Feasibility of duct-to-duct biliary reconstruction in adult living related liver transplantation (LRLTx) has been recently reported; however, little has been known of its surgical outcome in children. To assess the feasibility and safety of duct-to-duct biliary reconstruction in children, the surgical outcomes of duct-to-duct biliary reconstruction were retrospectively analyzed. The subjects were three children who underwent LRLTx in our hospital each utilizing allografts with a right lobe, a left robe and a lateral segment, respectively. The cause of end-stage liver disease in each of them was fulminant Wilson's disease, fulminant hepatic failure and unresectable hepatoblastoma. Duct-to-duct anastomosis was performed in younger patients and adolescents with interrupted and continuous sutures, respectively. The diameter of bile duct in allografts was from 4 to 6 mm and 12 or 13 stitches were required for anastomosis. Post-operative choledochography from the external tube showed neither stenosis nor leakage and the tube was evacuated within 3 months after LRLTx. No biliary complications were observed with the median follow-up of 28 months. In conclusion, our results show that duct-to-duct biliary reconstructions in pediatric LRLTx seemed to be feasible and safe. Further studies are required to elucidate its real impact on pediatric LRLTx.
16497628##2006-2-25##Poor cognitive development and abdominal pain: Wilson's disease.##An 8-year-old boy was referred to our hospital because of learning disabilities. His general cognitive functions were below the level for age, and he was diagnosed with dysphasia. The boy was transferred to a special class for children with learning problems. Three months later he was again referred to us because of acute epigastric pain. The only abnormal laboratory finding was a slightly elevated level of alanine aminotransferase. Although the symptoms disappeared in a few days, the transaminase levels remained above normal for the next 6 months. Further diagnostic work-up revealed low serum ceruloplasmin concentration and high 24-h urinary copper excretion. The hepatic copper concentration in liver biopsy was high (2900 microg/g dry weight), confirming the diagnosis of Wilson's disease. Brain MRI showed slight changes in white matter. The patient's asymptomatic sister was also diagnosed with Wilson's disease. Both siblings started penicillamine therapy and a copper-restricted diet. The copper content of the household water was found to be above average and a new plumbing system was installed. After 1 year from the initiation of the therapy, the transaminase concentrations normalized and both siblings were free of symptoms. After 2 years of therapy the patient was able to return to normal school. Wilson's disease must be borne in mind, when children are evaluated because of poor school performance, especially if they complain of abdominal symptoms.
16549190##2006-3-22##Tacrolimus-related neurologic and renal complications in liver transplantation: A single-center experience.##Among 71 patients, 19 (26.7%) experienced tacrolimus-related complications including 15 neurologic reactions and four problems with nephrotoxicity. Seven of these patients received grafts from cadaveric donors and 12 from living donors. Nine patients were children. The cohort included 5 female and 14 male subjects of mean age 26 +/- 20 (min 6, max 65) years. The common indications for the liver transplantation were cholestatic and metabolic diseases in pediatric patients, and viral hepatitis in adult patients. Blood tacrolimus levels were within the normal range. All patients with neurologic complications received antiepileptic therapy and drug conversion to rapamycin in 4 cases and to cyclosporine (CsA) in 11 cases. Six cases with Wilson disease and all cases with tyrosinemia experienced neurologic complications, which reversed in all but one case. In four cases with nephrotoxicity, we switched to rapamycin. Renal function improved in all cases. Patients with Wilson disease and tyrosinemia were more susceptible to the neurologic side effects of tacrolimus. In these cases we recommend the use of drugs with fewer neurologic side effects. Tacrolimus also has nephrotoxic effects, which can be reversed by converting to rapamycin.
16549187##2006-3-22##Venous complications after orthotopic liver transplantation.##We report venous complications, including portal vein and hepatic vein stenoses, that required interventional radiological treatment in three pediatric and two adult living related liver transplant recipients. Between April 2001 and April 2005, 81 liver transplantations were performed at our hospital. Sixty-two grafts were from living donors. During follow-up, three portal vein stenoses were identified in three pediatric recipients, and two hepatic vein stenoses in two adult patients. In the children, two had received left lateral segment grafts, and one had received a right lobe graft from two mothers and one father, respectively. The etiologies of liver failure were Alagille syndrome, biliary atresia, and fulminant Wilson's disease. Portal vein stenoses were identified at 8, 11, and 12 months after transplantation; all three patients underwent percutaneous transhepatic portal venous angioplasty with a success rate of 100%. The mean follow-up was 102 days; no recurrence has occurred. In contrast, hepatic venous stenoses were diagnosed in two adult recipients. One of them was a 24-year-old woman with autoimmune hepatitis and the other a 43-year-old man with cryptogenic cirrhosis. Hepatic vein stenoses were diagnosed at 3 and 4 months after transplantation. Both hepatic vein stenoses were dilated with balloon angioplasties via the transjugular route. Venous complications identified by Doppler ultrasonography were confirmed by computerized tomographic angiography. Angioplasty represents an effective and safe alternative to reconstructive surgery in the treatment of venous complications after liver transplantation.
16476937##2006-2-16##Clinical correlates of cerebral water diffusion in Wilson disease.##
16436657##2006-1-27##Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice.##Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b-/- mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b-/- livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.
16448326##2006-2-2##Novel therapeutic approaches to the treatment of Wilson's disease.##The treatment of Wilson's disease has changed considerably in recent times, from the use of penicillamine (Cuprimine, Merck) for all stages and types of disease, to the use of three other anticopper drugs at appropriate times for appropriate patients. Each type and stage of the disease can be considered as a therapeutic target, for which specialised therapy is appropriate. This paper systematically reviews the various types and stages of Wilson's disease presentation, and provides opinion on the appropriate therapy for each. For patients presenting with neurological disease, the use of tetrathiomolybdate is optimum; for patients presenting with mild-to-moderate hepatic failure, a combination of trientine (Syprine, Merck) and zinc is recommended, whereas liver transplantation is necessary for those with severe failure; zinc therapy alone or trientine alone as second choice is recommended for patients presenting with hepatitis or cirrhosis without liver failure, for maintenance therapy, for treatment of presymptomatic patients and for treatment of paediatric and pregnant patients.
16472602##2005-4-22##ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion.##
16537999##2006-3-16##Prevention of lethal hepatic injury in Long-Evans Cinnamon (LEC) rats by D-galactosamine hydrochloride.##Repeated injections of D-galactosamine hydrochloride (GalN) increase the survival rate of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. The aim of the present study was to investigate the mechanism of GalN for prevention of spontaneous lethal hepatic injury in LEC rats. Male LEC rats were given a single subcutaneous injection of 300 mg/kg of GalN or vehicle (0.9% NaCl) at 14 weeks, and killed at 28 weeks of age. Next, 6-week-old male LEC rats were given weekly subcutaneous injections of 300 mg/kg of GalN or vehicle for 3 or 12 weeks, and their hepatic 8-hydroxydeoxy-2'-guanosine (8-OHdG), glutathione peroxidase (GPX), and catalase activities were measured. None of GalN-treated rats died of hepatic injury (0/12), whereas the mortality rate of control rats given 0.9% NaCl was 17% (2/12). GalN administration for 12 weeks decreased the hepatic 8-OHdG, and GalN administration for either 3 or 12 weeks increased the glutathione peroxidase activity. GalN administration increased the serum level of alanine aminotransferase, and accelerated megalocytic degeneration of the hepatocytes. GalN treatment is effective in preventing lethal hepatitis in LEC rats and decrease of oxidative DNA damage by GalN plays an important role in increase of the survival rate.
16229009##2005-10-18##History of Wilson's disease: 1912 to 2000.##
16211609##2005-10-8##p.H1069Q mutation in ATP7B and biochemical parameters of copper metabolism and clinical manifestation of Wilson's disease.##We compared the effect of the p.H1069Q mutation and other non-p.H1069Q mutations in ATP7B on the phenotypic expression of Wilson's disease (WD), and assessed whether the clinical phenotype of WD in compound heterozygotes depends on the type of mutation coexisting with the p.H1069Q. One hundred forty-two patients with clinically, biochemically, and genetically diagnosed WD were studied. The mutational analysis of ATP7B was performed by direct sequencing. A total number of 26 mutations in ATP7B were identified. The p.His1069Gln was the most common mutation (allelic frequency: 72%). Seventy-three patients were homozygous for this mutation. Of compound heterozygotes, 37 had frameshift/nonsense mutation, and 20 had other missense mutation on one of their ATP7B alleles. Twelve patients had two non-p.H1069Q mutations. Patients homozygous for the p.H1069Q mutation had the less severe disturbances of copper metabolism and the latest presentation of first WD symptoms. The most severely disturbed copper metabolism and the earliest age at initial disease manifestation was noticed in non-p.H1069Q patients. In compound heterozygotes, the type of mutation coexisting with the p.H1069Q to a small extent influenced WD phenotype. The phenotype of WD varied considerably among patients with the same genotype. The p.H1069Q mutation is associated with late WD manifestation and with a mild disruption of copper metabolism. In compound heterozygotes, the phenotype of WD to a small extent depends on the type of mutation coexisting with the p.H1069Q. Besides genotype, additional modifying factors seem to determine WD manifestations.
16700326##2006-5-17##Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease.##Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.
16416207##2005-5-2##A new mutation of Wilson's disease P-type ATPase gene in a patient with cirrhosis and coombs-positive hemolytic anemia.##
16837801##2006-7-11##Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg?##A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.
16357618##2005-12-17##Late onset of Wilson's disease in a family with genetic haemochromatosis.##We report the coexistence of Wilson's disease and genetic haemochromatosis in one family. The diagnosis of genetic haemochromatosis was established in a 52-year-old man. Among his siblings, one 57-year-old sister and one 55-year-old brother had decreased copper and ceruloplasmin levels in serum and increased urinary copper excretion. The sister shared the same human leucocyte antigen haplotypes and was homozygous for the HFE mutation C282Y, like the propositus. However, she had normal liver iron content and increased liver copper content. Her dietary copper intake was probably excessive. The association of Wilson's disease and genetic haemochromatosis is rare and has only been described twice. The onset of Wilson's disease after 50 years of age is rare; Wilson's disease should be considered in any patient with unexplained chronic liver disease; an excess in liver copper content might be induced by excessive dietary input in a susceptible individual.
16636554##2005-7-26##A novel mutation in ATP7B gene associated with severe neurological and psychiatric symptoms.##
16393628##2006-1-6##[Wilson's disease].##
16444072##2006-1-31##Wilson's disease presenting as respiratory failure.##Wilson's disease in an 11-year-old girl with generalized weakness and respiratory failure is reported. The child succumbed to severe hypokalemia refractory to therapy progressing to acute renal failure and death. This atypical presentation and course prompted this clinical brief.
17236700##2007-1-24##The bane of a silent illness: when Wilson's disease takes its course.##We present the case of a 21-year-old young lady with Wilson's disease, asymptomatic at first and consequently declining prophylaxis with chelating agents, who presented years after her diagnosis was made with multiple motor and neuropsychiatric manifestations of the disease, causing extensive morbidity and a major decrease in her quality of life. Following extensive education and supportive therapy, she showed conviction in the need for therapy. On close follow-up she continues to show compliance with appointments, the prescribed chelating agents, and psychotropic medication.
16868859##2006-5-8##NMR assignment of the Wilson disease associated protein N-domain.##
16423616##2005-7-22##Early diagnosis of Wilson Disease in a six-year-old child.##
16423615##2004-11-4##Direct diagnosis of Wilson disease by molecular genetics.##In 3 children with chronic liver disease, although multiple studies of copper metabolism were normal, which made the diagnosis of Wilson disease unlikely, analysis of ATP7B gene showed disease causing mutations in all. Molecular diagnosis should be considered in children with enigmatic liver disease, especially those with features of nonalcoholic fatty liver disease.
16528929##2006-3-15##[Amyotrophic lateral sclerosis in younger age associated with abnormality of copper level].##Amyotrophic lateral sclerosis is a progressive degenerative neuromuscular disease in adults that occurs in familial and sporadic forms. The mean age of onset of symptoms is 56 years and the mean duration of disease is 3 years. One of the theories on the pathogenesis suggests on mutation in gene that encodes superoxide dismutase, which is involved in metabolism of free radicals (copper, zinc). In this article we showed patient with early onset of disease associated with abnormality of copper level. Co morbidity with Wilson disease has not been proved. According to this case it is possible to think about changes in cuprum level at ALS patients.
16359826##2005-9-30##Alpha-thiolamines such as cysteine and cysteamine act as effective transglycating agents due to formation of irreversible thiazolidine derivatives.##Non-enzymatic glycation of proteins and some phospholipids is considered to be an important factor in the genesis of diabetic complications. While this process has been viewed traditionally as entirely non-enzymatic and unidirectional, the discovery of fructosamine-3-phosphate (FN3K) and identification of FN3K-mediated deglycation mechanisms have made it apparent that non-enzymatic glycation is not unidirectional and that it can be reversed by deglycation reactions. While FN3K operates on ketosamines, the second intermediate in the non-enzymatic glycation cascade, we recently identified another potential deglycation mechanism that can operate on Schiff bases, the first intermediates of the non-enzymatic glycation process. The initial step in this postulated deglycation process is a transglycation reaction between a L.M.W. intracellular nucleophiles and a macromolecule-bound aldosamines, which regenerate unmodified proteins or phospholipids with a concomitant production of aldose-nucleophile transglycation byproducts. In vitro, transglycation occurs readily with amino acids, polyamines, thiols and thiolamines. There are indications that this reaction also occurs in vivo since in an initial GC/MS analysis of human urine we detected significant amounts of a transglycation product, glucose-cysteine (G-Cys), which was markedly increased in diabetics. Despite these encouraging early data, it is not yet clear to what extent transglycation is important in vivo and which intracellular nucleophiles are most relevant to this process. As discussed by us previously in this journal, one likely candidate for this role is glutathione since it is distributed universally and since there are well described mechanisms for removal of S-linked glutathione adducts from cells by the multi-drug-resistance (MDR) pumps. In this paper we report on another class of likely transglycating agents, alpha-thiolamines such as cysteine and cysteamine. While concentrations of these compounds in tissues are significantly lower than those of GSH, they react with Schiff bases more rapidly than GSH and, most significantly they form stable and irreversible thiazolidine products such as glucose-cysteine (G-Cys) and glucose-cysteamine (G-Ctm) that can subsequently be removed from cells. The possibility that alpha-thiolamines may play a physiological role as deglycating agents in vivo is very attractive since it suggests a possible strategy for inhibiting nonenzymatic glycation and diabetic complications that could be readily implemented through nutritional or pharmacological approaches. Such intervention is eminently feasible since there are at least three thiolamines already approved for human use. These include cysteamine used for the treatment of cystinosis; N-acetylcysteine utilized as a mucolytic and antioxidant agent, in the therapy of acetaminophen poisoning and radiocontrast-induced nephrotoxicity; and penicillamine used for treatment of Wilson's disease. Consequently, determining whether these compounds have the expected anti-glycating effects in vivo should be relatively straightforward.
16447797##2006-2-2##[Case of Sanfilippo syndrome type B and Wilson disease born to unrelated parents].##A 5-year-old boy visited a hospital because of macrocephalus, mental retardation and hepatic dysfunction, and was suspected to have Wilson's disease since his father had this disease. The serum level of ceruloplasmin was low, but urinary copper excretion was not increased markedly. He was treated with D-penicillamine. He was then reffered to our hospital because of his facial features suggesting mucopolysaccharidosis. Based on mucopolysacchariduria and the deficiency of N-acetylglucosaminidase, the diagnosis of Sanfilippo syndrome type B was made. Molecular analyses identified him as a compound heterozygote for both the ATP7B (A844V/2659delG) and alpha-N-acetylglucosaminidase (V241M/R482W) genes, responsible for Wilson's disease and Sanfilippo syndrome type B, respectively. Although born to non-consanguineous parents, he had two rare autosomal recessive diseases. In this case, liver dysfunction was attributed to Wilson's disease, and mental retardation to Sanfilippo syndrome.
16504704##2006-3-1##The use Prometheus FPSA system in the treatment of acute liver failure: preliminary results.##
16435711##2006-1-27##[Wilson's disease].##
16317609##2005-12-1##[Alpha 1-proteinase inhibitor deficiency and isolated liver cirrhosis without pulmonary emphysema in a 53-year-old female patient].##
16310588##2004-8-31##Apolipoprotein E genotype analysis in Chinese Han ethnic children with Wilson's disease, with a concentration on those homozygous for R778L.##Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by a large number of different mutations in the ATP7B gene. R778L mutation is mostly observed in Chinese, Japanese and Korean patients, whereas the H1069Q point mutation in the ATP7B gene is the most frequent mutation in European patients with WD. In our previous study we did not find a significant correlation between genotype and phenotype (age of onset and clinical presentation) in patients homozygous (37 patients) or heterozygous (52 patients) for R778L. It was reported that European patients homozygous for H1069Q who were also homozygous for the ApoE genotype epsilon3/3 developed clinical symptoms 5-11 years later than did patients with genotypes other than ApoE epsilon3/3. In the present study (i) we firstly observed that ApoE epsilon3/3 did not delay the onset of WD; (ii) no association between ApoE genotype and WD clinical presentation in Chinese Han children, including those patients homozygous for R778L. Thus we conclude that the onset of WD in Chinese children is not related to ApoE epsilon3/3, although the high frequency of ApoE epsilon3/3 in Chinese Han children with WD was not significantly different from that in controls.
16283886##2005-11-15##COMMD1 (MURR1) as a candidate in patients with copper storage disease of undefined etiology.##
16283883##2005-11-15##Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.##Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical phenotype of the disease is varied. It is proposed that this variation may be a result of differential functional disruption of ATPase7B (ATP7B) resulting from mutations in the gene ATP7B. We aimed to assess the relationship between specific mutational defects in ATP7B and divergence in the phenotypic expression of WD. One hundred and forty-two patients with clinically, biochemically and genetically diagnosed WD were included in the study. The phenotypic expression of WD was compared between patients with different types of mutations in ATP7B, detected by direct sequencing of exons 1-21 of the gene. Twenty-six mutations were identified in ATP7B; eleven of them were mutations predicted to result in the absence of a full-length normal protein [frameshift/nonsense mutations; classified as 'severe' mutations (SMs)], 14 were missense mutations (MMs) and one was a splice site mutation. Patients with one or two SMs on their alleles had lower serum copper and ceruloplasmin and were younger when the first symptoms of the disease appeared, compared with individuals with two MMs. The effect of SMs on the WD phenotype was dose-dependent. It is concluded that mutations within ATP7B are very heterogeneous. Frameshift and nonsense mutations are associated with a severe phenotype of WD.
16313864##2005-11-30##Hepatic Wilson's disease: initial treatment and long-term management.##This article is based on the experience of 320 patients with Wilson's disease who were seen between the years 1954 and 2000. These patients were seen at The Boston City Hospital, 1954 thru 1955, University College Hospital, London,1955 thru 1957; Addenbrooke's Hospital, Cambridge, 1967 thru 1987, and The Middlesex Hospital London, 1988 thru 2000. Wilson's disease is not strictly a gastroenterologic disease but a genetically determined metabolic disease that is mediated by a failure of copper excretion through the bile. The mutation carried on chromosome 13q14.3: it involves a copper-carrying ATPase (ATPase 7B); more than 250 mutations are now known. The first organ to be affected is the liver, then many other tissues, principally the brain but also the eyes, the kidneys, the bone marrow, and the osteoskeletal system. It is with the hepatic form of the disease that this article is concerned. The hepatic illness may be acute, subacute or chronic; it may be progressive or, apparently, self-limiting. In 10% of patients hemolysis may also be found which can later lead to the formation of pigment gallstones. The management of liver disease is not considered in this article, which is strictly confined to the therapeutic options available for the elimination of copper and the long-term welfare of the patient. It must be remembered that all close relatives of the patient must be screened for the presymptomatic stage of the disease so, if they are found to be homozygous carriers for the mutation, they can be started on preventive treatment.
16521309##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's Disease.##
16521294##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521293##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521292##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521291##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521267##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521266##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521265##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16521264##2006-3-8##Gene symbol: ATP7B. Disease: Wilson's disease.##
16402213##2006-1-13##Gene symbol: ATP7B. Disease: Wilson's disease.##
16372532##2005-12-24##Expression profile of copper transporters in sensitive and cisplatin/oxaliplatin-resistant tumor cell lines.##
16293159##2005-11-19##A case study: identifying a new case of Wilson's disease.##
16317117##2005-12-1##Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice.##The final steps in the absorption and excretion of copper at the molecular level are accomplished by 2 closely related proteins that catalyze the ATP-dependent transport of copper across the plasma membrane. These proteins, ATP7A and ATP7B, are encoded by the genes affected in human genetic copper-transport disorders, namely, Menkes and Wilson diseases. We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. Our results indicate that ATP7A is retained in the trans-Golgi network under copper-limiting conditions, but relocalized to a vesicular compartment adjacent to the basolateral membrane in intestines perfused with copper. The findings support the hypothesis that the basolateral transport of copper from the enterocyte into the portal blood may involve ATP7A pumping copper into a vesicular compartment followed by exocytosis to release the copper, rather than direct pumping of copper across the basolateral membrane.
16382340##2005-12-31##Wilson disease.##Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism, resulting in pathological accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings. The leading neurologic symptoms in WD are dysathria, dyspraxia, ataxia, and Parkinsonian-like extrapyramidal signs. Changes in the basal ganglia in brain magnetic resonance imaging (MRI) are characteristic features of the disease. In presence of liver cirrhosis, some features may resemble hepatic encephalopathy. Symptoms and MRI abnormalities may be fully reversible on treatment with zinc or copper chelators. Improvement can be monitored by serial recording of brain-stem-evoked responses. The basic defect is an impaired trafficking of copper in hepatocytes. ATP7B is the gene product of the WD gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. While about 40% of patients preset with neurologic symptoms, little is known about the role of copper and ATP7B in the central nervous system. In some brain areas, like in the pineal gland, ATP7B is expressed and functionally active. Increasing evidence supports an important role for metals in neurobiology. Two proteins related to neurodegeneration are copper-binding proteins (1) the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and (2) the Prion protein, related to Creutzfeldt-Jakob disease. A major source of free-radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. APP is a major regulator of neuronal copper homeostasis and has a copper-binding domain (CuBD). The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter. There are several copper-containing enzymes in the brain, like dopamine beta hydroxylase or Cu/Zn superoxide dismutase (SOD1). Their function may be altered because of copper overload. WD appears to be associated with a dopaminergic deficit. Mutations in the SOD1gene cause familial amyotrophic lateral sclerosis. Survival of transgenic mice with a mutant SOD1 which fails to incorporate Cu((2+)) in its active site was improved by copper depletion. Wilson disease (WD) is an autosomal recessive inherited disorder in which copper pathologically accumulates primarily within the liver and subsequently in the neurologic system and many other organs and tissues. Presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings are the hallmarks of the disease.
16092117##2005-8-11##Diagnostic significance of reduced serum caeruloplasmin concentration in neurological disease.##This study covers patients seen at a Wilson disease clinic between 1960 and 2002. The diagnosis of Wilson disease was confirmed in 316. Of 40 patients with a neurological presentation who were found not to have the disease, caeruloplasmin concentration was found to be reduced in 19. These 19 patients comprised 17 men and 2 women. The various diagnoses included Huntington's disease, multiple sclerosis, subacute sclerosing panencephalitis (SSPE), Hallervorden Spatz syndrome, and acaeruloplasminemia; in 9 no definite diagnosis was made. In view of the marked male preponderance, the lower limit of caeruloplasmin is calculated as for males. In an earlier study this was found to be 33.3 mg/dl (standard deviation, 6.1 mg/dl); therefore, 21.1 mg/dl is taken as the lower limit of normal. Particular attention is paid to 3 patients, 2 of whom had zero concentrations of caeruloplasmin and 1 had a very low level of the protein. Only 1 of these patients conformed to the classical picture of acaeruloplasminemia. The significance of a low caeruloplasmin concentration in patients with a variety of neurological syndromes is not clear but can lead to diagnostic confusion. When the concentration of this protein is very low or absent the diagnosis of acaeruloplasminemia must be considered.
16363699##2005-12-21##[Liver regenerative therapy using glycoside-modified bone marrow].##Recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency with which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase more efficiently. An attempt was made to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor (ASGPR) and galactose-exposing BMCs. Galactose-exposing BMCs that expressed green fluorescent protein (GFP) were injected into Long-Evans-Cinnamon (LEC) rats, a Wilson's disease (WD) model, via the tail vein. The WD is an autosomal-recessive disorder characterized by impaired biliary copper excretion and copper toxicosis, all due to mutations in the atp7b gene. At 5 months after transplantation, GFP-expressing hepatocyte nodules accounted for 2.4% of total liver mass, and the normal ceruloplasmin was detectable in the sera of these LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated and the new genes derived from BMCs, such as ATP7B and GFP, can be transferred to LEC rats by the direct accumulation of BMCs in liver without hematopoietic reconstitution in need of preparative lethal irradiation.
16381639##2005-12-31##[Clinical characteristics and ultrastructural features of livers in children with Wilson disease manifested mainly as hepatic injuries].##
16195917##2005-3-11##Extensive cortico-subcortical lesions in Wilson's disease: clinico-pathological study of two cases.##Wilson's disease (WD) with extensive cortico-subcortical lesions represents a rare neuropathological subgroup, the pathogenesis of which is not clearly determined. We report two new cases with identical lesions. In the families of each of the patient, there were mutations in the ATPase7B gene, especially in the family of proband 1, and in the first cousin of proband 2. These cases included massive destruction of the white matter in superior gyri, mostly frontal, extending to the deep cortex with neuronal loss and capillary proliferation. Astrocytes were of Alzheimer type 1 and 2; and type 1 were labeled by anti-metallothionein. Opalski cells were abundant and their macrophagic lineage was confirmed by immunostaining. Among the possible mechanisms proposed, the role of vascular factors and penicillamine treatment could be excluded. Cerebral copper content in white matter and putamen of case 1 was at the same level as in common WD but accumulation of unbound copper in the white matter was a distinctive feature, which suggested a pathological neurotoxic effect.
16222684##2005-10-14##Homozygosity for a gross partial gene deletion of the C-terminal end of ATP7B in a Wilson patient with hepatic and no neurological manifestations.##We identified a partial gene deletion of ATP7B in a patient with Wilson disease with hepatic onset. The deletion covered exon 20 including major parts of the flanking introns. The breakpoints were identified and the size of the deletion determined to be 2144 bp. The deletion is predicted to lead to a mutated protein product containing 45 aberrant amino acids after transmembrane domain 7, and lacking the transmembrane domain 8 as well as the entire C-terminal cytoplasmic tail. This is the first time a partial gene deletion has been demonstrated in ATP7B. The patient presented at age 10 with hepatic manifestations, including severe jaundice, hepato-splenomegaly, ascites, and spider naevi. The liver biopsy showed fibrosis and early signs of cirrhosis. There was a Kayser-Fleischer ring but no neurological manifestations. All symptoms disappeared with penicillamine therapy. This suggests that the C-terminal cytoplasmatic tail of ATP7B, is not essential for its neurological function. Large deletions in ATP7B may be an overlooked cause of Wilson disease. Patients that are homozygotes for deletions may be valuable for the understanding of the function of various regions of the ATP7B protein.
15994426##2005-6-30##NH2-terminal signals in ATP7B Cu-ATPase mediate its Cu-dependent anterograde traffic in polarized hepatic cells.##Cu is an essential cofactor of cellular proteins but is toxic in its free state. The hepatic Cu-ATPase ATP7B has two functions in Cu homeostasis: it loads Cu+ onto newly synthesized apoceruloplasmin in the secretory pathway, thereby activating the plasma protein; and it participates in the excretion of excess Cu+ into the bile. To carry out these two functions, the membrane protein responds to changes in intracellular Cu levels by cycling between the Golgi and apical region. We used polarized hepatic WIF-B cells and high-resolution confocal microscopy to map the itinerary of endogenous and exogenous ATP7B under different Cu conditions. In Cu-depleted cells, ATP7B resided in a post-trans-Golgi network compartment that also contained syntaxin 6, whereas in Cu-loaded cells, the protein relocated to unique vesicles very near to the apical plasma membrane as well as the membrane itself. To determine the role of ATP7B's cytoplasmic NH2 terminus in regulating its intracellular movements, we generated seven mutations/deletions in this large [approximately 650 amino acid (AA)] domain and analyzed the Cu-dependent behavior of the mutant ATP7B proteins in WIF-B cells. Truncation of the ATP7B NH2 terminus up to the fifth copper-binding domain (CBD5) yielded an active ATPase that was insensitive to cellular Cu levels and constitutively trafficked to the opposite (basolateral) plasma membrane domain. Fusion of the NH2-terminal 63 AA of ATP7B to the truncated protein restored both its Cu responsiveness and correct intracellular targeting. These results indicate that important targeting information is contained in this relatively short sequence, which is absent from the related CuATPase, ATP7A.
16212637##2005-10-11##Living donor liver transplantation for pediatric patients with inheritable metabolic disorders.##Forty-six pediatric patients who underwent living donor liver transplantation (LDLT) using parental liver grafts for inheritable metabolic disorders (IMD) were evaluated to determine the outcomes of the surgery, decisive factors for post-transplant patient survival and the impact of using donors who were heterozygous for the particular disorder. Disorders included Wilson disease (WD, n = 21), ornithine transcarbamylase deficiency (OTCD, n = 6), tyrosinemia type I (TTI, n = 6), glycogen storage disease (GSD, n = 4), propionic acidemia (PPA, n = 3), methylmalonic acidemia (MMA, n = 2), Crigler-Najjar syndrome type I (CNSI, n = 2), bile acid synthetic defect (BASD, n = 1) and erythropoietic protoporphyria (EPP, n = 1). The post-transplant cumulative patient survival rates were 86.8 and 81.2% at 1 and 5 years, respectively. Post-transplant patient survival and recovery of the growth retardation were significantly better in the liver-oriented diseases (WD, OTCD, TTI, CNSI and BASD) than in the non-liver-oriented diseases (GSD, PPA, MMA and EPP) and pre-transplant growth retardation disadvantageously affected post-transplant outcomes. Although 40 of 46 donors were considered heterozygous for each disorder, neither mortality nor morbidity related to the heterozygosis has been observed. LDLT using parental donors can be recommended as an effective treatment for pediatric patients with IMD. In the non-liver-oriented diseases, however, satisfactory outcomes were not obtained by hepatic replacement alone.
16269323##2004-10-19##Ceruloplasmin in neurodegenerative diseases.##For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.
16207219##2005-10-7##Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population.##
16305350##2005-11-25##Control of copper status for cancer therapy.##Copper is a trace element which is tightly regulated in mammals and lower animals. Disruptions of copper homeostasis in humans are rare and they cause serious disorders such as Wilson's disease and Menke's disease. Copper plays an important role in promoting physiological and malignant angiogenesis. Formation of new blood vessels by a tumor enables tumor growth, invasion, and metastasis are copper requiring processes. The copper chelator tetrathiomolybdate (TM), which quickly and effectively depletes copper stores, is under investigation as an anti-angiogenic agent. Promising results from in vitro experiments, in pre-clinical animal models, and in a phase I clinical trial have led to several phase II trials of TM in patients with advanced cancers.
16286255##2005-11-16##Liver regeneration after split liver transplantation.##
16340066##2005-12-13##Wilson's disease presenting as depressive disorder.##
16272867##2005-11-8##Magnetic resonance imaging morphometry of the midbrain in patients with Wilson disease.##In this study, the focus is on midbrain magnetic resonance imaging morphometric measures (transverse diameter of the midbrain peduncle [Tp], transverse diameter of the tegmentum, anteroposterior diameter of the midbrain, interpeduncular distance [IPD], and interpeduncular angle [IPA]) in a group of 47 consecutive patients with neurologic (37 patients) and hepatic (10 patients) forms of Wilson disease (WD). Morphometric measures were significantly different between the group of patients with WD and healthy controls (51 subjects) as well as patients with Parkinson disease (15 patients) and multiple sclerosis (15 patients). Among the studied variables, IPA, Tp, and IPD were particularly useful in differentiating patients from healthy subjects (probability reaching 93%).
16447770##2006-2-2##[MRI diagnosis of neurodegenerative disorders].##Routine use of high field MRI has greatly contributed to the clinical diagnosis of neurodegenerative disorders, because MRI enables to visualize degenerative process showing either atrophy of the specific areas or degeneration of specific structures. Among many specific MRI signs which have been hitherto proposed to be diagnostic for certain neurodegenerative disorders, the author discussed here some clinically useful ones with neuropathological interpretations. "Humming-bird sign" is highly diagnostic for progressive supranuclear palsy (PSP) because it represents focal atrophy of the rostro-dorsal portion of mid-brain tegmentum where the neural centers for vertical gaze specifically affected in PSP are located. Un-treated Wilson disease patients show frequently "face of giant panda sign" of mid-brain which disappears after successful treatment. Although the sign is pathognomonic for Wilson disease, neuropathological entity of this MRI abnormality has not been known yet. MRI enables to discriminate two types of cerebellar atrophies; cerebellipetal atrophy in which ponto-, spino- and olivo-cerebellar fibers are lost, and cerebellofugal atrophy in which loss of Purkinje cells is the main pathological process. In cerebellipetal atrophy, cerebellar white matter shows T2 high signal due to the degeneration of nerve fibers in it but T2 low signal of dentate nucleus is usually well preserved. This combination of degenerative process realized" black teeth sign" of dentate nucleus in MRI. On the other hand, cerbellofugal atrophy shows "white teeth sign" of dentate nucleus, because the loss of Purkinje cell axons causes signal change of dentate nucleus where the axons of Purkinje cells are concentrating. "White teeth sign" could also be observed in case of the degeneration of dentate nucleus itself, like in DRPLA, but differential diagnosis between Purkinje cell loss and dentate degeneration is not so difficult, because the atrophy of the superior cerebellar peduncle is detectable in the latter but never seen in the former condition.
16039066##2005-5-3##Inhibition kinetics of mushroom tyrosinase by copper-chelating ammonium tetrathiomolybdate.##With a strategy of chelating coppers at tyrosinase active site to detect an effective inhibitor, several copper-specific chelators were applied in this study. Ammonium tetrathiomolybdate (ATTM) among them, known as a drug for treating Wilson's disease, turned out to be a significant tyrosinase inhibitor. Treatment with ATTM on mushroom tyrosinase completely inactivated enzyme activity in a dose-dependent manner. Progress-of-substrate reaction kinetics using the two-step kinetic pathway and dilution of the ATTM revealed that ATTM is a tight-binding inhibitor and high dose of ATTM irreversibly inactivated tyrosinase. Progress-of-substrate reaction kinetics and activity restoration with a dilution of the ATTM indicated that the copper-chelating ATTM may bind slowly but reversibly to the active site without competition with substrate, and the enzyme-ATTM complex subsequently undergoes reversible conformational change, leading to complete inactivation of the tyrosinase activity. Thus, inhibition by ATTM on tyrosinase could be categorized as complexing type of inhibition with a slow and reversible binding. Detailed analysis of inhibition kinetics provided IC50 at the steady-state and inhibitor binding constant (K(I)) for ATTM as 1.0+/-0.2 microM and 10.65 microM, respectively. Our results may provide useful information regarding effective inhibitor of tyrosinase as whitening agents in the cosmetic industry.
16216950##2005-10-12##Wilson disease with an initial manifestation of polyneuropathy.##
16377579##2005-12-27##Expression of ATP7B in normal human liver.##ATP7B is a copper transporting P-type ATPase, also known as Wilson disease protein, which plays a key role in copper distribution inside cells. Recent experimental data in cell culture have shown that ATP7B putatively serves a dual function in hepatocytes: when localized to the Golgi apparatus, it has a biosynthetic role, delivering copper atoms to apoceruloplasmin; when the hepatocytes are under copper stress, ATP7B translocates to the biliary pole to transport excess copper out of the cell and into the bile canaliculus for subsequent excretion from the body via the bile. The above data on ATP7B localization have been mainly obtained in tumor cell systems in vitro. The aim of the present work was to assess the presence and localization of the Wilson disease protein in the human liver. We tested immunoreactivity for ATP7B in 10 human liver biopsies, in which no significant pathological lesion was found using a polyclonal antiserum specific for ATP7B. In the normal liver, immunoreactivity for ATP7B was observed in hepatocytes and in biliary cells. In the hepatocytes, immunoreactivity for ATP7B was observed close to the plasma membrane, both at the sinusoidal and at the biliary pole. In the biliary cells, ATP7B was localized close to the cell membrane, mainly concentrated at the basal pole of the cells. The data suggest that, in human liver, ATP7B is localized to the plasma membrane of both hepatocytes and biliary epithelial cells.
16365517##2005-12-21##Inhibitory effects of trientine, a copper-chelating agent, on induction of DNA strand breaks in kidney cells of Long-Evans Cinnamon (LEC) rats.##The effects of treatment with trientine, a specific copper-chelating agent, on the accumulation of copper and induction of DNA strand breaks were investigated in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. Copper accumulated in the kidneys of LEC rats in an age-dependent manner from 12 to 18 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, renal copper contents did not increase and were maintained at the same levels as those in 4-week-old LEC rats. Estimation of the amounts of DNA single-strand breaks (SSBs) by comet assay showed that SSBs of DNA were induced in a substantial population of LEC rat renal cortex cells around 12 weeks of age and that the amounts of SSBs increased in an age-dependent manner from 12 to 18 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, the observed number of cells with DNA damage decreased, suggesting that induction of SSBs of DNA was inhibited and/or SSBs were repaired during the period of treatment with trientine. The results show that SSBs of DNA in LEC rat kidney cells are induced prior to occurrence of clinical signs of hepatic injury and that treatment of LEC rats with trientine decreases the number of DNA strand breaks.
16198620##2005-9-29##Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH).##Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.
16175588##2005-9-22##Wilson Disease--keeping the bar for diagnosis raised.##
16133174##2005-2-24##Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype-phenotype correlation in Indian patients.##Wilson disease (WD) is an autosomal recessive disorder caused by defects in the copper-transporting P-type ATPase gene (ATP7B) resulting in the accumulation of copper in the liver and the brain. We identified prevalent mutations in the ATP7B of Indian WD patients and attempted to correlate those with the disease phenotype. Patients from 62 unrelated families and their first-degree relatives comprising 200 individuals were enrolled in this study. Three dinucleotide repeat markers flanking WD locus and a few intragenic SNPs were used to determine the genotypes and construct haplotypes of the patients. Seven recurring haplotypes accounting for 58% of the total mutant chromosomes were identified, and four underlying defects in the ATP7B representing 37% of WD chromosomes were detected. In addition, five other rare mutations were characterized. Thus a total of nine mutations including five novel changes were identified in the ATP7B of WD patients. Interestingly, homozygotes for different mutations that would be expected to produce similar defective proteins showed significant disparity in terms of organ involvement and severity of the disease. We also observed WD patients with neurological symptoms with little or no manifestation of hepatic pathogenesis. In one WD family, the proband and a sib had remarkably different phenotypes despite sharing the same pair of mutant chromosomes. These findings suggest a potential role for yet unidentified modifying loci for the observed phenotypic heterogeneity among the WD patients.
16174091##2005-9-22##Two male patients with Wilson's disease treated using trientine and iron reduction therapy.##
16388188##2006-1-3##Isolated tongue involvement--an unusual presentation of Wilson's disease.##
16190972##2005-9-30##Combination treatment with penicillamine and trientine in a patient with Wilson's disease.##
16281749##2005-11-12##[Epidural anesthesia and analgesia in a patient with cerebral manifestations of Wilson's disease].##
16215951##2005-10-11##[Effect of the mutation of promoter region in Wilson disease ATP7B gene on the expression of reporter gene].##
16255295##2005-11-1##[Liver cirrhosis in adults: etiology and specific treatments].##Cirrhosis is the result of chronic inflammation and of the progressive increase of fibrosis. In France, hepatitis C infection is the second cause of cirrhosis after alcohol abuse. The other causes of cirrhosis are: hepatitis B infection, genetic haemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, drug-induced cirrhosis, secondary biliary cirrhosis, Wilson's disease and al-antitrypsin deficiency. Etiological treatment is based upon: abstinence in case of alcoholic cirrhosis, the combination of pegylated interferon alpha (PEG IFN) with ribavirin in case of C viral cirrhosis, the PEG IFN and the nucleoside analogs in case of B viral cause; corticosteroids and immunosuppressive drugs in case of autoimmune cirrhosis; venesections in case of genetic haemochromatosis and stopping the drug in case of drug-induced cirrhosis. The complications of cirrhosis such as ascites, oesophageal varices, bleeding, hepatic encephalopathy and hepatocellular carcinoma mainly explain the high rate of morbidity and mortality. Liver transplantation is the established therapy for decompensated liver disease of any etiology significantly changed the outcome of patients with advanced cirrhosis.
16148750##2005-9-9##Effects of copper on A-type potassium currents in acutely dissociated rat hippocampal CA1 neurons.##The effects of copper on voltage-gated A-type potassium currents were investigated in acutely dissociated rat hippocampal CA1 neurons using the whole-cell patch-clamp technique. Extracellular application of various concentrations of copper (1-1000 microM) reversibly reduced the amplitude of voltage-gated A-type potassium currents in a dose-dependent manner with a 50% inhibitory concentration value of 130 microM. Copper (300 microM) increased the V1/2 of the activation curve and state-inactivation curve by 17.2 and 9.0 mV, respectively. Thus, copper slowed down the activation and inactivation process of voltage-gated A-type potassium currents. This study indicated that copper reversibly inhibits the hippocampal CA1 neuronal voltage-gated A-type potassium current in a dose-dependent and voltage-dependent manner, and such actions are likely involved in the regulation of the neuronal excitability and the pathophysiology of Wilson's disease.
16081251##2005-3-22##Oxidative stress and pro-apoptotic conditions in a rodent model of Wilson's disease.##Wilson's disease (WD) is an inherited disorder, characterized by selective copper deposition in liver and brain, chronic hepatitis and extra-pyramidal signs. In this study, we investigated changes of biochemical markers of oxidative stress and apoptosis in liver, striatum and cerebral cortex homogenates from Long-Evans Cinnamon (LEC) rats, a mutant strain isolated from Long Evans (LE) rats, in whom spontaneous hepatitis develops shortly after birth. LEC and control (LE) rats at 11 and 14 weeks of age were used. We determined tissue levels of glutathione (GSH/GSSG ratio), lipid peroxides, protein-thiols (P-SH), nitric oxide metabolites, activities of caspase-3 and total superoxide-dismutase (SOD), striatal levels of monoamines and serum levels of hepatic amino-transferases. We observed a decrease of protein-thiols, GSH/GSSG ratio and nitrogen species associated to increased lipid peroxidation in the liver and striatum - but not in the cerebral cortex - of LEC rats, accompanied by dramatic increase in serum amino-transferases and decrease of striatal catecholamines. Conversely, SOD and caspase-3 activity increased consistently only in the cortex of LEC rats. Hence, we assume that enhanced oxidative stress may play a central role in the cell degeneration in WD, at the main sites of copper deposition, with discrete pro-apoptotic conditions developing in distal areas.
16170647##2005-4-8##[Acute liver failure and hemolysis in a 16-year-old woman. First manifestation of Wilson's disease].##
16212003##2005-10-11##[Wilson's disease: Clinical presentations].##Wilson's disease is a rare genetic condition, transmitted on a recessive autosomal mode, which involves a disturbance of copper metabolism. Its prevalence is 1: 30000. It is treatable but may be lethal if not managed early and treated adequately. It is caused by the loss of function of an adenosine triphosphatase (ATP 7B), which is due to a mutation in the ATP 7B gene on chromosome 13. This leads to a decrease or absence of copper transport to the bile and its accumulation within certain organs, particularly the liver and the brain. In this article we present two cases of Wilson's disease in two young male patients. We also briefly review the pathophysiology of the illness, discuss the latest guidelines for diagnosis and treatment and outline the recent genetic discoveries.
16230279##2005-3-18##[Wilson disease: clinical and biological aspects].##Wilson disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene (chromosome 13, MIM# 277900). The discovery of the gene allowed a better understanding of cytosolic copper trafficking and its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This genetic disease which can be efficiently treated was formerly biologically suspected after a careful but sometimes invasive study of copper metabolism. Genetic advances can now give a definite answer using linkage analysis and research for disease-causing mutations. However, this diagnosis strategy is limited since currently over 320 mutations and 80 polymorphisms have been currently identified.
16172734##2005-9-09##[Wilson's disease: clinical diagnosis and "faces of panda" signs in magnetic resonance imaging].##
16088907##2005-8-10##Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry.##Wilson disease (WND), an autosomal recessive disorder of copper transport, shows wide genotypic and phenotypic variability, with hepatic and/or neurological symptoms. The WND gene, ATP7B, encodes a copper transporting ATPase that is involved in the transport of copper into the plasma protein ceruloplasmin, and in the excretion of copper from the liver. ATP7B mutations result in copper storage in liver and brain. From 247 WND patients worldwide whose DNA has been sequenced in our laboratory, we have identified 24 new mutations. The origins of the patients were European white (one deletion, one nonsense, one splice site, and 18 missense), Chinese (one deletion, one missense) and Bangladeshi (one missense). Most of these had strong support as disease causing mutations, based on conservation between species, structural changes, and absence in controls. One missense mutation in a Chinese patient was considered uncertain because of its conservative nature and position in the protein. We also identified 15 nucleotide substitutions (11 of them new) causing silent or intronic changes, none of which produce an additional splice site that could lead to disease. Characterization of mutations, both disease-causing and normal variants, is essential for accurate molecular diagnosis of this condition.
16023247##2004-10-2##Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2.##
16123950##2005-8-27##Liver transplantation for Wilson's disease: The burden of neurological and psychiatric disorders.##A retrospective data analysis on liver transplantation for Wilson's disease (WD) was performed among Italian Liver Transplant Centers. Thirty-seven cases were identified. The main indication for liver transplantation was chronic advanced liver disease in 78% of patients. Mixed hepatic and neuropsychiatric symptoms were recorded in 32.3%. Eight patients presented with fulminant liver failure; 44.8% were on medical treatment. Patient and graft survival at 3 months, 12 months, 3 years, 5 years, and 10 years after transplantation were, respectively, 91.8%, 89.1%, 82.9%, 75.6%, and 58.8%, and 85.3%, 83.0%, 77.1%, 70.3%, and 47.2%. Neurological symptoms significantly improved after orthotopic liver transplantation (OLT), but the survival of patients with mixed hepatic and neuropsychiatric involvement was significantly lower than in patients with liver disease alone (P = 0.04). WD characterized by hepatic involvement alone is a rare but good indication for liver transplantation when specific medical therapy fails. Patients with neuropsychiatric signs have a significantly shorter survival even though liver transplantation has a positive impact on neurological symptoms. In conclusion, a combination of hepatic and neuropsychiatric conditions deserves careful neurological evaluation, which should contraindicate OLT in case of severe neurological impairment.
15996499##2005-5-12##Commentary on Vrabelova et al.##The paper by Vrabelova et al. reflects a comprehensive genetic approach in characterizing genetically patients with Wilson disease (WD). They studied mutations within ATP7B-the gene encoding the defective WD protein ATPase 7B-in 227 WD patients from 200 unrelated Czech and Slovak families, which represents a very large cohort for WD, and therefore, the impact of their findings are highly important. There are accumulating papers published on mutations in WD, but besides reporting new mutations, mostly the genetic analysis is presented by sequencing data of limited exon analysis and the lack of additional screening techniques used. This in turn complicates the current interpretation of the reported mutations within ATP7B and the role of genetic testing for WD in general. The real distribution of mutations within ATP7B are not well established, there is limited information on the mutational detection rate, and there is still little known on the promoter region of ATP7B.
15967699##2005-3-5##Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease.##Wilson disease (WD) is an autosomal recessive disorder of copper transport. WD patients are presenting with a wide range of heterogeneous clinical syndromes including hepatic, neurological, or psychiatric presentations. The disease is caused by mutations in the ATP7B gene. This study presents the results of comprehensive mutation analysis in 227 WD patients from 200 unrelated families (173 from Czech Republic and 27 from Slovakia). More than 80% of all mutant alleles were identified, using a combination of PCR/RFLP, DGGE, TTGE, DHPLC, and sequencing. A total of 40 different mutations and 18 polymorphisms were detected on 400 independent mutant chromosomes. The most common molecular defect was H1069Q (57% of all 400 studied alleles). Each of the other 39 mutations was present in no more than 4% of WD alleles and 23 mutations were found in only one WD allele each (0.25%). Thirteen novel mutations were identified, including seven missense mutations (L641S, T737R, D918E, T1033S, G1111D, D1271N, and G1355C), four small deletions (19_20delCA, 1518_1522del5, 3140delA, and 3794_3803del10), and two splice-site mutations (2446-2A>G, 2865+1G>A). We did not find a significant correlation between H1069Q homozygosity and age of onset, and clinical and biochemical manifestation. Our data provide evidence that the H1069Q mutation-the most common molecular defect of the ATP7B gene in the Caucasian population-originates from Central/Eastern Europe. Screening of five prevalent mutations is predicted to reveal 70% of all mutant alleles presented in WD patients. This will provide a good starting point for early clinical classification of WD in our population.
16213328##2005-10-11##Living-related liver transplantation in pediatric patients.##
16182195##2005-9-27##Anticopper therapy against cancer and diseases of inflammation and fibrosis.##Anticopper drugs that have been developed to treat Wilson's disease, a disease of copper toxicity, include tetrathiomolybdate, zinc, penicillamine, and trientine. Lowering copper levels by a modest amount in non-Wilson's patients with tetrathiomolybdate inhibits angiogenesis, fibrosis and inflammation while avoiding clinical copper deficiency. Through this mechanism tetrathiomolybdate has proven effective in numerous animal models of cancer, retinopathy, fibrosis, and inflammation. Penicillamine has efficacy in rheumatoid arthritis and trientine has efficacy in diabetic neuropathy and diabetic heart disease. If clinical studies support the animal work, anticopper therapy holds promise for therapy of cancer, fibrotic disease and inflammatory and autoimmune diseases.
16234011##2005-10-20##Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease.##
16233999##2005-10-20##Wilson's Disease.##Wilson's disease (WD) is an autosomal recessive inherited disorder leading to impaired intrahepatic trafficking and biliary excretion of copper, resulting in the accumulation of copper in various organs including the liver, cornea, and brain. The WD gene (OMIM 277900) codes for a copper transporting P-type ATPase (ATP7B). Although the finding of the gene resulted in a major breakthrough for understanding the pathophysiology of WD, the role of genetic testing in the clinical management of WD patients is not yet established. There is no gold standard for diagnosis of WD. Diagnosis requires a combination of clinical and biochemical tests. None of these parameters alone allows a certain diagnosis of WD. To facilitate diagnosis, a scoring system was developed at the 8th International Meeting on Wilson Disease in Leipzig, Germany in 2001. For clinical purposes, the use of mutation analysis is limited by the occurrence of many mutations (more than 200) causing WD. In contrast to direct DNA sequencing, direct mutation detection by using allele-specific probes is rapid and clinically very helpful, if a mutation occurs with a reasonable frequency in the population (ie, H1069Q in European WD patients or R778L in WD patients from the Far East). To date, mutation analysis is the only reliable tool for screening the family of an index case with known causative mutation. Alternatively, haplotype analysis can be used to address diagnostic dilemmas in differentiating heterozygote gene carriers and affected asymptomatic siblings.
16008592##2005-7-13##Living-related liver transplantation for Wilson's disease.##Liver transplantation with liver grafts from deceased donors is the treatment of choice for patients suffering from Wilson's disease (WD) with end-stage liver disease. There are few reports, however, on the use of liver grafts from living-related donors for WD. Five (two pediatric and three adult recipients) underwent living-related liver transplantation (LRLT) for WD at the University of Tokyo. Two patients presented with fulminant hepatic failure with hemolysis, and the other three presented with decompensating cirrhosis, one with an overlapping neurologic WD. All recipients had a low serum ceruloplasmin level (median: 18 mg/dL), high urinary copper level (mean: 1119 microg/d), and presented with Kayser-Fleischer rings before transplantation. Although one patient died from early graft thrombosis unrelated to WD, the other four patients have shown an excellent long-term prognosis. Following successful transplantation, there was a significant reduction in urinary copper excretion (median: 64 microg/d) in all patients. The neurologic symptoms of WD in one patient, however, worsened after 2 months and gradually subsided, but not completely, over the 2-yr follow-up. For advanced liver failure in WD, we consider LRLT a valuable life-saving option. The improvement of neurologic symptoms, however, requires further evaluation.
16143887##2005-1-31##Hypertransaminasemia in childhood as a marker of genetic liver disorders.##
15978062##2005-6-28##A novel H28Y mutation in LEC rats leads to decreased NAT protein stability in vivo and in vitro.##Nocturnal melatonin production is reportedly controlled by the rhythms of serotonin N-acetyltransferase (NAT, or arylalkylamine N-acetyltransferase). While analyzing the melatonin synthetic pathways of Long Evans cinnamon (LEC) rats mutant for PINA, a pineal night-specific ATPase defective in Wilson disease, we discovered that NAT activity and protein levels are greatly reduced in LEC rats, and that the highly conserved histidine 28 is mutated to tyrosine. To study the effect of H28Y, we isolated a new strain of rat termed LPN that is mutant for NAT but wildtype for both PINA and coat color. Compared with control rats, the LPN rats displayed low NAT protein levels and enzyme activities. These results suggest that the H28Y mutation in NAT is the cause of reduced NAT levels in vivo. The identical H28Y mutation was also found in Sprague-Dawley rats from Zivic-Miller, suggesting it may be a common mutation in rodents. When analyzed in bacterial cells and HEK293 cells, the mutation resulted in reduction of both NAT protein stability and catalytic activity, confirming that the in vivo NAT phenotype in LPN rats was due to the H28Y mutation. Further analysis of the NAT-H28Y will focus on the mechanisms of the increased degradation both in vitro and in vivo, which will facilitate our understanding of how melatonin synthesis is controlled at the molecular level.
15998441##2005-7-7##Efficacy of zinc supplementation in preventing acute hepatitis in Long-Evans Cinnamon rats.##
16006499##2005-7-8##Prognostic factors in patients presenting with severe neurological forms of Wilson's disease.##
16253182##2005-10-29##[Therapeutic effectiveness of liver transplantation: a single center study of 203 consecutive cases].##
15963506##2005-4-1##Purification and functional reconstitution of the human Wilson copper ATPase, ATP7B.##Wilson disease is a disorder of copper metabolism, due to inherited mutations in the Wilson copper ATPase gene ATP7B. To purify and study the function of the ATPase, the enzyme was truncated by five of the six metal binding domains and endowed with an N-terminal histidine-tag for affinity purification. This construct, delta1-5WNDP, was able to functionally complement a yeast strain defective in its native copper ATPase CCC2. Delta1-5WNDP was purified by Ni-affinity chromatography and reconstituted into proteoliposomes. This allowed, for the first time, the functional study of the Wilson ATPase in a purified, reconstituted system.
16034158##2004-6-29##Zinc supplementation decreases hepatic copper accumulation in LEC rat: a model of Wilson's disease.##The effect of dietary zinc (Zn) supplementation on copper (Cu)-induced liver damage was investigated in Long-Evans Cinnamon rats (LEC), a model for Wilson's disease (WD). Four-week-old LEC (N=64) and control Long-Evans (LE) (N=32) female rats were divided into two groups; one group was fed with a Zn-supplemented diet (group I) and the other was given a normal rodent diet (group II). LEC rats were killed at 6, 8, 10, 12, 18, and 20 wk of age; the LE control rats were killed at 6, 12, 18, and 20 wk of age. Cu concentration in the liver was reduced in LEC rats fed the Zn-supplemented diet compared with LEC rats on the normal diet between 6 and 18 wk of age. Metallothionein (MT) concentration in the livers of LEC rats in group I increased between 12 and 20 wk of age, whereas hepatic MT concentration in LEC rats from group II decreased after 12 wk. Hepatocyte apoptosis, as determined by TUNEL, was reduced in Zn-supplemented LEC rats at all ages. Cholangiocellular carcinoma was observed only in LEC rats in group II at wk 20. These results suggest that Zn supplementation can reduce hepatic Cu concentration and delay the onset of clinical and pathological changes of Cu toxicity in LEC rats. Although the actual mechanism of protection is unknown, it could be explained by sequestration of dietary Cu by intestinal MT, induced by high dietary Zn content.
15790590##2005-3-24##Apoptosis and age-dependant induction of nuclear and mitochondrial etheno-DNA adducts in Long-Evans Cinnamon (LEC) rats: enhanced DNA damage by dietary curcumin upon copper accumulation.##Long-Evans Cinnamon (LEC) rats, a model for human Wilson's disease, develop chronic hepatitis and liver tumors owing to accumulation of copper and induced oxidative stress. Lipid peroxidation (LPO)-induced etheno-DNA adducts in nuclear- and mitochondrial-DNA along with apoptosis was measured in LEC rat liver. Levels of etheno-DNA adducts (1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine) increased with age reaching a peak at 8 and 12 weeks in nuclear and mitochondrial DNA, respectively. This is the first demonstration that etheno-DNA adducts are also formed in mitochondrial DNA. Apoptosis was assessed by TUNEL+ cells in liver sections. CD95L RNA expression was also measured by in situ hybridization in the same sections. The highest nuclear DNA adduct levels coincided with a reduced apoptotic rate at 8 weeks. Mitochondrial-DNA adducts peaked at 12 weeks that coincided with the highest apoptotic rate, suggesting a link of etheno-DNA adducts in mitochondrial DNA to apoptosis. The DNA damage in liver was further enhanced and sustained by 0.5% curcumin in the diet. Treatment for 2 weeks elevated etheno-DNA adducts 9- to 25-fold in nuclear DNA and 3- to 4-fold in mitochondrial-DNA, providing a plausible explanation as to why in our earlier study [Frank et al. (2003) Mutat. Res., 523-524, 127-135], curcumin failed to prevent liver tumors in LEC rats. Our results also confirm the reported in vitro DNA damaging potential of curcumin in the presence of copper ions by reactive oxygen species. LPO-induced adduct formation in nuclear and mitochondrial DNA appear as early lesions in LEC rat liver carcinogenesis and are discussed in relation to apoptotic events in the progression of malignant disease.
15930910##2005-6-3##Trigonocephaly and Wilson's disease in two siblings.##Trigonocephaly and Wilson's disease (WD) are two different entities. The former is a type of craniosynostosis that occurs because of fusion of the metopic suture and the latter, also called hepatolenticular degeneration, is caused by an accumulation of copper in tissues all over the body because of failure of copper excretion. No single gene has been identified for trigonocephaly whereas the ATP7B gene has been shown to be responsible for Wilson's disease. Here we present two siblings born to nonconsanguineous parents who both presented with trigonocephaly, Wilson's disease and facial dysmorphism. In addition, the female has renal agenesis and the male has a history of undescended testis. Karyotypes were normal and no mutation of the ATP7B gene has been identified in the patients or their parents.
15952988##2005-6-15##Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene.##Wilson disease (WD) is a copper metabolism disorder characterized by hepatic and/or neurological damage. More than 200 mutations in the ATP7B gene causing this autosomal recessive defect have been reported. In certain populations, a high prevalence of particular mutations allows rapid screening and diagnosis of the disease. We identified the ATP7B alterations in Spanish patients with WD. Mutations in the ATP7B gene were analysed in a total of 64 individuals from 40 different WD families by PCR amplification, single-strand conformation polymorphism (SSCP) analysis and sequencing. Twenty-one different ATP7B gene mutations were identified, eight of which were novel. 74% of the disease alleles were characterized among the 40 unrelated probands. We identified a prevalent mutation in our population (Met645Arg), present in 55% of this 40 patients. The frequency of the remaining ATP7B alterations was low. In addition, 17 different polymorphic variants were found. There is remarkable allele heterogeneity in WD in the Spanish population. Nevertheless, SSCP screening for the most frequent mutations in our population is feasible and leads to the detection of about 74% of the mutated chromosomes. Molecular diagnosis of WD is very useful in clinical practice to confirm or support clinical suspicion.
16144289##2005-9-8##Elastosis perforans serpiginosa secondary to D-penicillamine therapy with coexisting cutis laxa.##Elastosis perforans serpiginosa (EPS) is a rare complication of D-penicillamine therapy. EPS has been reported in patients with Wilson disease, cystinuria, and rheumatoid arthritis after many years of high-dose therapy. We report a case of D-penicillamine-induced EPS with coexisting acquired cutis laxa in a patient with cystinuria. Although both EPS and acquired cutis laxa can be associated with D-penicillamine therapy, few cases have been reported with overlapping clinical presentations, and previously only in patients with Wilson disease. We review the characteristic clinical and histologic features of EPS and discuss the potential dermatologic manifestations of D-penicillamine therapy.
16156028##2005-9-13##Gene symbol: ATP7B. Disease: Wilson disease.##
16156019##2005-9-13##Gene symbol: ATP7B. Disease: Wilson disease.##
16156016##2005-9-13##Gene symbol: ATP7B. Disease: Wilson disease.##
16156015##2005-9-13##Gene symbol: ATP7B. Disease: Wilson disease.##
16156014##2005-9-13##Gene symbol: ATP7B. Disease: Wilson disease.##
15915361##2005-5-26##[Wilson disease].##Wilson disease is an autosomal recessive inherited disorder of human copper metabolism that leads to neurological symptoms and hepatic damage of variable degree. The affected gene ATP7B encodes a hepatic copper transport protein, which plays a key role in human copper metabolism. Clinical symptoms are complex with neurologic symptoms such as tremor, dysarthria, psychiatric disorders etc., predominant hepatic disease or mixed forms. Copper deposition in the liver results in acute liver failure, chronic hepatitis or liver cirrhosis. Early recognition by means of clinical, biochemical or genetic examination and early initiation of therapy with chelators or zinc-salts are essential for outcome and prognosis. Liver transplantation is an alternative in cases with acute and chronic liver failure and cures the hepatic disease. Frequent monitoring of drug therapy, adverse effects, and compliance is critical for the prognosis of the disease.
15990694##2004-8-20##Hepatitis C virus associated arthritis in absence of clinical, biochemical and histological evidence of liver disease--responding to interferon therapy.##
15806570##2005-4-5##Wilson's disease presenting with an unusual cough.##A 26-year-old man developed an unusual repetitive, nonproductive cough. Extensive pulmonary and otolaryngology investigations failed to disclose a cause. It was only after he developed additional neurological manifestations ultimately leading to the diagnosis of Wilson's disease (WD) that a neurological basis for the cough was suspected. Features of the cough suggest it was a form of respiratory dyskinesia, a previously unreported presentation of WD.
16053699##2005-8-2##Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma.##Penicillamine is an oral agent used to treat intracerebral copper overload in Wilson's disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had a median age of 54 years and a median Karnofsky performance status of 90. Surgical resection was performed in 83% of these patients. Normal serum copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of <50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.
15911138##2004-12-16##Ferrous and ferric iron accumulates in the brain of aged Long-Evans Cinnamon rats, an animal model of Wilson's disease.##The Long-Evans Cinnamon (LEC) rat, which accumulates excess copper (Cu) in its liver, is an animal model of Wilson's disease. We evaluated and compared the distributions of Cu, ferrous (Fe2+), and ferric (Fe3+) iron in four-brain regions, namely, in the cerebral cortex, cerebellum, substantia nigra (SN), and striatum of LEC and Long-Evans Agouti rats at 30 and 55 weeks. Cu levels were elevated in the striatum of LEC rats, and Fe2+ and Fe3+ were higher in the striatum and SN of LEC rats. Ratios of Fe2+ to Fe3+ were > 1 in four regions, and were highest in the striatum and SN of LEC rats. Cu and iron levels were found to be augmented during aging, and we suggest that these accumulations may exert deleterious effects in aged LEC rats. This study is the first report that demonstrates regional differences of Fe2+ and Fe3+ accumulation in the brain of aged LEC rats. Further studies are required to elucidate the mechanisms of Cu and iron accumulations and of their effects.
16076079##2005-8-4##Kinetic study of zinc sulphate release from lipophilic matrices prepared for the therapy of Wilson's disease.##The rate and extent of drug release from the most controlled release wax matrices are influenced by the drug loading/embedding excipient ratio of the systems. In the present study hydrophobic wax - zinc sulphate matrices with different drug loadings were prepared for the therapy of Wilson's disease. The drug release was tested by the paddle method of USP and the dissolution data were analysed. Both the dissolution rate and kinetic profile can be controlled by alteration in the quantity of embedding material. Matrices of 75% zinc sulphate loadings showed steady state diffusion-controlled matrix release with good correlation in vitro. Good absorption of zinc sulphate from the gastrointestinal tract was proven by significant elevation of serum zinc level in patients with Wilson's disease.
16623255##2006-4-21##[Multimodal evoked potential abnormalities in patients with Wilson's disease].##The aim of this study was to investigate the involvement of the following functional systems: somatosensory evoked potentials (SSEP), visual evoked potentials (VEP), and event related potentials (ERP), in twenty patients with Wilson's disease (WD). VEP and SSEP abnormalities were discovered in 8 patients respectively (40%), whereas ERP were either absent or, in the case of 10 patients (50%), had significantly prolonged P-300 latencies. Taken together, at least one evoked potential abnormality was discovered in 17 patients (85%). Only in 3 patients (15%), involving either the isolated hepatic type of disease or short illness duration of the neurological type, were normal evoked potential findings observed. Our findings suggest the usefulness of multimodal evoked potential abnormalities in the evaluation of subclinical manifestations in patients with WD.
15968722##2005-6-22##Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation.##
15950762##2004-11-8##A new strain of rat for functional analysis of PINA.##Long Evans cinnamon (LEC) rat is an animal model for human Wilson disease (WD) due to a deletion in Atp7b, the copper transporter defective in WD patients. Previously, we have demonstrated presence of an alternative product termed PIneal Night-specific ATPase (PINA) generated by an intronic promoter in Atp7b gene. Analysis of LEC rat in this study demonstrates that PINA is absent in the LEC pineal establishing its usefulness for investigating PINA function. Studies of the LEC pineal, however, revealed an additional defect in serotonin N-acetyltransferase (NAT), the key enzyme in melatonin production. Linkage studies confirm that the NAT phenotype is entirely independent of PINA mutation in the pineal gland of LEC rats, and sequence analysis demonstrates that NAT defect is due to a point mutation in NAT coding region. In addition, we demonstrate that the cinnamon coat color of the LEC rat is unlinked to PINA and NAT deficiencies in these animals. To facilitate further functional analysis of PINA in pineal physiology, we crossed LEC rats with PVG rats that are wildtype for PINA, NAT and coat color, and obtained rats that are defective only in PINA/Atp7b locus (termed LPP rats) and normal for NAT activity and coat color. Furthermore, we have identified the deletion breakpoint of Atp7b gene in LPP rats, which allows simplified genotyping of mutant animals. The separation of PINA mutation from both NAT and coat color mutations in the new LPP rats will permit better functional studies of PINA in pineal circadian physiology.
15876342##2005-5-7##Classification of fine-motoric disturbances in Wilson's disease using artificial neural networks.##Patients suffering from Wilson's disease are divided into several types according clinical symptoms only at time of manifestation. Thereby two main subgroups exist: neurologic and non-neurologic types. After long-term therapy the neurological symptoms occurring in hepatolenticular degeneration may be improved but frequently with remaining fine-motoric disturbances which should be used for evaluation of the actual patient state. These disturbances are difficult to assess in an exact and objective manner by clinical examination. Therefore we measured fine-motoric passive and active abilities based on a standardized test set using the VSCOPE-system. The parallel evaluation of all fine-motoric data using an artificial neural network leads to a reclassification of these patients based on actual fine-motoric abilities but not reflecting the clinical classification at time of manifestation.
16030471##2005-7-21##Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human solid carcinomas.##
16007400##2004-8-23##D-Penicillamine improved laparoscopic and histological findings of the liver in a patient with Wilson's disease: 3-year follow-up after diagnosis of Coombs-negative hemolytic anemia of Wilson's disease.##We report a 13-year-old girl who presented with hepatic failure and hemolytic anemia. Laboratory findings showed a normal serum copper level (104 microg/dl), high urinary copper level (2370 microg/dl), and low serum ceruloplasmin level (14.3 microg/dl). Slit-lamp examination revealed Kayser-Fleischer rings on her cornea, and she was diagnosed with Wilson's disease. Plasma exchange and continuous hemodiafiltration relieved the serious condition, after that laparoscopic examination was performed. Administration of D-penicillamine and restriction of dietary copper (<1 mg/day) were started, leading to a normalized serum alanine amino transferase (ALT) level. After 3 years, she again underwent laparoscopic examination, and the laparoscopic and histological findings of her liver were obviously improved. Management of the copper level can reverse severe liver fibrosis in Wilson's disease.
15742108##2004-6-16##Wilson's disease-cause of mortality in 164 patients during 1992-2003 observation period.##We studied the cause of death in a consecutive series of 164 patients with Wilson's disease (WD) diagnosed over an 11 year period. A total of 20 [12% (95% CI 10.3-16.0)] died during the observation period. The relative survival rate of all patients in our group was statistically smaller than in Polish population. The main cause of death was the diagnosis in advanced stage of disease, but in six patients presenting with mild signs, we observed the progression of the disease despite treatment. There was no difference in mortality rate in patients treated with d-penicillamine or zinc sulphate as initial therapy. The prognosis for survival in the majority of WD patients is favourable, provided that therapy is introduced early.
15910506##2005-5-25##Evaluation of the scoring system for the diagnosis of Wilson's disease in children.##
15959750##2005-6-17##[Classification of Wilson's disease based on neurophysiological parameters].##In addition to hepatolenticular degeneration in Wilson's disease, sensory and extrapyramidal motoric systems are also disturbed. In this study a classification on the basis of neurophysiological parameters (EAEP, VEP, MSEP, TSEP and MEP) was established according to subclinical disturbances of these pathways in patients with Wilson's disease on long-term treatment. A cluster analysis of latencies of these evoked potentials was performed. The results of cluster analysis revealed three types of electrophysiological profiles: type I with normal latencies and types II and III showing different patterns of prolonged latencies. However, there was no correlation between clinical classification and the results of cluster analysis based on the electrophysiological data. The neurophysiological based classification provides additional information about central manifestations and aids in characterizing the progress of the disease.
15949239##2005-6-14##Absence of nigrostriatal degeneration in LEC rats up to 20 weeks of age.##
15909172##2003-7-29##Acute putaminal necrosis and white matter demyelination in a child with subnormal copper metabolism in Wilson disease: MR imaging and spectroscopic findings.##Wilson disease (WD) that manifests solely with acute and severe neurological damage in the absence of hepatic disease and Kayser-Fleischer ring of the cornea is rare and difficult to diagnose at the acute setting. This report describes unusual diffusion and proton spectroscopic magnetic resonance (MR) imaging findings in a 12-year-old boy with WD who presented with hemichorea and subnormal copper metabolism. The MR imaging findings of lactate accumulation, decrease of N-acerylaspartate/creatinine (NAA/Cr) ratio and markedly increased apparent diffusion coefficient (ADC) value of the asymmetrical edematous putaminal lesions in the early stage were suggestive of acute necrosis with anaerobic metabolism of glucose leading to poor clinical outcome at follow-up.
15910288##2005-5-25##Living-related liver transplantation for Wilson's disease.##Orthotopic liver transplantation has been applied to the treatment of Wilson's disease (WD), living-related liver transplantation (LRLT) has also been indicated for WD with increasing frequency. Between January 2001 and November 2003, 22 LRLTs were performed on patients (19 pediatric, three adults) with WD in liver transplantation center. Two patients were transplanted because of a presentation coexistent with fulminant hepatic failure. Twenty presented with chronic advanced liver disease with (n = 9) or without (n = 11) associated neurologic manifestations. All the recipients had low serum ceruloplasmin levels with a mean value of 12.8 +/- 3.2 mg/dl before transplantation and increased to an average of 26.0 +/- 3.6 mg/dl after LRLT at the latest evaluation. The survival patients with neurologic manifestations such as tremor, dysarthia, dysphagia, dystonia and sialorrhea had improved after LRLT. This suggests that LRLT not only resolves the hepatic but also ameliorates the neurologic consequences of WD.
16252195##2005-10-28##Wilson disease in southern Iran.##
15911799##2005-5-25##Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease.##
15891161##2005-5-14##Proton MR spectroscopy in Wilson disease: analysis of 36 cases.##
15845031##2005-4-23##Wilson disease: high prevalence in a mountainous area of Crete.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The disorder is caused by mutations in the ATP7B gene, encoding a copper transporting P-type ATPase. The worldwide incidence is in the order of 30 cases per million, with a gene frequency of 0.56% and a carrier frequency of 1 in 90. The increased number of Wilson disease patients in the island of Crete led us to study the spectrum of mutations in a small village close to the city of Heraklion, from where many patients have been referred during the last 25 years. In order to estimate the frequency of the disease, we firstly investigated the number of births and the number of WD patients in the village since 1978. Six out of 90 births were diagnosed as WD patients, presenting the highest prevalence of WD reported so far. Analysis of the whole gene in three Wilson disease patients, and relatives of a boy who died from WD, led to the detection of 4 different point mutations. Two of them were missense (p.I1148T and p.G1176R) and cosegregated in cis in the same patient; the other allele of this patient carried a nonsense mutation (p.Q289X). This is the first report in the literature of three mutations co-segregating in the same WD patient. The fourth mutation identified was a novel frameshift mutation (c.398delT) with documented cosegregation. When screening 200 inhabitants originating from the same area, 18 were found to be carriers of one of these mutations. These findings indicate the need for health education intervention, genetic counselling and newborn screening for the Wilson disease.
15811015##2005-4-7##Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: genotype.##
15892619##2005-5-17##Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer.##Tetrathiomolybdate (TM) is a novel anticopper agent under development for use in Wilson's disease. It acts by forming a stable tripartite complex with serum albumin and copper, rendering the complexed copper unavailable for cellular uptake. TM is a very potent anticopper agent and has an excellent safety profile. It has been shown that normal copper levels are required for optimal angiogenesis. Based on this background, we decided to evaluate TM as an anticancer agent. TM treatment of Her/2neu mice, genetically programmed to develop breast cancer, completely prevented the development of visible mammary cancers, although avascular microscopic clusters of cancer cells were present in the breasts of TM treated animals. Controls developed grossly visible tumors. TM was able to strongly inhibit tumor growth in six other rodent models. In a phase 1/2 clinical trial of advanced and metastatic cancers, freedom from progression averaged 11 months, and some individual results were quite dramatic. Eight phase 2 studies of specific cancers have been launched. TM's hypothesized mechanism of action is inhibition of angiogenic cytokines. Unlike other current approaches to antiangiogenic therapy which target single agents, we hypothesize that TM inhibits multiple angiogenic cytokines. Part of this effect appears to stem from inhibition of nuclear factor kappa B (NF(K)B), which in turn controls transcription of many angiogenic and other cytokines. However, there are probably multiple mechanisms, in that some angiogenic cytokines appear to have separate mechanisms of copper dependence. The inhibition of multiple angiogenic cytokines gives TM the potential to be a more global inhibitor of angiogenesis.
15818147##2005-4-9##Inherited metabolic liver disease.##
16394408##2006-1-6##Penicillamine induced pseudoxanthoma elasticum with elastosis perforans serpiginosa.##Long term D-penicillamine therapy, especially when used to treat Wilson's disease has been shown to cause elastosis perforans serpiginosa, pseudoxanthoma elasticum perforans and other degenerative dermatoses. We report a 23-year-old male patient who presented with multiple firm papules, nodules over the neck, axillae, front of elbows for five years. He was a known case of Wilson's disease on long-term treatment with penicillamine for the past 12 years. The papulonodular lesions were non-tender and some were discrete while others were arranged in a circinate pattern. There was central scarring of the skin within the circinate lesions. In addition, there were several small yellowish papules on both sides of the neck which eventually became confluent to form plaques. Histopathology confirmed the diagnosis of elastosis perforans serpiginosa and pseudoxanthoma elasticum. He was treated with cryotherapy (using liquid nitrogen through cryojet) for former lesions. The lesions showed remarkable improvement after five sittings. Now the patient is under trientine hydrochloride (750 mg twice daily) for Wilson's disease.
15923701##2005-6-1##Wilson's disease presenting as status epilepticus.##
15942090##2005-6-9##Small hepatocellular carcinoma associated with Wilson's disease.##We report a 66-year-old male patient with hepatocellular carcinoma (HCC) associated with Wilson's disease. The patient presented with unresolving abnormal liver function test, decreased serum ceruloplasmin levels and increased 24-hour urine copper excretion. Liver biopsy specimen revealed the presence of increased levels of copper and features suggestive of Wilson's disease. Abdominal imaging showed the existence of a small HCC. Three years after chemoembolization and microwave coagulation therapy for HCC, he died of hepatic failure, which apparently resulted from chemoembolization. Patients with Wilson's disease should be screened for HCC. We should elude therapies such as chemoembolization in these patients.
15756098##2005-3-10##Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia).##A 45-year-old patient was sent to our department because of highly elevated transaminases and elevated lactate dehydrogenase. His medical history was unremarkable and he took no medication on regular basis. Physical examination did not detect any abnormalities. There was no evidence for viral hepatitis, Epstein-Barr virus or cytomegalovirus, autoimmune hepatitis, Budd-Chiari syndrome, haemochromatosis or Wilson's disease. During the interview he admitted that for 'prophylactic reasons' he had been drinking the juice of Noni (Morinda citrifolia), a Polynesian herbal remedy made from a tropical fruit, during the preceding 3 weeks. This gave rise to the suspicion of herbal toxicity, which was confirmed by a liver biopsy. After ceasing the ingestion of Noni, transaminase levels normalized quickly and were within normal ranges 1 month after the first presentation. To our knowledge, this is the first report of hepatotoxicity caused by this herbal remedy, which has been highly praised in the tabloid press.
15790435##2004-7-8##Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a prognostic factor in human endometrial carcinoma.##
15758626##2005-3-11##Hepatic copper in patients receiving long-term total parenteral nutrition.##
15851088##2005-4-27##Wilson's disease with depression and parkinsonism.##Wilson's disease (WD) is an autosomal recessive disorder with reduced biliary excretion of copper plus impaired formation of ceruloplasmin, leading to copper accumulation in the liver, brain, kidney, and cornea. Clinical manifestations include liver damage, psychiatric symptoms, and neurological features. We report a 35-year-old woman with a history of deranged liver functions who had severe depression several years later and eventually presented with parkinsonian features. The underlying diagnosis is WD and family screening revealed WD in 2 other siblings. She could not tolerate penicillamine because of fever and leucopenia. While taking trientine hydrochloride and zinc sulphate, her parkinsonism improved and her depression remained in remission. WD should be considered in patients with unexplained liver function derangement or psychiatric symptoms. Early diagnosis and initiation of specific treatment are crucial in minimising any further cerebral and hepatic damage as well as securing possible improvement in organ functions.
15836726##2005-4-20##Two novel mutations (2976INSA, 4311insA) of ATP7B in a patient with Wilson's disease coexisting with glucose-6-phosphate dehydrogenase deficiency.##
15726258##2004-3-18##Improvement of cardiovascular autonomic dysfunction following anti-copper therapy in Wilson's disease.##
15776453##2005-3-19##Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.##Wilson's disease (WD) is a rare liver-based disorder of copper metabolism. Prognostic criteria described by our group in 1986 to predict death without transplantation have not been universally validated. The clinical features of 88 children were reviewed, retrospectively in 74 and prospectively in 14. Data from the retrospectively recruited patients that died or survived on long-term chelation were used to evaluate the validity of our old scoring system and to devise a new prognostic index, then assessed in the 14 prospectively recruited patients. Using the old scoring system, 5 children scoring > or = 7, the cutoff value for death without transplantation, survived, whereas 4 scoring < or = 7 died (sensitivity 87% and specificity 90%). A new index based on serum bilirubin, international normalized ratio, aspartate aminotransferase (AST), and white cell count (WCC) at presentation identified a cutoff score of 11 for death and proved to be 93% sensitive and 98% specific, with a positive predictive value of 88%. When the new index was evaluated prospectively in 14 patients, it predicted the need for transplantation in only the 4 who required it, although 1 child with a score of 11 survived on medical treatment. In conclusion, the new Wilson Index is more sensitive and specific in predicting mortality without transplantation than the old scoring system, but needs to be validated in a larger number of patients.
15985997##2005-6-30##[Inherited disorders of bilirubin metabolism].##Jaundice in an infant or older child may reflect accumulation of either unconjugated or conjugated bilirubin and could be related to inherited bilirubin disorders. Three grades of inherited unconjugated hyperbilirubinemia are recognised in humans. This spectrum of disorders is distinguished primarily on the basis of the plasma bilirubin level, the response to phenobarbital administration, and the presence or absence of bilirubin glucoronides in bile. The enzyme responsible for the conjugation of bilirubin is the bilirubin uridine-diphosphate-glucuronosyltransferase (UGT). Mutations in the gene encoding bilirubin-UGT (UGT1A1), lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler-Najjar syndrome type 1 (CN-1) and type 2 (CN-2). Gilbert syndrome (GS) is due to an insertional mutation at homozygous state of the TATAA element (seven TA repeats) of UGT1A1 producing a reduced level of expression of the gene. The association of GS with haemolytic anemias, e.g., Hereditary Spherocytosis (HS) or Congenital Dyserythropoietic Anemia type 2 (CDA 2), increase the hyperbilirubinemia level and the risk of cholelithiasis. Forms of chronic conjugated hyperbilirubinemia are Dubin-Johnson syndrome, Rotor syndrome, Alagille syndrome or arteriohepatic dysplasia, Wilson disease or hepatolenticular degeneration. Liver or liver cell transplantation is the therapy in some cases.
16076018##2005-8-4##Enhanced Mn-SOD immunoreactivity in the dopaminergic neurons of long-evans cinnamon rats.##The abundance of cellular superoxide dismutase (Mn-SOD) was examined immunocytochemically in different regions of the brain of Long-Evans Cinnamon (LEC) rats at 4 and 50 weeks of age. When all animals develop chronic hepatitis, the substantia nigra and striatum showed a marked increase in Mn-SOD immunoreactivity versus Long-Evans agouti (LEA) rats of the same age. Mn-SOD was localized predominantly in dopaminergic neurons. The elevation of Mn-SOD level in the dopaminergic neurons of LEC rats may reflect the oxidative stress caused by copper accumulation in this brain area. Our data suggest that LEC rats may contribute to the mechanistic study of neurological manifestations in nigro-striatal dopaminergic system of Wilson's disease.
15901034##2005-5-20##[Anesthesia in Wilson's disease].##
15733935##2004-5-11##Fe(II)/Cu(I)-dependent P-type ATPase activity in the liver of Long-Evans cinnamon rats.##This study examined Fe(II)-dependent ATPase activity in OTG (octylthioglucoside) -treated microsomes isolated from Wistar and LEC rats. The ATPase activity of the liver OTG-microsomes from Wistar rats increased sharply in the 5-150 microM range of Fe(II) with a K0.5 value of 23.9+/-3.6 microM, while the activity of LEC rat liver microsomes increased with increasing Fe(II) up to 500 microM with a K0.5 value of 64.4+/-8.1 microM. The K0.5 values for Fe(II)-dependent ATPase activity of spleen OTG-microsomes were nearly identical at 59.3 microM in the Wistar rat and 63.7 microM in the LEC rats with a similar level of activity at each Fe(II) concentration in both strains of animals. These results indicated that there are two types of Fe(II)-dependent ATPase with different Fe(II) sensitivity, a high sensitive (H) and a low sensitive (L) type, and that the H-type activity was specific to the liver. The H-type activity was, however, deficient in the liver of LEC rats that accumulate copper and iron in hepatocytes as a result of mutations in the Wilson's disease protein (WNDP). On the basis of these results, together with the similarity in optimal conditions required for full activity of the enzyme, we conclude that the Fe(II)-dependent ATPase (H-type) and WNDP may be identical.
15634671##2005-1-5##The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum.##Copper is essential for brain metabolism, serving as a cofactor to superoxide dismutase, dopamine-beta-hydroxylase, amyloid precursor protein, ceruloplasmin, and other proteins required for normal brain function. The copper-transporting ATPases ATP7A and ATP7B play a central role in distribution of copper in the central nervous system; genetic mutations in ATP7A and ATP7B lead to severe neurodegenerative disorders, Menkes disease and Wilson disease, respectively. Although both ATP7A and ATP7B are required, their specific roles and regulation in the brain remain poorly understood. Using high-resolution imaging and functional assays, we demonstrate that ATP7A and ATP7B show cell-specific distribution in adult cerebellum, have distinct enzymatic characteristics, and are regulated differently during development. ATP7B is continuously expressed in Purkinje neurons (PN) where it delivers copper to the ferroxidase ceruloplasmin. ATP7A is a faster copper transporter than Wilson disease protein as evidenced by faster rates of catalytic reactions. The expression of ATP7A switches during development from PN to Bergmann glia, the cells supporting PN function in adult brain. Inactivation of ATP7B (Wilson disease protein) by gene knock-out induces a striking shift in the expression of the ATP7B target protein, ceruloplasmin, from PN to Bergmann glia, where ATP7A (Menkes disease protein) is present. The induced cell-specific change in expression restores copper delivery to ceruloplasmin via ATP7A. Overall, the results provide evidence for distinct functions of ATP7A and ATP7B in the cerebellum and illustrate a tight link between copper homeostasis in PN and Bergmann glia.
15760883##2005-3-12##MR imaging of cerebral cortical involvement in aceruloplasminemia.##Aceruloplasminemia is a rare autosomal recessive disorder. The lack of ceruloplasmin ferroxidase activity leads to parenchymal and reticuloendothelial iron overload, resulting in diabetes and progressive neurodegeneration with extrapyramidal disorders, ataxia, and dementia. We describe the MR imaging findings in a 40-year-old woman with hereditary aceruloplasminemia. The abnormal T2 hypointensities were more marked than those seen in any other condition, including degenerative disorders of the basal ganglia and Wilson disease, and they may be typical of aceruloplasminemia. To our knowledge, involvement of the cortex has not been described and suggests that brain iron accumulation in aceruloplasminemia is more extensive than previously believed, even in asymptomatic patients.
15830089##2005-4-13##[Wilson's disease: clinical diagnosis and "faces of panda" signs in magnetic resonance imaging. Case report].##A 25 year-old man was admitted with polymorph symptomatology resembling basal ganglia disease associated with psychiatric manifestations. The patient had been treated with pericyazine. The drug was stopped but the symptomatology did not improve. The diagnosis of Wilson's disease was established through ophthalmologic examination with slit-lamp that revealed the Kayser-Fleischer ring and laboratory abnormalities showing a low serum ceruloplasmin level and increased urinary copper excretion. T2-weighted axial magnetic resonance imaging demonstrated the " face of panda signs" in the midbrain and pons.
15830060##2005-4-13##Status Dystonicus: study of five cases.##Status Dystonicus (SD) is characterized by generalized muscle contractions in dystonic patients. We report 5 cases of SD, two of which in patients with dystonic cerebral palsy, one in a patient with primary segmental dystonia, one in a patient with Hallervorden-Spatz syndrome and one in a patient with Wilson's disease (WD). Three patients were admitted to an intensive care unit and treated with propofol and midazolam, and two were submitted to neurosurgical procedures (bilateral pallidotomy and bilateral pallidal deep brain stimulation). Triggering factors were identified in three patients as follows: infection, stress-induced and zinc therapy for WD. On follow-up, two patients presented with significant improvement of dystonia, whereas the other three cases the clinical picture ultimately returned to baseline pre-SD condition.
15945319##2005-6-11##Deceased-donor liver transplantation: 10 years' experience at Change Gung Memorial Hospital-Kaohsiung Medical Center.##
16003865##2005-7-12##Expression of Menkes AtPase and Wilson ATPpase in different regions of the adult rat brain.##
15723329##2005-2-22##Wilson disease in septuagenarian siblings: Raising the bar for diagnosis.##Wilson Disease (WD) usually presents in the first decades of life, although rare patients have a later presentation. We report the clinical features, diagnostic evaluation, and outcome with treatment of two septuagenarian siblings evaluated as part of a research trial for treatment of neurological WD. The index case was a 72-year-old woman who suffered progressive neurological disability, then developed sub-fulminant liver failure. Her sibling was a 70-year-old man with minimal neurological symptoms and a mild depressive disorder. His liver biopsy revealed only steatosis and minimal fibrosis and an elevated hepatic copper content (671 mug/g dry weight liver). Molecular studies demonstrated compound heterozygosity for disease specific ATP7B mutations E1064A and H1069Q in both patients. Both individuals were treated with trientine and Zn followed by Zn maintenance therapy. Over the last 5 years, the clinical course stabilized and improved, although the index case recently died from bronchopneumonia. In conclusion, advanced age and different clinical presentations of these two subjects with identical ATP7B mutations raises the question of the degree of penetrance for these and other ATP7B mutations. Environmental and extragenic factors are pivotal determinants of disease phenotype. We suggest that WD must be considered at all ages in patients with hepatic disease, neurological disease, or psychiatric symptoms.
16004274##2005-7-12##[In vivo expression of copper transporting proteins in rat brain sections].##Expression of two copper-transporting P1-type ATPases (ATP7A and ATP7B), the CTR1 protein, a high-affinity copper transporter, and ceruloplasmin (CP), a copper-containing ferroxidase. The level of mRNA of these proteins was determined by RT-PCR analysis, the distribution of polypeptides encoded by these genes was determined by immunoblotting, and the type of cells expressing these genes was identified immunohistochemically. It was found that the major product of CP gene in the brain is cell membrane-bound CP. Secretory CP, whose molecule contains the greatest number of weakly associated copper atoms, is synthesized in the vascular plexus. CTR1 mRNA is evenly distributed in the brain; however, its content is twice higher in the vascular plexus. The Atp7a gene is active in all brain sections, whereas the Atp7b gene is active only in the hypothalamus. The membrane-bound CP is expressed in glial cells of all types and in ependyma cells. ATP7b and ATP7a are expressed predominantly in ependyomyocytes and neutrons, respectively. The organization of copper transport in mammalian brain is discussed.
15787078##2005-3-25##Rare auditory-electophysiology finding in Wilson's disease.##Wilson's disease is a rare genetic disease involving the malabsorption of copper by the body. The most common characteristic sign is the presence of Kayser-Fleischner ring surrounding the cornea. Other systemic and motor signs have been documented as well as MRI changes within the brain and brainstem. This rare case illustrates the potential importance of audiometric assessment for patients with Wilson's disease who complain of hearing loss, tinnitus and intra-aural pressure. Unilateral findings were significant for retrocochlear neural transmission delays.
15871305##2005-5-6##Treatment of Wilson's disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study.##Wilson's disease (WD) is an inherited disorder of copper metabolism characterized by a failure of the liver to excrete copper, leading to its accumulation in the liver, brain, cornea, and kidney, with resulting chronic degenerative changes. It is generally accepted that "presymptomatic" patients--in whom WD is diagnosed in childhood and who are defined as those who, although still asymptomatic, do have liver disease, as indicated by increased serum concentrations of transaminases--should be treated prophylactically. Here we report our results in 22 children treated with continuous oral zinc therapy for 10 years. Zinc sulfate was administered at a dosage of 25 mg elemental zinc twice a day until the age of 6 years, 25 mg three times a day between the ages of 7 and 16 years or until the child attained a body weight of 125 lb, and 50 mg three times a day thereafter. Five years after the start of zinc treatment, we noted highly significant decreases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and urinary copper excretion, but white blood cell counts did not vary significantly. Six of 22 patients continued to demonstrate greater-than-normal ALT concentrations and only 1 patient demonstrated an ALT concentration more than 1.5 times the upper normal limit. Further decreases in ALT, AST, and urinary copper excretion were observed at the end of the 10-year follow-up, but these decreases were not statistically significant. Only 1 patient continued to demonstrate abnormal ALT levels. Again, white blood cells showed no significant variations. All histologic scores (steatosis, inflammation, and fibrosis) were significantly decreased after treatment. Hepatic copper content was also significantly decreased, although it remained higher than normal in all patients. The removal of toxic copper was confirmed by disappearance of Kayser-Fleischer rings in 3 patients. Zinc did not have adverse effects on growth. The efficacy of zinc in WD in presymptomatic pediatric patients has been established in previous studies, and our study adds considerably to the earlier findings because it includes a large number of very young children, as many as 11 younger than 6 years and 20 younger than 10. The excellent clinical results in all patients, coupled with the improvement in hepatic histologic findings in the vast majority, indicate convincingly that zinc treatment can control the disease effectively and safely, preventing its progression over the course of 10 years. Histologic findings reportedly improved in 3 patients treated in an earlier study, but our data are numerically much more relevant. Notably, histologic study of the liver revealed that copper concentration was reduced by treatment, suggesting that oral zinc was able not only to prevent further accumulation of copper but also to promote, at least in part, the depletion of its stores. The lack of adverse effects of zinc on growth suggests that our patients received enough anticopper therapy to prevent damage resulting from copper toxicity but an adequate amount of copper for proper growth and development. In conclusion, our findings indicate that zinc is the treatment of choice in presymptomatic pediatric patients with WD.
15773321##2005-3-19##[Genetic disorders of copper transport--diagnosis and new treatment for the patients of Wilson's disease].##Wilson's disease and Menkes disease are inherited genetic disorders of copper metabolism. Each disease results from the absence or dysfunction of homologous copper-transporting ATPases present in the trans-Golgi network of cells. The Wilson ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, patients with Wilson's disease of the autosomal recessive trait present with signs and symptoms arising from impaired biliary copper excretion. The Menkes ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The different clinical features of each disease are the results of the tissue specific expression of these ATPases. In Wilson's disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected patients usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a results of copper accumulation in the basal ganglia and other brain regions. The diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the genes of patients with Wilson disease. Copper chelation drugs and zinc are effective in most cases. New treatment guidelines now advise physicians to start patients on zinc.
15929614##2005-6-3##[Argyria: new physio-pathological and therapeutic hypothesis].##The authors describe a case of sistemic argyria. They suggest a common physiopatologic mechanism with Wilson disease and they consider the utilization of penicillamine as a ligand for the silver, since there are not other available valid treatments.
15984949##2005-6-30##Severe hypogammaglobulinemia associated with hepatic vein stenosis causes cytomegalovirus infection after living-related liver transplantation.##Hepatic vein stenosis is a vascular complication that can lead to graft loss after liver transplantation. Although ascites frequently occurs as a symptom of hepatic vein stenosis, the development of severe hypogammaglobulinemia associated with hepatic vein stenosis has not been reported in the literature. An 8-year-old boy underwent living-related liver transplantation (LRLT) because of Wilson disease with chronic hepatic failure. Because de novo autoimmune hepatitis was diagnosed 1 year after LRLT, azathioprine, and prednisolone were added to the baseline immunosuppression of tacrolimus. The patient developed ascites with severe hypogammaglobulinemia (immunoglobulin G [IgG], 288 mg/dL) 2 years after LRLT. Ultrasonography and angiography disclosed stenosis of the hepatic vein. The ascites completely resolved after percutaneous balloon angioplasty. Despite serum IgG trough levels of >500 mg/dL maintained by the addition of immunoglobulin, cytomegalovirus reactivation and sepsis occurred. Serum IgG levels should be monitored to prevent opportunistic infections when hepatic vein stenosis is diagnosed after LRLT.
16252181##2005-10-28##Evaluation of oxidant stress in Wilson's disease and non-Wilsonian chronic liver disease in childhood.##
16201463##2005-10-6##[Analysis on prognostic factors of liver failure in children].##
15694191##2005-2-8##Is low serum tocopherol in Wilson's disease a significant symptom?##
15629136##2005-1-5##Copper-dependent toxicity in SH-SY5Y neuroblastoma cells involves mitochondrial damage.##Treatment of SH-SY5Y human neuroblastoma cells with copper sulphate (50-300microM) in complete medium for 24h caused an increase in the level of the metal both in whole cells and in isolated mitoplasts. Toxic effects of copper resulted in the impairment of the capability of mitochondrial dehydrogenases to reduce a tetrazolium salt, and, to a lesser extent, in the loss of the integrity of the plasma membrane. The mechanism of toxicity involved the production of reactive oxygen species, amplified by the presence of ascorbate. Decreases in the levels of several mitochondrial proteins (subunits of complex I, complex V, and of the pyruvate dehydrogenase complex) were observed. These findings demonstrate that mitochondria are an early and susceptible target of copper-mediated oxidative stress in neuronal cells and support the hypothesis that mitochondrial damage triggers the neurodegenerative processes associated with copper overload in Wilson's disease.
15655841##2005-1-19##Acquired hepatocerebral degeneration: a case report.##
15745378##2005-3-5##[The patient with slightly increased liver function tests].##The availability of serum blood chemistries for screening both symptomatic and asymptomatic patients has resulted in a marked increase in the number of abnormal liver chemistry tests that must be interpreted by physicians. Usually the first step in the evaluation of a patient with elevated liver enzymes is to repeat the test to confirm the result. If the result is still abnormal, it seems wise to differentiate between a predominant "necrotic pattern" of liver chemistry, as indicated by an elevation of ALT- or AST-activity or a predominant "cholestatic pattern", as indicated by elevated activities of g-GT and alkaline phosphatase. In patients with elevated serum amino transferases hepatic diseases should be excluded primarily with non-invasive serologic tests. The most common causes of elevated amino transferase levels are chronic hepatitis B and C, autoimmunhepatitis, non-alcoholic steatohepatitis, hemochromatosis, Wilson-disease and (only recently recognized) celiac sprue. In the case of a dominant "cholestatic pattern", primary biliary cirrhosis, primary sclerosing cholangitis, but also drugs and granulomatose hepatitis must be excluded. If non-invasive serologic studies remain inconclusive, ultrasound, mini-laparoscopy and liver biopsy will help to establish the final diagnoses.
15681833##2005-2-1##The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein.##Wilson disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion. Although the Wilson disease gene has been cloned, the cellular localization of the gene product (ATP7B) has not been fully clarified. Therefore, the precise physiological action of ATP7B is still unknown. We examined the distribution of ATP7B using an anti-ATP7B antibody, green fluorescent protein (GFP)-ATP7B (GFP-ATP7B) and ATP7B-DsRed in various cultured cells. Intracellular organelles were visualized by fluorescence microscopy. The distribution of ATP7B was compared with that of Rab7 and Niemann-Pick C1 (NPC1), proteins that localize in the late endosomes. U18666A, which induces the NPC phenotype, was used to modulate the intracellular vesicle traffic. GFP-ATP7B colocalized with various late endosome markers including Rab7 and NPC1 but not with Golgi or lysosome markers. U18666A induced the formation of late endosome-lysosome hybrid organelles, with GFP-ATP7B localized with NPC1 in these structures. We have confirmed that ATP7B is a late endosome-associated membrane protein. ATP7B appears to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes. Thus, defective copper ATPase activity of ATP7B in the late endosomes appears to be the main defect of Wilson disease.
15865413##2005-5-4##Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat--a feasibility study.##Copper is an essential trace element. However, excess copper can lead to oxidation of biomolecules and cell damage and copper levels must be carefully controlled. While copper homeostasis has been studied extensively at the cellular level, short-term body copper fluxes are poorly understood. Here, we assessed for the first time the feasibility of measuring whole body copper flux by positron emission tomography, using 64Cu. A comparative approach comparing the Long-Evans cinnamon (LEC) rat to the wild type was chosen. LEC rats are an accepted model for Wilson disease, an inherited disorder of copper excretion in humans. In LEC rats as well as in Wilson patients, the copper transporting ATPase, ATP7B, is defective. This ATPase is primarily expressed in the liver and serves in copper secretion via the bile. Dysfunction of ATP7B leads to accumulation of copper in the liver. A control and an LEC rat were transgastrically injected with 10 microg of 64Cu and the copper flux followed for three hours by whole animal PET and concomitant collection of bile, as well as the analysis of tissue following tomography. As seen by PET, the administered copper was largely trapped in the stomach and the proximal intestine, and without a significant difference between control and LEC rat. Due to an insufficient dynamic range of the PET technology, copper which was systemically absorbed and primarily transported to the liver could only be followed by sampling and by beta-counting. Biliary copper excretion ensued after 15 min in the control rat, but was absent in the LEC rat. Biliary excretion reached saturation one hour after copper administration. The trapping of orally administered copper in the gastrointestinal tract may be an important mechanism to prevent copper toxicity under conditions of a sudden, excessive copper load, which cannot be alleviated by increased biliary secretion. This trapping does however limit the utility of PET to measure whole animal copper flux.
15701295##2005-2-11##Wilson disease: new insights into pathogenesis, diagnosis, and future therapy.##Wilson disease is caused by disease-specific mutations of the copper transporting ATPase, ATP7B. The diagnosis is established by clinical and biochemical means, though advances in molecular diagnostics will someday permit de novo diagnosis. The patient may present with hepatic, neurologic, or psychiatric symptoms, or a combination of these. Both environmental and extragenic effects contribute to the varied phenotypic presentations of this disease. Patients can be treated effectively with chelating agents or zinc salts, or with liver transplantation. Liver cell transplant and gene therapy offer potential cures for this disorder, but at present only data from preclinical studies on animal models are available. Future advances in immunotolerization and gene therapy will likely enable human trials for treatment of this disorder and other genetic disorders of hepatic metabolism.
15661498##2005-1-22##Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases.##Metal ions accumulate in the brain with aging and in several neurodegenerative diseases. Aside from the copper storage disease, Wilson's disease, recent attention has focused on the accumulation of zinc, copper and iron in the Alzheimer's disease (AD) brain and the accumulation of iron in Parkinson's disease. In particular, the parenchymal deposition of beta-amyloid (Abeta) and its interaction with metal ions has been postulated to play a role in the progression of AD. Thus, the strategy of lowering brain metal ions and targeting the interaction of Abeta peptide and metal ions through the administration of chelators has merit. Our recent finding that nanoparticle delivery systems can cross the blood-brain barrier has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. In the present studies, the Cu (I) chelator D-penicillamine was covalently conjugated to nanoparticles via a disulfide bond or a thioether bond. Nanoparticle-chelator conjugates were stable between pH 6-8 in aqueous suspension if stored at 4 degrees C, and did not aggregate when challenged with salts and serum. Release of D-penicillamine from the nanoparticles was achieved using reducing agents such as dithiothreitol (as a model for glutathione). Nanoparticles treated only under reducing conditions that released the conjugated D-penicillamine were able to effectively resolubilize copper-Abeta (1-42) aggregates. These results indicate that nanoparticles have potential to deliver D-penicillamine to the brain for the prevention of Abeta (1-42) accumulation, as well as to reduce metal ion accumulation in other CNS diseases.
15681902##2005-2-1##Sialorrhea: a review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease.##Saliva is produced by the major salivary glands (parotid, submandibular, and sublingual), as well as several smaller glands. Salivary flow can be altered by multiple entities. There is much written regarding xerostomia ("dry mouth"), the condition related to inhibited or decreased salivary flow. This condition is widely recognized in certain systemic diseases, particularly Sjögren syndrome, diabetes mellitus, after anticholinergic, antihistamine, and decongestant medications, as well as states of enhanced sympathetic drive, such as anxiety or emotional disturbances and various other psychosocial conditions. On the other hand, sialorrhea or ptyalism, the condition of increased salivary flow, is rarely discussed in the clinical literature. Sialorrhea can occur with various neurologic disorders, infections, the secretory phase of the menstrual cycle, heavy metal poisoning, Wilson disease, Angelman syndrome, as well as a relatively unknown condition called idiopathic paroxysmal sialorrhea. Normal salivation may be altered by drugs (such as clozapine, risperidone, nitrazepam, lithium, and bethanecol) that have a cholinergic effect that induces sialorrhea. This report focuses on sialorrhea as it relates to disorders of the oropharynx and esophagus. The patient typically recognizes a problem with excessive "foamy mucus" but does not understand its origin. Infections and obstruction are the most common oropharyngeal causes. Increased salivary flow occurs as a typically subtle manifestation of gastroesophageal reflux disease. This occurrence is referred to as water brash. Idiopathic achalasia and megaesophagus due to the parasite Trypanosoma cruzi are regularly associated with sialorrhea. Esophageal obstruction (foreign body, cancer, or stricture formation), infection, and nasogastric intubation are the more common conditions associated with the symptomatic sequelae of sialorrhea. Sialorrhea-related respiratory and pulmonary complications are greatest in those with a diminished sensation of salivary flow and hypopharyngeal retention. Extremes of age, the chronically debilitated, or those in chronic care facilities, especially associated with cerebrovascular accidents and esophageal cancer, typically comprise this population. For the patient with an intact awareness of saliva, sialorrhea can present with significant social stigmas. Occult drooling or regular oral evacuation into a tissue or "spit cup" is socially incapacitating. This report provides a review of the physiology, pathogenesis, clinical manifestations, and therapeutic options for sialorrhea. Physicians and other healthcare professionals should recognize the importance of sialorrhea as a possible indicator or complication of a variety of disease states of the oropharynx and esophagus as well as its impact on the patient's physical and social quality of life.
15698392##2005-2-9##Cognition in liver disease.##
15667623##2005-1-26##Fulminant hepatic failure: Wilson's disease or autoimmune hepatitis? Implications for transplantation.##Fulminant hepatic failure (FHF) accounts for 10-15% of pediatric liver transplants in the USA annually. Because the onset of FHF may be the first presentation of Wilson's disease (WD) and autoimmune hepatitis (AIH) in previously asymptomatic adolescents, determination of the etiology of FHF is critical as treatment and prognosis differ between these two entities. Patients with AIH may be salvaged by medical treatment. On the contrary, liver transplantation is currently the only life saving therapeutic option available for patients with WD who present with fulminant liver failure. To establish the diagnosis of WD and AIH in the setting of FHF remains challenging for diagnosticians and decisions regarding liver transplantation may be necessary before a diagnosis is firmly established. We report a previously asymptomatic patient who presented with FHF and clinical and laboratory features suggestive of both WD and AIH and who underwent successful therapeutic liver transplantation before the diagnosis of WD could be confirmed.
15715949##2005-2-18##Production and characterization of monoclonal antibodies against human ceruloplasmin.##Ceruloplasmin (CP) is the major plasma antioxidant and copper transport protein. Monoclonal antibodies (mAbs) against human CP were produced and characterized. A total of five hybridoma cell lines were established (CP2, CP10, CP20, CP25, CP30). From the epitope mapping analysis, two subgroups of mAbs recognize different peptide fragments were identified. When the purified CP was incubated with the mAbs, the ferroxidase activity of CP was inhibited up to a maximum 57 %. Immunoblotting with various tissue homogenates indicated that all the mAbs specifically recognize a single protein band of 130 kDa. They also appear to be extensively cross-reactive among different mammalian including human and avian sources. These results demonstrated that only one type of immunologically similar CP is present in all of the mammalian tissues including human. The CP mAbs could be of great benefit to design the diagnostic kit for CP-related diseases such as Wilson's disease.
15719801##2005-2-22##[Diagnosis and therapy of inheritable liver diseases: hemochromatisis, Wilson's disease and alpha-1-antitrypsin deficiency].##The recent years have seen significant progress in the area of genetically determined liver diseases. For hereditary hemochromatosis, Wilson's disease and alpha-1 antitrypsin deficiency the underlying genetic defects have been described and well characterized. Although a direct relationship between genetic defect and disease manifestation exists genetic test only have a limited diagnostic usefulness which requires exact knowledge of the underlying molecular pathology. The classical C282Y and H63D mutations of the HFE gene only show a penetrance of 10-20% in hemochromatosis and are not useful for population screening. Genetic screening for ATP7B (Wilson's disease) and alpha-1 antitrypsin deficiency variants is limited by the existence of a plethora of individual mutations. Genetic tests are mainly restricted to the counseling of families in whom these diseases are present. Foremost the diagnosis of the three diseases is reached by clinical, biochemical and in some instances also histological means which are supplemented and confirmed by the use of appropriate genetic tests.
15832584##2005-4-19##Genes and metals: a deadly combination.##Wilson's disease is an autosomal recessive disease of copper metabolism, with an estimated prevalence of 1:30000. The most common presentations of WD are liver disease and neurological disturbance. For many years the diagnosis was based on the results of several clinical and biochemical tests, for which several limitations had been reported. In recent years the developments of new techniques in genetic and molecular biology have provided useful tools in the diagnosis of Wilson's disease. However, the presence of several mutations and the fact that most patients are compound heterozygote means that the problem is not completely resolved. Chelators and zinc salts have been largely used in the treatment of WD patients with a favorable outcome, but the debate continues as to the agents of first choice. Liver transplantation is a cure for patients with decompensated liver disease but its effect on the neurological outcome is still not clear.
16383225##2005-12-31##Behavioral abnormalities in Wilson's disease.##
16277669##2005-3-15##Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats.##Tetrathiomolybdate (TM), a drug developed for Wilson's disease, produces an anti-angiogenic and anti-inflammatory effect by reducing systemic copper levels. TM therapy has proved effective in inhibiting the growth of tumors in animal tumor models and in cancer patients. We have hypothesized that TM may be used for the therapy of rheumatoid arthritis and have examined the efficacy of TM on adjuvant-induced arthritis in the rat, which is a model of acute inflammatory arthritis and inflammatory cachexia. TM delayed the onset of and suppressed the severity of clinical arthritis on both paw volume and the arthritis score. Histological examination demonstrated that TM significantly reduces the synovial hyperplasia and inflammatory cell invasion in joint tissues. Interestingly, TM can inhibit the expression of vascular endothelial growth factor in serum synovial tissues, especially in endothelial cells and macrophages. Moreover, the extent of pannus formation, which leads to bone destruction, is correlated with the content of vascular endothelial growth factor in the serum. There was no mortality in TM-treated rat abnormalities. TM also suppressed inflammatory cachexia. We suggest that copper deficiency induced by TM is a potent approach both to inhibit the progression of rheumatoid arthritis with minimal adverse effects and to improve the well-being of rheumatoid arthritis patients.
16403986##2006-1-13##Copper related toxic effects on cellular protein metabolism in human astrocytes.##
15810701##2005-4-7##[Orthotopic liver transplantation in adult patients with cadaveric grafts. Experience of the Fundeni Center of General Surgery and Liver Transplantation].##We analyze the experience of the Center of General Surgery and Liver Transplantation from the Fundeni Clinical Institute (Bucharest, Romania) regarding orthotopic liver transplantation (OLT) in adult recipients, with whole liver grafts from cadaveric donors, between April 2000 (when the first successful LT was performed in Romania) and December 2004. This series includes 37 OLTs in adult recipients (16 women and 21 men, aged between 29-57 years--average 46 years). Other two LT with whole liver cadaveric grafts and two reduced-size LT were performed in children; also, in the same period, due to the acute organ shortage, other methods of LT were performed in 28 patients (21 living donor LT, 6 split LT and one "do mino" LT), that were not included in the present series. The indications for OLT were HBV cirrhosis--10, HBV+HDV cirrhosis--4, HCV cirrhosis--11, HBV+HCV cirrhosis--2, biliary cirrhosis--5, Wilson disease--2, alcoholic cirrhosis--1, non-alcoholic liver disease--1, autoimmune cirrhosis--1. With three exceptions, in which the classical transplantation technique was used, the liver was grafted following the technique described by Belghiti. Local postoperative complications occurred in 15 patients (41%) and general complications in 17 (46%); late complications were registered in 18 patients (49%) and recurrence of the initial disease in 6 patients (16%). Intrao- and postoperative mortality was 8% (3/37). There were two patients (5%) who died because of immunosuppressive drug neurotoxicity at more than 30 days following LT. Four patients (11%) died lately because of PTLD, liver venoocclusive disease, recurrent autoimmune hepatitis and liver venoocclusive disease, myocardial infarction, respectively. Thirty-four patients survived the postoperative period (92%); according to Kaplan-Meier analysis, actuarial patient-survival rate at month 31 was 75%.
15607310##2004-12-21##Identification of apo- and holo-forms of ceruloplasmin in patients with Wilson's disease using native polyacrylamide gel electrophoresis.##
15606625##2004-12-21##Contribution of Va24Vb11 natural killer T cells in Wilsonian hepatitis.##Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. There is no evidence that the WD patient's immune system attacks copper accumulated hepatocytes. Here we describe that the frequency and absolute number of Valpha24+Vbeta11+ natural killer T (NKT) cells were significantly increased in 3 cases of WD, whereas those of CD3+CD161+ NKT cells were within the normal range. Patients no. 1 and 2 had a presymptomatic form of WD. Their tissue specimens showed pathological changes of mild degeneration of hepatocytes with a few infiltrating mononuclear cells and a low degree of fatty change. Patient no. 3 displayed fulminant hepatitis with Coombs-negative haemolytic anaemia. The tissue specimens of patient no. 3 showed macronodular cirrhosis with thick fibrosis, inflammatory infiltrates and spotty necrosis. Human Valpha24+Vbeta11+ NKT cells are almost equal to CD1d-restricted NKT cells. Therefore we investigated CD1d-restricted NKT cells in the LEC rat as an animal model of WD. In LEC rats before hepatitis onset, the number and phenotype of liver NKT cells were normal. At about 4 months of age all LEC rats developed acute hepatitis accompanied by acute jaundice, and CD161high NKT cells developed in their livers. CD161highalphabetaTCRbright NKT cells developed in some of them. Their hepatitis was severe. CD161highalphabetaTCRbright NKT cells expressed an invariant rat Valpha14-Jalpha281 chain, which is CD1d-restricted. Furthermore, liver lymphocytes in the acute jaundiced LEC rats with CD161highalphabetaTCRbright NKT cells had significant and CD1d-specific cytotoxic activity.
15740174##2005-3-3##Neurologically presenting Wilson's disease: epidemiology, pathophysiology and treatment.##Wilson's disease is a rare autosomal recessive disease of copper accumulation and copper toxicity, due to mutations in the ATP7B gene, which leads to a failure of copper excretion in the bile. It presents clinically primarily as liver disease, psychiatric disease, neurological disease, or a combination of these. The neurological disease is a movement disorder, with abnormalities of speech, tremor, incoordination and dystonia being common features. Diagnosis of neurologically presenting patients is usually straightforward, with Kayser-Fleischer rings and a urine copper over 100 microg/day almost invariably present. In the treatment of neurologically presenting patients, penicillamine should always be avoided, because of the high risk of permanent, drug-induced, additional neurological deterioration. A new drug we have developed, tetrathiomolybdate, given for 8-16 weeks, in combination with zinc, is our first choice for treating these patients. In the absence of availability of tetrathiomolybdate, zinc or trientine are the next best choices.
15607932##2004-12-21##Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs.##Recent studies have demonstrated that the major Cu influx transporter CTR1 regulates tumor cell uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP), and that the two Cu efflux transporters ATP7A and ATP7B regulate the efflux of these drugs. Evidence for the concept that these platinum (Pt) drugs enter cells and are distributed to various subcellular compartments via transporters that have evolved to manage Cu homeostasis includes the demonstration of: (1) bidirectional cross-resistance between cells selected for resistance to either the Pt drugs or Cu; (2) parallel changes in the transport of Pt and Cu drugs in resistant cells; (3) altered cytotoxic sensitivity and Pt drug accumulation in cells transfected with Cu transporters; and (4) altered expression of Cu transporters in Pt drug-resistant tumors. Appreciation of the role of the Cu transporters in the development of resistance to DDP, CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs.
15604549##2004-12-18##Elastosis perforans serpiginosa associated with pseudo-pseudoxanthoma elasticum during treatment of Wilson's disease with penicillamine.##
15783020##2005-3-24##The clinical experience of Chinese patients with Wilson's disease.##
18333156##2008-3-12##Epidemiology and carcinogenesis of hepatocellular carcinoma.##The incidence of hepatocellular carcinoma (HCC) shows marked variation worldwide but the magnitude of this tumor is reflected by the occurrence of at least 1 million new cases annually and the uniformly dismal outlook with median survivals of <25 months after resection and <6 months with symptomatic treatment. The strikingly uneven distribution of this tumor parallels the prevalence of hepatitis B infection with rising incidence in western countries attributed to hepatitis C infection. Chronic hepatitis and cirrhosis constitute the major preneoplastic conditions in the majority of HCCs and may be related to other etiologic agents such as environmental chemical carcinogens including nitrites, hydrocarbons, solvents, organochlorine pesticides, and the chemicals in processed foods, cleaning agents, cosmetics and pharmaceuticals, as well as plant toxins such as anatoxins produced by fungi that cause spoilage of grain and food in the tropics. Genetic diseases such as genetic hematochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency, and the inborn errors of metabolism including hereditary tyrosinemia and hepatic porphyria, are known to be associated with HCC. Numerous genetic alterations and the modulation of DNA methylation are recognized in HCC and it is likely that these genetic and epigenetic changes combine with factors involved in chronic hepatocyte destruction and regeneration to result in neoplastic growth and multiple molecular pathways may be involved in the production of subsets of hepatocellular tumors.
15698506##2005-2-9##Wilson's disease: clinical, genetic and pharmacological findings.##Wilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation and toxicity in the liver and in other tissues. WD presents with liver disease, neurological or psychiatric disturbances or other less common clinical features. Diagnosis of WD is often difficult and may be formulated through clinical, biochemical, imaging, histochemical and genetic evaluations. Pharmacological approach in WD consists in copper chelating agents such as D-penicillamine, trientine, dimercaprol and tetrathiomolybdate. In 1997 zinc was approved for maintenance therapy of WD by the U.S. FDA. Orthotopic Liver Transplantation is indicated in fulminant hepatic failure, progressive hepatic insufficiency despite therapy, cirrhosis with complications of portal hypertension. However the most appropriate therapy, including OLT, remains controversial in WD and further studies are needed especially in order to differentiate the possibility of specific therapies for different WD phenotypes.
16240485##2005-10-22##Metabolic and endocrinological causes of dementia.##Deficiencies of vitamins B12, B3 and folate, abnormalities of cortisol metabolism, Wilson's disease, renal and hepatic failure, chronic obstructive pulmonary disease, hypo- and hypernatremia, thyroid and parathyroid dysfunction, hyper- and hypoglycemia and Marchiafava-Bignani disease are metabolic and endocrinological abnormalities that may be associated with cognitive impairment. In some cases these abnormalities may be causative of impaired cognition and in other situations merely associated with cognitive impairment. The existence of these conditions provides some justification for routine investigations commonly performed on patients presenting with possible early dementia.
15777568##2004-12-18##Wilson's disease: clinical management and therapy.##
15902551##2004-9-1##Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism.##Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.
15625427##2004-12-31##Removal of metabolites, cytokines and hepatic growth factors by extracorporeal liver support in children.##
15793350##2005-3-29##Severe autonomic dysfunction as a presenting feature of Wilson's disease.##
16052801##2005-8-2##[Prevalence of Kayser-Fleischer ring in patients with Wilson's disease].##The aim of the study was to assess prevalence of Kayser-Fleischer ring in children with Wilson's disease. 36 patients aged 7-17 years were enrolled into the study. All of them underwent ophthalmic examination by slit-lamp biomicroscopy. Kayser-Fleischer ring was found in 2 children (5.6%)--16 years old boy and girl with liver insufficiency. In addition, the girl had neurological symptoms. After 2 years of treatment K-F ring was not detected in the girl's eyes. Our data indicate that Kayser-Fleischer ring is rare in children and its absence does not exclude diagnosis of Wilson's disease.
15390041##2004-9-25##Cannabis sativa and dystonia secondary to Wilson's disease.##A patient with generalized dystonia due to Wilson's disease obtained marked improvement in response to smoking cannabis.
16391388##2005-8-13##Expression profiling of p53-target genes in copper-mediated neuronal apoptosis.##Copper toxicity associated with Wilson's disease is known to cause neuronal damage and death in the basal ganglia and frontal cortex leading to Parkinson-like symptoms and cognitive deficits. Our previous work in cultured human NTERA-2-N neurons showed that copper-induced neuronal apoptosis is dependent on the induction and nuclear translocation of the tumor suppressor protein, p53. Because p53 acts as a DNA-binding transcription factor, this work used an oligonucleotide array to identify p53 target genes that are differentially regulated in copper-loaded neurons. Arrays representing 145 human genes expressed downstream of p53 were hybridized with labeled mRNA from control and copper-treated neurons. Differentially regulated mRNAs included those involved in the regulation of the cell cycle, cytoprotective mechanisms, and apoptotic mechanisms. Transfection of cells with a dominant-negative p53 construct enabled us to determine which molecular events were dependent on p53 expression. Copper treatment resulted in the upregulation of p21, reprimo, stathmin, and Tp53INP1, all known to participate in cell cycle arrest. Protective mechanisms included the upregulation of stat-3, and the heat-shock proteins, heat-shock protein (Hsp) 70 and Hsp 27. Both p53-dependent and -independent mechanisms leading to apoptosis were identified including insulin-like growth factor binding protein-6, glutathione peroxidase, bcl-2, RB-1, PUMA, and several members of the redox active PIG family of proteins. Thus it appears that following copper-mediated neuronal DNA damage, the regulation of a variety of pro- and antiapoptotic genes are responsible for determining neuronal fate.
15589977##2004-12-14##Protection from spontaneous hepatocellular damage by N-benzyl-d-glucamine dithiocarbamate in Long-Evans Cinnamon rats, an animal model of Wilson's disease.##The Long-Evans Cinnamon (LEC) rat is a mutant strain that accumulates excessive tissue copper (Cu) and models the clinical symptoms and biological features of Wilson's disease in humans. We compared the effects of three metal chelating agents, N-benzyl-d-glucamine dithiocarbamate (BGD), d-penicillamine (D-PEN), and triethylenetetramine (TETA), on the biliary and urinary excretions of Cu using LEC rats. The animals were treated ip with each chelating agent (1 mmol/kg body weight) and then the bile and urine samples were collected for 3 h. Because single treatment with BGD markedly stimulated biliary excretion of Cu, the protective effect of repeated BGD injection on spontaneous hepatocellular damage was further examined. Separate groups received two weekly injections of BGD starting at 11 weeks of age and were compared to saline-injected controls. Serum alanine aminotransferase (ALT) activity and bilirubin level were significantly increased in control LEC rats by 19 weeks of age and histopathological analysis demonstrated extensive hepatic damage in these rats. However, repeated BGD injections prevented the increases in serum ALT and bilirubin and blocked the histopathological changes in the liver. Furthermore, although Cu rapidly accumulated in the liver, kidney, spleen, and serum of control LEC rats during the test period, repeated BGD injection largely prevented these increases. These results indicate that BGD treatment is effective in blocking excessive Cu accumulation in LEC rats that, in turn, provides protection from spontaneous liver damage.
17057792##2006-10-24##Polychromasia capsulare (multicolored capsule): report of three families.##
15769390##2005-3-17##[Ceruloplasmin level of patients with liver disease in China].##
15627313##2005-1-1##Adult-to-adult living donor liver transplantation at the Asan Medical Center.##Between February 1997 and December 2003, 580 adult-to-adult living donor liver transplants (A-A LDLTs) were performed at the Asan Medical Center for patients above 20 years of age. Indications for A-A LDLT were: chronic hepatitis B (309), chronic hepatitis C (18), hepatocellular carcinoma (144), alcoholic cirrhosis (20), Wilson's disease (4), autoimmune hepatitis (4), hepatic tuberculosis (1), cholangiocarcinoma (2), cryptogenic cirrhosis (5), secondary biliary cirrhosis (7), primary biliary cirrhosis (2), fulminant hepatic failure (18), primary sclerosing cholangitis (2), vanishing bile duct syndrome (1) and re-transplantation (4). Of 580 A-A LDLTs, 119 were of high medical urgency, 96 were for acute on chronic liver failure, 18 were for acute and subacute hepatic failure, 1 was for Wilson's disease, and 4 were for re-transplantation. Recipient age ranged from 20 to 69 years. The age of the donors ranged from 16 to 63 years. There was no donor mortality. Implanted liver grafts were categorized into seven types: 307 modified right lobes (MRL), 85 left lobes, 44 left lobe plus caudate lobes, 41 right lobes, 93 dual grafts, 5 extended right lobes, 4 posterior segments, and 1 extended left lateral segment. In the MRL, the tributaries of the middle hepatic vein were reconstructed by interpositioning a vein graft. Indication for dual graft implantation was the same as single graft A-A LDLT, and seventeen of 93 were emergency cases. As a right-sided graft, 47 received left lobes; 31 received a extended left lateral segment or a lateral segment; 13 received a right lobe with or without the reconstruction of middle hepatic vein tributaries; and 2 received a posterior segment. Graft volume ranged from 26.5% to 83% of the standard liver volume of the recipients. There were 46 (8.0%) one year mortalities among the 576 patients after 580 A-A LDLTs. Of the 119 patients who received emergency transplants, 108 (90.8%) survived. These encouraging results justify the expansion of A-A LDLT to adjust to increasing demands, even in urgent situations. We have aimed establish the efficacy of A-A LDLT in various end-stage chronic and acute liver diseases, as well as new technical advances to overcome the small-for-size graft syndrome by using dual-graft implantation and MRL, both of which were first developed in our department.
16093630##2005-8-12##Symmetrical lesions of the middle cerebellar peduncle: MR imaging and differential diagnosis.##The purpose of this paper is to show several diseases that manifest symmetrical hyperintense lesions on the middle cerebellar peduncles, the largest connecting peduncles between the brainstem and the cerebellum, in conventional magnetic resonance (MR) images. We retrospectively reviewed cranial MR images obtained with 0.3-, 0.5-, 1.0-, and 1.5-Tesla scanners. We found symmetrical middle cerebellar peduncular lesions in patients with Wilson's disease; hepatic encephalopathy; extrapontine myelinolysis; acute disseminated encephalomyelitis; wallerian degeneration of the pontocerebellar tracts after either pontine infarction, pontine hemorrhage, or central pontine myelinolysis; leukodystrophy; olivopontocerebellar atrophy; and toluene abuse. Definitive diagnosis of these diseases can be made relatively easily on the basis of clinical data; however, examination of associated brainstem or supratentorial lesions in MR images is also important.
15456785##2004-10-1##Copper inhibits the water and glycerol permeability of aquaporin-3.##Aquaporin-3 (AQP3) is an aquaglyceroporin expressed in erythrocytes and several other tissues. Erythrocytes are, together with kidney and liver, the main targets for copper toxicity. Here we report that both water and glycerol permeability of human AQP3 is inhibited by copper. Inhibition is fast, dose-dependent, and reversible. If copper is dissolved in carbonic acid-bicarbonate buffer, the natural buffer system in our body, doses in the range of those observed in Wilson disease and in copper poisoning caused significant inhibition. AQP7, another aquaglyceroporin, was insensitive to copper. Three extracellular amino acid residues, Trp128, Ser152, and His241, were identified as responsible for the effect of copper on AQP3. We have previously shown that Ser152 is involved in regulation of AQP3 by pH. The fact that Ser152 mediates regulation of AQP3 by copper may explain the phenomenon of exquisite sensitivity of human erythrocytes to copper at acidic pH. When AQP3 was co-expressed with another AQP, only glycerol but not water permeability was inhibited by copper. Our results provide a better understanding of processes that occur in severe copper metabolism defects such as Wilson disease and in copper poisoning.
15571607##2004-12-2##The other mutation is found: follow-up of an exceptional family with Wilson disease.##
15523622##2004-11-4##Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B).##Wilson disease (WND) is caused by mutations in the ATP7B gene and exhibits substantial allelic heterogeneity. In this study we report the results of molecular analyses of 20 WND families not described previously. When combined with our prior results, the cohort includes 93 index patients from 69 unrelated families. Twenty different mutations accounted for 86% of the WND chromosomes. The most frequent were p.H1069Q (35%), p.R969Q (12%), c.2530delA (7%), p.L936X (7%), p.Q289X (7%), and p.I1148T (3%). We also present here a detailed phenotypic assessment for patients whose molecular result was previously reported. Thirty cases were homozygous for 9 different mutations, 13 of which were homozygous for p.H1069Q, and 7 for p.R969Q. Mutations p.H1069Q and p.R969Q appeared to confer a milder disease as patients showed disease onset at a later age, and were associated with milder severity when found in trans with severe mutations. Predicted nonsense and frameshift mutations were associated with severe phenotypic expression with earlier disease onset and lower ceruloplasmin values. WND can be treated by copper-chelation therapy, particularly if the disease is diagnosed before irreversible tissue damage occurs. Our results on the effect of predicted nonsense and frameshift mutations are especially important for early medical intervention in presymptomatic infants and children with these genotypes.
15622480##2003-10-14##Recent clinical features of Wilson's disease with hepatic presentation.##
15541506##2004-11-16##Inhibition of key cytokines by tetrathiomolybdate in the bleomycin model of pulmonary fibrosis.##Tetrathiomolybdate is an anticopper drug with a unique mechanism of action. Tetrathiomolybdate complexes copper to protein and itself, rendering the copper unavailable for cellular uptake. It was originally developed for Wilson's disease, and is now being developed as an antiangiogenic agent for the treatment of cancer. Many angiogenic cytokines require normal levels of copper, and lowered copper levels reduce cytokine signaling while cellular copper requirements are met. Cytokines of fibrosis and inflammation may be similarly copper dependent, since tetrathiomolybdate inhibits bleomycin induced pulmonary inflammation and fibrosis. The basis for this inhibition was evaluated here by examination of tetrathiomolybdate effects on cytokines in lung pathophysiologically important in the bleomycin mouse model of pulmonary damage. Results in mice injected endotracheally with bleomycin confirmed that tetrathiomolybdate therapy was effective in reducing fibrosis. This effect was associated with significant inhibition of bleomycin-induced tumor necrosis factor alpha and transforming growth factor beta expression in lung homogenates. These effects were shown to be independent of one another. This indicates that tetrathiomolybdate therapy can be effective even when fibrosis is at a more chronic stage, wherein inflammatory cytokines are playing a diminishing role. The inhibition of tumor necrosis factor alpha suggests that diseases of tumor necrosis factor alpha overexpression are also potential targets of tetrathiomolybdate therapy.
15614251##2004-12-23##Value of an enzymatic assay for the determination of serum ceruloplasmin.##The serum concentration of the copper protein ceruloplasmin has been an important diagnostic indicator of Wilson's disease (WD). It is widely quoted that 95% of people with WD have low serum ceruloplasmin concentrations. Current evidence suggests that a normal serum ceruloplasmin concentration is more common in patients with WD, particularly those with liver disease, perhaps in part because of the routine use of an immunologic assay. This assay might indicate a normal level of ceruloplasmin when the enzymatic activity is lower. Enzymatic activity is the biologically relevant parameter. We compared the immunologic measurement with the enzymatic assessment of oxidase activity in patients with liver or neurologic symptoms of unknown origin in whom WD was considered in the differential diagnosis. Although a strong correlation of ceruloplasmin protein concentration with oxidase activity was observed in controls, this was not the case for these patients. Twelve patients, presenting with various types of hepatic disease, demonstrated a weak correlation between ceruloplasmin protein concentration and oxidase activity. Ten percent of patients with neurologic symptoms ( n = 41) had low ceruloplasmin concentrations and oxidase activity, and another 8% had normal ceruloplasmin concentrations associated with low oxidase activity. Although the enzymatic method is preferred for its biologic relevance, ceruloplasmin analysis is not a reliable diagnostic parameter for the diagnosis of WD in patients with liver disease. An important use of the ceruloplasmin oxidase assay is in the follow-up of patients with WD. Ceruloplasmin oxidase activity was undetectable in sera from patients with WD who were undergoing long-term chelation therapy, suggesting an early sign of copper depletion and a need for subsequent monitoring for symptoms of copper deficiency.
15554419##2004-11-24##Pathophysiology and clinical features of Wilson disease.##Wilson disease is an autosomal recessive inherited disorder of copper metabolism resulting in pathological accumulation of copper in many organs and tissues. ATP7B is the gene product of the Wilson disease gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. Mutations of the gene result in impaired trafficking of copper in and through the hepatocytes. More than 200 mutations of Wilson disease gene were found, the most common ones being H1069Q (in Europe) and R778L (in Asia). Wilson disease may present under a variety of clinical conditions, commonly as liver and/or neuropsychiatric disease. The pathogenesis of hepatic and neurologic Wilson disease is a direct consequence of copper accumulation. Presence of copper causes oxidative stress resulting in cell destruction. The diagnosis of Wilson disease requires a combination of a variety of clinical symptoms, biochemical tests, and detection of gene mutations, which are the basis of a score proposed by a group of international experts. Initial treatment for symptomatic patients should include a chelating agent (penicillamine or trientine). Treatment of presymptomatic patients or maintenance therapy can also be accomplished with zinc.
15390062##2004-9-25##Postural tremor in Wilson's disease: a magnetoencephalographic study.##The following study included 5 Wilson's disease (WD) patients showing a right-sided postural forearm tremor (4-6 Hz) and addressed the question of whether the primary motor cortex (M1) is involved in tremor generation. Using a 122-channel whole-head neuromagnetometer and surface electromyogram (EMG), we investigated cerebromuscular coupling. Postural tremor was observed in a sustained 45-degree posture of the right-sided forearm. Data were analyzed using dynamic imaging of coherent sources (DICS), revealing cerebromuscular coupling between EMG and cerebral activity. Coherent sources were superimposed on individual high-resolution T1-weighted magnetic resonance images (MRI). Phase lags between EMG and cerebral areas showing strongest coherence were determined by means of a Hilbert transform of both signals. In all patients, postural tremor was associated with strong coherence between tremor EMG and activity in contralateral primary sensorimotor cortex (S1/M1) at tremor or double tremor frequency. Phase lag values between S1/M1 activity and EMG revealed efferent and afferent components in the corticomuscular coupling. Taken together, our results indicate that postural tremor in WD is mediated through a pathological oscillatory drive from the primary motor cortex.
15660875##2005-1-22##Hemolytic crisis with fulminant hepatic failure in Wilson disease without consanguinity.##
15375657##2004-4-7##Juvenile cirrhosis in a 16th century Italian mummy. Current technologies in pathology and ancient human tissues.##The natural headless mummy of a young man from the Basilica of Saint Domenico Maggiore in Naples (16th century) showed at autopsy a well-preserved fibrous liver with a nodular surface, suggesting a case of cirrhosis. Stereo and light microscope study confirmed this diagnosis. To identify the possible etiology of this cirrhosis, additional techniques currently used in pathology were performed. Hemochromatosis and alpha1-antitrypsin deficiency were investigated without results. Investigation regarding Wilson's disease gave positive results, since the use of rhodamine staining, which is specific to detect the presence of copper in tissues, resulted in red-brown grains at light microscopy. The positive rhodamine test was invalidated by atomic absorption spectroscopy (AAS), which revealed normal copper levels in the tissues. These negative results and the clear and diffuse macronodularity of the liver suggest a case of post-necrotic cirrhosis.
15650792##2005-1-15##[Clinical features of liver failure in children].##
15557537##2004-11-24##Strokelike presentation of Wilson disease with homozygosity for a novel T766R mutation.##
15511628##2004-10-30##Restoration of copper metabolism and rescue of hepatic abnormalities in LEC rats, an animal model of Wilson disease, by expression of human ATP7B gene.##Hepatic abnormalities in Long-Evans Cinnamon (LEC) rats, an animal model of Wilson disease (WD), were restored by the expression of the human ATP7B cDNA under the control of CAG promoter. Expression of ATP7B transcript and protein in the liver of the transgenic rats resulted in the restoration of biosynthesis of holoceruloplasmin and biliary copper excretion. Meanwhile, transgenic rats showed striking improvements in their hepatic abnormalities, i.e., rescue from fulminant hepatitis, late onset of hepatic cholangiofibrosis, suppression of hepatocellular carcinoma and much improved survival rates. Moreover, dramatic decreases were noted both in the levels of hepatic copper and iron in transgenic rats before the occurrence of hepatitis. These results indicated that the human ATP7B product compensated for the deficiency of the endogenous rattus protein and did function in intrahepatic copper transport by secreting copper into the plasma via incorporation into ceruloplasmin and by the excretion of copper into the bile, and that ATP7B is critical to hepatic dysfunctions in WD. This first successful transgenic rescue has important implications for the gene therapy of WD.
15505300##2004-10-27##Wilson's disease with chronic active hepatitis: monitoring by in vivo 31-phosphorus MR spectroscopy before and after medical treatment.##
15541301##2004-11-16##Inhibitory effects of trientine, a copper-chelating agent, on induction of DNA strand breaks in hepatic cells of Long-Evans Cinnamon rats.##Effects of treatment with trientine, a specific copper-chelating agent, on accumulation of copper and induction of DNA strand breaks were investigated in Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. Copper accumulated in the livers of LEC rats in an age-dependent manner from 4 to 13 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, hepatic copper contents did not increase and were maintained at the same levels as those in 10-week-old LEC rats. When the amounts of DNA single-strand breaks (SSBs) were estimated by a comet assay, SSBs of DNA were induced in a substantial population of LEC rat hepatic cells around 8 weeks of age and the amounts of SSBs increased in an age-dependent manner from 8 to 15 weeks of age. When LEC rats were treated with trientine from 10 weeks of age, the observed number of cells with DNA damage decreased dramatically, suggesting that induction of SSBs of DNA was inhibited and/or SSBs were repaired during the period of treatment with trientine. The results show that treatment of LEC rats with trientine decreases the number of DNA strand breaks observed, although copper contents remain high in the liver.
15464656##2004-10-7##Wilson disease: pathophysiology, diagnosis, treatment, and screening.##Wilson disease is an autosomal recessive condition of copper metabolism that was once considered fatal. The identification of the gene for Wilson disease has led to a better understanding of the molecular defect underlying this disorder and has impacted on disease diagnosis for some individuals. Medical therapy with chelating agents or zinc salts remains the mainstay of therapy for most patients, and liver transplant is lifesaving for those with advanced disease refractory to medical therapy or with fulminant hepatic failure. Future cell-based and genetic therapies may provide a cure for this disorder.
15609699##2004-12-22##Hepatocellular carcinoma associated with Wilson's disease.##A 23-year-old man was admitted to our department due to hemorrhage from gastric varices. He had been diagnosed as having Wilson's disease at the age of 17. Abdominal ultrasonography and computed tomography (CT) showed portal thrombosis and a large mass occupying most of the right lobe in the liver. The tumor was diagnosed as hepatocellular carcinoma (HCC) by image views and tumor markers. He died 3 months after the diagnosis, and an autopsy was performed. Histologic examination of the tumor showed moderately to poorly differentiated HCC. The nontumorous lesion of the liver revealed cirrhosis. HBX-DNA sequence was not detected in the liver. Hepatic cirrhosis is a well-recognized complication of Wilson's disease, but HCC is extremely rare. We describe the clinical findings of this patient and discuss the relationship of the development of HCC with a review of the relevant literature.
15609692##2004-12-22##Wilson disease and hepatocellular carcinoma.##
15660417##2005-1-22##Proteomic analyzes of copper metabolism in an in vitro model of Wilson disease using surface enhanced laser desorption/ionization-time of flight-mass spectrometry.##In Wilson disease, mutations in the ATP7B-gene lead to hepatic accumulation of copper that becomes toxic when the hepatic binding capacity is exceeded, leading to oxidative stress and acute liver failure. Several proteins are probably involved in dealing with the excess copper and oxidative stress. As a first step towards biomarker discovery and analyzes of copper metabolism in Wilson disease patients we characterized copper-induced changes in protein expression in cell lysates and culture media from an in vitro copper-overload model using surface enhanced laser desorption/ionization (SELDI) proteomics technology. HepG2 cells were cultured for 48 h with a physiological (0.5 microM) or a pathological (100 microM) copper concentration. Samples were applied to weak cation exchange (WCX) proteinchip arrays and chips were analyzed by time of flight (TOF)-mass spectrometry. Copper-coated IMAC chips were used to detect copper-binding proteins in cell lysate of copper depleted cells using buffers with increasing imidazole concentrations. Data from the 2 to 50 kDa range indicate that high extra-cellular copper substantially altered both intra-cellular protein expression as well as the composition of the secretome. In the lysate 15 proteins were found up-regulated, while 6 proteins were down-regulated. In culture media 21 proteins were increased while 4 proteins were decreased in abundance. Copper-coated protein chips revealed the presence of 18 high-affinity copper-binding proteins. Further identification is necessary to determine the exact cellular roles of the discovered proteins.
15482536##2004-10-16##Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease.##
15519648##2004-11-3##The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis.##
15592743##2004-12-14##Serial diffusion-weighted MRI in a case of Wilson's disease with acute onset hemichorea.##
15516801##2004-11-2##[Wilson's disease and its pharmacological treatment].##Wilson's disease is an inherited copper toxicosis caused by defective putative copper transporting ATPase in the liver. Because of impaired biliary secretion, copper remains in the liver, resulting in chronic hepatic lesions including fatty metamorphosis, chronic hepatitis and cirrhosis. In the latter stage, extrapyramidal syndromes may develop with and without symptomatic hepatic lesions. Acute liver damage associated with hemolysis and deep jaundice may be the first manifestation. The majority of patients show hypoceruloplasminemia, which has been used as a screening test for the disease. A large number of mutations in the ATP7B gene have been reported. Thus, genetic diagnosis might be limitedly used to presymptomatic diagnosis of siblings when mutations are identified in an index patient. Introduction of penicillamine caused a revolution in the treatment of patients. Another chelater, trientine, is now available for those intolerant of penicillamine. Tetrathiomolibdate and zinc acetate are additional alternatives currently being tested. Hypoceruloplasminemia and further reduction after chelation therapy may be associated with iron overload. This complication is closely related with impaired transport of ferrous ion due to ferroxidase deficiency. Noncompliance and teratogenicity are other major concerns because any treatment with the agents listed above is a life long regimen. Despite various side effects of penicillamine, its teratogenicity is negligible. These data indicate that penicillamine is the first choice of drug for this disease.
15381069##2004-9-24##Copper-dependent protein-protein interactions studied by yeast two-hybrid analysis.##An important step in copper homeostasis is delivery of copper to a specific P-type ATPase in the Golgi apparatus (Ccc2 in yeast, ATP7A and ATP7B in humans) by a small copper chaperone protein (Atx1 in yeast, ATOX1 in humans). Atx1 and ATOX1 both contain an MXCXXC motif that is also present in Ccc2 (two motifs) and ATP7A/B (six motifs). Protein-protein interactions probably require coordination of one Cu(I) by cysteines from both MXCXXC motifs. We applied yeast two-hybrid analysis to screen systematically all possible interactions between MXCXXC-containing domains in these proteins. We demonstrate that ATOX1 and Atx1 preferentially interact with domains 2 and 4 of ATP7B and that Atx1 interacts with both Ccc2 domains. All combinations show a remarkable bell-shaped dependency on copper concentration that is maximal just below normal copper levels. Our results suggest that yeast two-hybrid analysis can be used to study the intracellular copper status of a cell.
15566072##2004-11-30##[Wilson disease].##Wilson disease is an autosomal, recessive inherited disorder of copper metabolism, characterized by the accumulation of copper in the body due to defective biliary copper excretion of hepatocytes. Recently, novel components involved in copper metabolism, Wilson disease protein (ATP7B) and copper chaperones, have been identified. It has been demonstrated that ATP7B functions in copper secretion into the plasma, coupled with coeruloplasmin synthesis and biliary copper excretion. Genetic testing may help early diagnosis and with the beginning of therapy the development of symptoms can be prevented. Various mutations of ATP7B have been identified, the most common is in Hungary, the H1069Q mutation. Genetic screening should only be advised if there is a predominant mutation characteristic for the geographic area. The authors discuss the modern diagnostic and therapeutic possibilities of Wilson disease.
15524314##2004-11-5##Identification of three novel insertion/deletion mutations in Wilson disease's gene.##
15459818##2004-10-2##Subchondral cyst of the tibia secondary to Wilson disease.##We present the case of a 40-year-old male patient who had been suffering from Wilson disease for over 20 years, whose knee was diagnosed as osteoarthritis combined with subchondral cyst of the tibia. Preoperative examinations (X-ray, CT and MRI) confirmed the diagnosis. The microscopic examination detected thickening of the synovial membrane, and histopathological findings revealed that lymphoid cells and plasma cells were infiltrated at the synovial membrane. On copper-specific staining, no copper pigmentation was identified. However, the energy-dispersive X-ray (EDX) microanalysis revealed copper pigmentation in high concentration. These findings may contribute to our better comprehension of the development process of the arthropathy in patients with Wilson disease. The combination of subchondral cyst with Wilson disease is extremely rare, as only about 16 such cases have been reported in the English literature.
15531840##2004-11-9##Wilson's disease--unusual features.##Two cases of Wilson's disease with unusual features are reported. In one case neurological abnormality was the presenting feature without any clinical involvement of the liver. In the other case, neurologic manifestations were associated with rickets and cholelithiasis, a result of chronic hemolytic state. Apart from clinical profile both the cases were diagnosed by grossly reduced serum ceruloplasmin level. However, Kayser-Fleischer rings were found in each case.
15448420##2004-9-28##Serum transaminases in children with Wilson's disease.##
15382286##2004-9-24##MELD/PELD and the allocation of deceased donor livers for status 1 recipients with acute fulminant hepatic failure, primary nonfunction, hepatic artery thrombosis, and acute Wilson's disease.##1. Historical perspective of donor allocation to patients with fulminant hepatic failure (FHF). 2. Predicting prognosis in patients with FHF using the London and Clichy criteria. 3. Model for end-stage liver disease (MELD) is a predictor of mortality in patients with FHF. 4. Outcomes of adults listed as Status 1 in the United States. 5. Outcomes of pediatric candidates listed as Status 1 in the United States. 6. Proposed redefinition for Status 1 in adult and pediatric candidates.
15561239##2004-11-25##Acute renal failure after cadaveric related liver transplantation.##Acute renal failure (ARF) is a frequent medical complication after liver transplantation (LT). We analyzed cadaveric related liver transplant recipients who had developed ARF early in the postoperative course. Between January 1982 and August 2003, a total of 67 patients underwent cadaveric related LT. Their mean age was 28.64 years at LT. The 67 recipients had the following indications: biliary atresia (n = 17), Wilson's disease (n = 15), hepatitis B-related liver cirrhosis (n = 14), hepatitis C-related liver cirrhosis (n = 4), primary biliary cirrhosis (n = 4), hepatitis B-related liver cirrhosis with hepatoma (n = 3), hepatitis C-related liver cirrhosis with hepatoma (n = 2), Budd-Chiari syndrome (n = 2), neonatal hepatitis (n = 1), choledochus cyst (n = 1), autoimmune cirrhosis (n = 1), neuroendocrine tumor (n = 1), and hemangioendothelioma (n = 1). Forty-nine patients received cyclosporine (CsA), azathioprine, and steroids and 18, a combination with tacrolimus (FK506). Eight (11.94%) patients developed ARF at a mean time of 17.25 days after LT. The mean peak serum creatinine was 2.24 mg%. Four of these patients had a diagnosis of hepatitis B-related liver cirrhosis; two, hepatitis C-related liver cirrhosis; one, primary biliary cirrhosis; and one, hepatitis B-related liver cirrhosis with hepatoma. The ARF etiology was multifactorial for the majority of patients. Eight ARF patients had a history of liver cirrhosis, which may be a risk factor for intraoperative ARF. ARF treatment included fluid replacement, decreased or altered immunosuppressive agents, avoiding exposure to nephrotoxic drugs, and adjusting antibiotic dosages. The majority of patients returned to normal renal function at 1 to 3 weeks after the diagnosis of ARF. No patient required dialysis and/or experienced a mortality. We conclude that the incidence of ARF is relatively low and with good outcomes. ARF etiology was multifactorial for the majority of patients, but eight patients had a history of liver cirrhosis, which may be a risk factor for intraoperative ARF. We suggest that in the early postoperative period of LT cases diagnosis and treatment of ARF are important.
15561215##2004-11-25##Successful case of adult ABO-incompatible liver transplantation: beneficial effects of intrahepatic artery infusion therapy: a case report.##
15561206##2004-11-25##Eighteen living related liver transplants for Wilson's disease: a single-center.##The aim of this study was to review our experience with living related liver transplantation (LRLT) for Wilson's disease. From January 2001 to July 2003 LRLT were performed in 18 patients with Wilson's disease, seven of whom had neurologic complications. The mean age of the patients was 13.5 +/- 2.3 years (range 6 to 20). Before transplantation all recipients displayed low serum ceruloplasmin levels (mean value = 118.4 +/- 32.6 mg/L). The serum ceruloplasmin levels increased to an average of 236.8 +/- 38.5 mg/L after LRLT at the latest evaluation, which ranged between 2 and 32 months after transplantation. A marked reduction in urinary copper excretion was observed in all recipients after transplantation. All recipients are alive and remain well. None have developed signs of recurrent Wilson's disease after a mean follow-up of 18.2 +/- 9.4 months (range 2 to 32 months). The donors were 17 mothers and one father of mean age 34.0 +/- 3.0 years (range 30 to 45 years). The serum ceruloplasmin levels were within normal limits in all donors (mean 226 +/- 27.8 mg/L). Two donors had biliary leakage and percutaneous drainage Grafts included four right lobes without the hepatic middle vein and 14 left lobe grafts with the middle vein. LRLT is a curative procedure for Wilson's disease presenting with fulminant hepatic failure and the others with end-stage hepatic insufficiency. After liver transplantation, the serum ceruloplasmin level increases to the normal range, urinary copper excretion decreases, and neurological manifestations improve to various extents.
15561202##2004-11-25##Do patients with acute liver failure have a better chance to receive liver grafting?##
15365158##2004-9-15##Effect of D-penicillamine on neuromuscular junction in patients with Wilson disease.##
15337266##2004-9-1##New mutation (T1232P) of the ATP-7B gene associated with neurologic and neuropsychiatric dominance onset of Wilson's disease in three unrelated Colombian kindred.##Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism caused by mutations in a gene encoding a copper-transporting P-type ATPase. We report the clinical and molecular characterization of six members from three unrelated Colombian kindred. Completed sequence DNA analysis linked to the gene ATP-7B from patient wd-1 revealed a novel A to C transversion in exon 17 at position 3856 (A3856C) of the ATP-7B mRNA resulting in a threonine for proline substitution at position 1232 of the ATP-7B protein (T1232P). Additionally, two novel polymorphisms were detected (2785G:Gly875 in exon 11; and intron at +38 a > c:tgcgcccga in exon 19). All affected individuals were homozygous for the T1232P mutation and displayed neurologic and neuropsychiatric dominant onset. This work expands the knowledge about the number, type, and implication of mutations in WD.
15581028##2004-12-8##Co-occurrence of Wilson's disease and glioblastoma multiforme--is it a chance association?##We report a patient with glioblastoma multiforme who was subsequently diagnosed to have Wilson's disease. Immunohistochemical studies of the tumor revealed high (> 60%) labeling index for p53 and Rb retinoblastoma protein. Whether this association is like the co-occurrence of retinoblastoma and Wilson's disease due to possible somatic mutation in chromosome 13 needs to be explored.
15487036##2004-10-16##Frequency and clinical course of hepatitis E in tertiary care hospitals.##
15337600##2004-9-1##Copper(I) interaction with model peptides of WD6 and TM6 domains of Wilson ATPase: regulatory and mechanistic implications.##With the aim to investigate the mechanism of Cu(I) transport by Wilson ATPase (ATP7B), we have studied the interaction of the peptides 2K10p (CH(3)CO-Lys-Gly-Met-Thr-Cys-Ala-Ser-Cys-Val-His-Asn-Lys-CONH(2)), and 2K8p (CH(3)CO-Lys-Leu-Cys-Ile-Ala-Cys-Pro-Cys-Ser-Lys-CONH(2)), part of the sixth metal binding domain (WD6) and the sixth transmembrane segment (TM6) of Wilson ATPase, respectively, by means of CD, NMR spectroscopy and homology modeling. In addition, the interaction of Cu(I) with the 2K8p mutants 1s (CH(3)CO-Lys-Leu-Ser-Ile-Ala-Cys-Pro-Cys-Ser-Lys-CONH(2)), 2s (CH(3)CO-Lys-Leu-Cys-Ile-Ala-Ser-Pro-Cys-Ser-Lys-CONH(2)) and 3s (CH(3)CO-Lys-Leu-Cys-Ile-Ala-Cys-Pro-Ser-Ser-Lys-CONH(2)), containing two cysteines in various positions, have been studied with the same methods, in order to understand the role of each cysteine in copper binding. Our studies show that the three cysteine thiolates present in the 2K8p peptide sequence act mainly as bridging ligands for Cu(I) binding, and dithiothreitol acts as an important ligand in Cu(I) ligation by 2K10p and the 2K8p mutants. Formation of oligomeric species has been evidenced for all peptides except 2s. Shift of the equilibrium between the various oligomeric species has been accomplished by reducing the Cu(I):peptide ratio. Significant shifts of proline protons upon interaction with Cu(I) have been observed for all proline containing peptides implying a possible role of proline in facilitating Cu(I) binding. These findings have been further discussed with respect to the molecular basis of copper trafficking and intermolecular interactions.
15205742##2004-6-19##Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients.##Wilson disease is a human disorder of copper metabolism resulting in toxic copper accumulation. Patients present with a high clinical variability, even when sharing identical mutations. MURR1, the gene causing canine copper toxicosis in Bedlington terriers, maps to chromosome 2 in humans, a region different to the Wilson gene locus. MURR1 might influence human copper metabolism and the clinical presentation of Wilson disease patients. This study analyzed MURR1 gene sequence in Wilson disease patients and MURR1 gene transcription in selected patients. Mutation analysis of three exons of the MURR1 gene including the intron-exon boundaries was performed in 63 Wilson disease patients by direct sequencing. Of the 63 Wilson patients 19 (30%) had basepair changes in the MURR1 gene. Three intronic base pair changes, one new sequence variation and two known polymorphisms were detected, including the GAT/GAC heterozygous state at codon Asn 164 in 15 (24%) of the analyzed patients. This suggests that GAT/GAC heterozygous state at codon Asn 164 is associated with an earlier onset of disease.
15518373##2004-11-3##Wilson's disease: a review.##
15470529##2004-10-8##Wilson's Disease: a challenge of diagnosis. The 5-year experience of a tertiary centre.##
15205462##2004-6-19##The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F.##Copper transport by the P(1)-ATPase ATP7B, or Wilson disease protein (WNDP),1 is essential for human metabolism. Perturbation of WNDP function causes intracellular copper accumulation and severe pathology, known as Wilson disease (WD). Several WD mutations are clustered within the WNDP nucleotide-binding domain (N-domain), where they are predicted to disrupt ATP binding. The mechanism by which the N-domain coordinates ATP is presently unknown, because residues important for nucleotide binding in the better characterized P(2)-ATPases are not conserved within the P(1)-ATPase subfamily. To gain insight into nucleotide binding under normal and disease conditions, we generated the recombinant WNDP N-domain and several WD mutants. Using isothermal titration calorimetry, we demonstrate that the N-domain binds ATP in a Mg(2+)-independent manner with a relatively high affinity of 75 microm, compared with millimolar affinities observed for the P(2)-ATPase N-domains. The WNDP N-domain shows minimal discrimination between ATP, ADP, and AMP, yet discriminates well between ATP and GTP. Similar results were obtained for the N-domain of ATP7A, another P(1)-ATPase. Mutations of the invariant WNDP residues E1064A and H1069Q drastically reduce nucleotide affinities, pointing to the likely role of these residues in nucleotide coordination. In contrast, the R1151H mutant exhibits only a 1.3-fold reduction in affinity for ATP. The C1104F mutation significantly alters protein folding, whereas C1104A does not affect the structure or function of the N-domain. Together, the results directly demonstrate the phenotypic diversity of WD mutations within the N-domain and indicate that the nucleotide-binding properties of the P(1)-ATPases are distinct from those of the P(2)-ATPases.
15326235##2004-8-25##Clinical correlation of brain MRI and MRS abnormalities in patients with Wilson disease.##
15147237##2004-5-19##Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations.##WNDP (Wilson's disease protein) is a copper-transporting ATPase that plays an essential role in human physiology. Mutations in WNDP result in copper accumulation in tissues and cause a severe hepato-neurological disorder known as Wilson's disease. Several mutations were surmised to affect the nucleotide binding and hydrolysis by WNDP; however, how the nucleotides bind to normal and mutated WNDP remains unknown. To aid such studies, we performed the molecular modelling of the spatial structure and dynamics of the ATP-binding domain of WNDP and its interactions with ATP. The three-dimensional models of this domain in two conformations were built using the X-ray structures of the Ca2+-ATPase in the E1 and E2 states. To study the functional aspects of the models, they were subjected to long-term molecular dynamics simulations in an explicit solvent; similar calculations were performed for the ATP-binding domain of Ca2+-ATPase. In both cases, we found large-scale motions that lead to significant changes of distances between several functionally important residues. The ATP docking revealed two possible modes of ATP binding: via adenosine buried in the cleft near residues H1069, R1151 and D1164, and via phosphate moiety 'anchored' by H-bonds with residues in the vicinity of catalytic D1027. Furthermore, interaction of ATP with both sites occurs if they are spatially close to each other. This may be achieved after relative domain motions of the 'closure' type observed in molecular dynamics simulations. The results provide a framework for analysis of disease mutations and for future mutagenesis studies.
15469163##2004-10-8##Cavernous transformation of the portal vein causing jaundice, presenting in the form of Wilson's disease.##The following is a case review of portal vein cavernous malformation presenting with intermittent cholestasis and jaundice in a 4 year old child. Correct assessment was supported by radiology, later laparoscopy, yet hindered by histopathology representative Wilson's disease and elevated urinary copper excretion. During surgical procedure the stenosis of the common bile duct secondary to extremely dilated portal vein reticulation was solved by Roux-en-Y choledochojejunostomy. After a one-year follow up the child remains asymptomatic.
15274886##2004-7-28##[Osteoarthropathy in three siblings with Wilson's disease].##Osteoarthropathies are one of the less usual manifestations of Wilson's disease. They appear in different forms such as osteoporosis (the most frequent), inflammatory changes in small joints, osteomalacia, osteoarthritis in younger ages, spine osteochondritis, fractures and heterotopic ossification. This article describes the different osteoarthropathies in three children: two brothers and one sister with Wilson's disease that first manifested in early childhood with severe neurological signs. After drug treatment and an intense rehabilitation program, the clinical signs stabilized. During the course of the disease, all three children presented fractures of the ulna and radius after low energy trauma, several heterotopic ossifications, some of which were asymptomatic, and inflammatory processes such as hip synovitis and reduction in mineral bone density. The etiology of this kind of manifestation is not yet clear, although the most widely accepted explanation is alteration in calcium and phosphate metabolism.
15321772##2004-8-24##[Postoperative complications after orthotopic liver transplantation: clinical analysis of 18 cases].##
15313676##2004-8-18##Pathological changes and clinical manifestations of 1020 children with liver diseases confirmed by biopsy.##
15457968##2004-10-2##[Hereditary liver diseases].##In recent years the identification and characterization of gene defects underlying hereditary liver diseases lead to a better understanding of their pathogenesis. Heditary hemochromatosis, Wilson's disease and alpha1-antitrypsin deficiency are the most common hereditary liver diseases. While gene defects and disease manifestation may correlate, genetic testing is generally not contributing to diagnosis. This review summarizes the clinical manifestations, diagnosis and therapy of the most frequent hereditary liver diseases: hereditary hemochromatosis, Wilson's disease and alpha1-antitrypsin deficiency.
15130608##2004-5-8##In vitro assessment of copper-induced toxicity in the human hepatoma line, Hep G2.##Copper, though essential, is highly toxic when present in excess, as in Wilson disease, a genetic disorder of hepatic copper metabolism. We hypothesized that mitochondria are a major target of copper-induced cytotoxicity in Wilson disease. We used the human hepatoma line Hep G2 to examine copper-mediated cytotoxicity and three different methods to assess organelle damage: MTT assay (mitochondria), neutral red (NR; lysosomes) and Trypan blue exclusion assay (TB; plasma membrane). For all assays, cells at approximately 60% confluence in microtitre plates were incubated with CuCl(2) (concentration range: 50-100-150-200 microM) for 24 or 48 h. Results were expressed as percent of untreated control. At 24 h, cytotoxicity as detected by NR assay was significantly higher at all concentrations of copper than for MTT or TB ( p<0.005 at all concentrations). Cytotoxicity as detected by MTT was higher than that detected by TB at all concentrations except at 200 microM (p<0.05 for 50 microM, p<0.005 for 100 microM, p = 0.001 for 150 microM). Results at 48 h were similar (NR versus others: p <0.001 MTT versus TB: NS except at 150 microM where p<0.01). We investigated reactive oxygen species (ROS) production in copper-associated hepatocytoxicity by incubating sub-confluent cells with 2('),7(')-dichlorodihydrofluorescein diacetate dye plus copper (concentration range: 0-200 microM) for 1-1.5 h. Copper, but not zinc, produced significant increases in ROS (p<0.001). In summary, Hep G2 lysosomes appeared more susceptible to Cu-mediated damage than mitochondria; the cell membrane was highly resistant to damage.
15205951##2004-6-19##Wilson disease.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Since daily copper intake exceeds the body's requirements, effective means of excreting excess copper are essential. These are accomplished by ATP7B, a new member of the cation-transporting p-type ATPase family, which is mainly expressed in the liver and mediates both copper secretion into plasma (coupled with ceruloplasmin synthesis) and its excretion into bile. Thus far, more than 200 mutations of the WD gene have been detected, causing impairment of ATP7B function and, ultimately, copper accumulation. Excess copper, however, induces free-radical reactions and lipid peroxidation. Resultant liver damage leads to steatosis, inflammation, cirrhosis, and, occasionally, fulminant liver failure. The diagnosis of WD is commonly made on the basis of typical clinical and laboratory findings, including low serum ceruloplasmin, increased urinary copper excretion, and increased hepatic copper content. Since liver morphology is non-specific, and copper histochemistry may lead to both false-negative and false-positive results, the pathologist usually only suspects the disease or assists in its confirmation. Although the value of molecular genetic testing is limited due to the high number of possible gene mutations, polymerase chain reaction may be useful for the evaluation of family members of homozygous index patients.
15216551##2004-6-25##Infant with severe penicillamine embryopathy born to a woman with Wilson disease.##We report a chromosomally normal infant boy with congenital diffuse cutis laxa, severe micrognathia, contractures of all limbs, and central nervous system abnormalities including agenesis of the corpus callosum, born to a woman taking D-penicillamine (DP) for Wilson disease (WD) throughout her pregnancy. His postnatal course was remarkable for chronic lung disease, profound developmental delays, and probable cortical blindness, as well as resolution of his cutis laxa. Embryopathy is a rare complication in babies born to pregnant women treated with DP, and there have been only seven previous reports of birth defects in exposed infants (three of which had favorable postnatal outcomes). The etiology of the severe outcome in this boy is unclear, but prenatal measurement of maternal copper and zinc levels may be indicated for management.
15178679##2004-6-5##PINA is essential for growth and positively influences NIMA function in Aspergillus nidulans.##The phospho-Ser/Thr-directed prolyl-isomerase Pin1 was originally identified in vertebrate systems as a negative regulator of NIMA, a Ser/Thr protein kinase that regulates the G(2)/M transition in Aspergillus nidulans. Here we explore the physiological roles of the Pin1 orthologue, PINA, in A. nidulans and evaluate the relevance of the interaction of PINA with NIMA in this fungus. We find pinA to be an essential gene in A. nidulans. In addition, when PINA levels are reduced 50-fold the cells grow at a reduced rate. Upon germination under conditions that repress PINA expression, the cells are delayed in the interphase activation of NIMX(cdc2), whereas they traverse the other phases of the cell cycle at a similar rate to controls. These results indicate that a marked reduction of PINA results in a lengthening of G(1). Additionally, PINA repression increases the rate at which the cells enter mitosis following release from a hydroxyurea arrest without altering the sensitivity of the fungus to agents that activate the replication or DNA damage checkpoints. In contrast to predictions based on Pin1, the physical interaction between PINA and NIMA is primarily dependent upon the prolylisomerase domain of PINA and the C-terminal 303 amino acids of NIMA. Finally, reduction of PINA levels exacerbates the nimA5 temperature-sensitive mutant, whereas overexpression of PINA decreases the severity of this mutation, results that are consistent with a positive genetic interaction between PINA and NIMA. Thus, although PINA is essential and positively regulates NIMA function, A. nidulans is most sensitive to a reduction in PINA concentration in G(1) rather than in G(2)/M.
15276868##2004-7-28##Copper induces histone hypoacetylation through directly inhibiting histone acetyltransferase activity.##The abnormal accumulation of Cu2+ is closely correlated with the incidence of different diseases, such as Alzheimer's disease and Wilson disease. To study in vivo functions of Cu2+ will lead to a better understanding of the nature of these diseases. In the present study, effect of Cu2+ on histone acetylation was investigated in human hepatoma cells. Exposure of cells to Cu2+ resulted in a significant decrease of histone acetylation, as indicated by the decrease of the overall histone acetylation and the decrease of histone H3 and H4 acetylation. Since histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlled the state of histone acetylation in vivo, we tested their contribution to the inhibition of Cu2+ on histone acetylation. One hundred nanomolar trichostatin A, the specific inhibitor of HDAC, did not attenuate the inhibitory effect of Cu2+ on histone acetylation. Combined with that Cu2+ showed no effect on the in vitro activity of HDAC, these results led to the conclusion that it is HAT, but not HDAC that is involved in Cu2+ -induced histone hypoacetylation. This conclusion was confirmed by the facts that (1) Cu2+ significantly inhibited the in vitro activity of HAT, (2) Cu2+ -treated cells possessed a lower HAT activity than control cells, and (3) 50 or 100 microM bathocuproine disulfonate, a chelator of Cu2+, significantly attenuated the inhibition of Cu2+ on HAT activity and histone acetylation in the similar pattern. Combined with that Cu2+ showed no or obvious cytotoxicity at 100 or 200 microM in human hepatoma cells, and the previous study that Cu2+ inhibits the histone H4 acetylation of yeast cells at nontoxic or toxic levels, the data presented here suggest that inhibiting histone acetylation is probably one general in vivo function of Cu2+, where HAT is its molecular target.
15194000##2004-6-15##Cellular pharmacology of cisplatin in relation to the expression of human copper transporter CTR1 in different pairs of cisplatin-sensitive and -resistant cells.##The molecular mechanism of cisplatin uptake remains poorly defined and impaired drug accumulation may be implicated in the acquisition of resistance to cisplatin. Thus, we used cell lines of different tumor types (ovarian carcinoma A2780 and IGROV-1, osteosarcoma U2-OS, cervix squamous cell carcinoma A431) and stable cisplatin-resistant sublines, exhibiting variable levels of resistance (between 2.5 and 18.4), to investigate the mechanisms of cellular accumulation of cisplatin. Among the resistant lines we found that reduced cisplatin uptake was a common feature and ranged between 23 and 76%. In an attempt to examine the role of human copper transporter 1 (CTR1) in cisplatin accumulation by human cells, we selected the well characterized A431 cell line and the resistant variant A431/Pt. As compared with A431/Pt cells, A431/Pt transfectants overexpressing CTR1 (3.4-fold) exhibited increased uptake of copper, thereby supporting the expression of a functional transporter. However, no changes in cisplatin uptake and cellular sensitivity to drug were observed. Also overexpression of CTR1 in A431 cells did not produce modulation of cisplatin accumulation. An analysis of the expression of other factors that could affect drug accumulation indicated that A431/Pt cells displayed increased expression of ATPase, Cu(2+) transporting, alfa polypeptide. In conclusion, our results indicate that the overexpression of a functional CTR1 in a human cell line characterized by impaired cisplatin uptake fails (a) to restore cellular drug accumulation to the level of the parental cell line and (b) to modulate cisplatin sensitivity. Our data are consistent with the interpretation that the defects in cellular accumulation by resistant cells are not mediated by expression of CTR1, that plays a marginal role, if any, in cisplatin transport.
15367380##2004-9-16##Comparison of urinary excretion of phenolsulfonphthalein in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Wistar rats: involvement of primary active organic anion transporter.##
15249607##2004-7-14##Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.##
15298280##2004-8-10##[Grave's disease associated with Wilson disease].##
15133031##2004-5-11##A novel role for the immunophilin FKBP52 in copper transport.##FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans-isomerase (PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library. We identified an interaction between FKBP52 domain I and Atox1, a copper-binding metallochaperone. Atox1 interacts with Menkes disease protein and Wilson disease protein (WD) and functions in copper efflux. The interaction between FKBP52 and Atox1 was observed in both glutathione S-transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506. Interestingly, the FKBP52/Atox1 interaction was enhanced when HEK 293T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, bathocuproine disulfate, suggesting that the interaction is regulated in part by intracellular copper. Overexpression of FKBP52 increased rapid copper efflux in (64)Cu-loaded cells, as did the overexpression of WD transporter. Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity.
15240550##2004-7-9##Confocal microscopic analysis of the interaction between cisplatin and the copper transporter ATP7B in human ovarian carcinoma cells.##Some cisplatin (DDP)-resistant cells overexpress the copper export transporter ATP7B, and cells molecularly engineered to overexpress ATP7B are resistant to DDP. The interaction of Cu with ATP7B normally triggers its relocalization from the perinuclear region to more peripheral vesicles. To investigate the interaction of DDP with ATP7B, we examined the effect of DDP on the subcellular localization of ATP7B using human ovarian carcinoma cells expressing a cyan fluorescent protein (ECFP)-tagged ATP7B (2008/ECFP-ATP7B). ATP7B expression was confirmed in 2008/ECFP-ATP7B cells by Western blotting, and its functionality was documented by showing that it rendered the cells 1.9-fold resistant to CuSO(4) and 4.1-fold resistant to DDP and also reduced the accumulation of both drugs. There was greater sequestration of Pt into intracellular vesicles in the 2008/ECFP-ATP7B cells than in the 2008/ECFP cells. Confocal digital microscopy revealed that ECFP-ATP7B localized in the perinuclear region in absence of drug exposure and that both Cu and DDP triggered relocalization to more peripheral vesicular structures. A fluorescein-labeled form of DDP that retained cytotoxicity and was subject to the same mechanisms of resistance as DDP colocalized with ECFP-ATP7B in the 2008/ECFP-ATP7B cells, whereas the same fluorochrome lacking the DDP moiety did not. These results provide evidence that DDP directly interacts with ATP7B to trigger its relocalization and that ATP7B mediates resistance to DDP by sequestering it into vesicles of the secretory pathway for export from the cell.
15193985##2004-6-15##Comparison of ultrafiltration and solid phase extraction for the separation of free and protein-bound serum copper for the Wilson's disease diagnosis.##
15645994##2005-1-14##Cardiac involvement in Wilson's disease--an electrocardiographic observation.##
15645993##2005-1-14##Wilson's disease.##
15645987##2005-1-14##Early white matter changes in Wilson disease.##We describe a 12 years old male who presented with one year history of cognitive decline with extrapyramidal features. Wilson disease was diagnosed on basis of biochemical studies and MRI. MRI showed increased signal intensity on T2 weighted images in basal ganglia and supratentorial with infratentorial gray and white matter. Our patient developed white matter changes early in course of disease.
15213293##2004-6-24##Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B.##The copper efflux transporters ATP7A and ATP7B sequester intracellular copper into the vesicular secretory pathway for export from the cell. The influence of these transporters on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin was investigated using human Menkes' disease fibroblasts (Me32a) that do not express either transporter and sublines molecularly engineered to express either ATP7A (MeMNK) or ATP7B (MeWND). Cellular copper levels were significantly higher in the Me32a cells than in the MeMNK and MeWND sublines. These transporter-proficient sublines were resistant to the cytotoxic effect of copper, cisplatin, and carboplatin but were hypersensitive to oxaliplatin. Whole-cell accumulation of platinum after a 24-h exposure was significantly increased in the MeMNK and MeWND cells for all three platinum drugs, but this was accompanied by an increase in the amount of platinum reaching the DNA only for oxaliplatin. Vesicles isolated from MeMNK cells contained more platinum after exposure to cisplatin and carboplatin, whereas the platinum content of vesicles from MeWND cells was increased after exposure to all three drugs. Although copper triggered relocalization of ATP7A from the perinuclear region to more peripheral locations, the platinum drugs did not. These results demonstrate that both ATP7A and ATP7B modulate the pharmacodynamics of all three clinically used platinum drugs. The data are consistent with the hypothesis that these copper exporters sequester the platinum drugs into subcellular compartments, limiting their cytotoxicity, similar to their effect on copper. However, in this model system, although copper is readily exported after vesicular sequestration, the platinum drugs are not.
15135234##2004-5-12##Expression and localization of menkes and Wilson copper transporting ATPases in human placenta.##Copper is an essential trace element necessary for normal growth and development. During pregnancy, copper is transported from the maternal circulation to the fetus by mechanisms which have not been clearly elucidated. Two copper transporting ATPases, Menkes (ATP7A; MNK) and Wilson (ATP7B; WND) are known to be expressed in the placenta and are thought to have a role in copper transport to the fetus. In this study, the expression and localization of the MNK and WND proteins in the human placenta were investigated in detail using immunoperoxidase and double-label immunohistochemistry. MNK and WND are differentially localized within the placenta. MNK is present in the syncytiotrophoblast, the cytotrophoblast and the fetal vascular endothelial cells whereas WND is only in the syncytiotrophoblast. Placental levels of both proteins, measured by Western blot analysis, did not change across pregnancy. These data offer some insights into possible roles for MNK and WND within the placenta.
15158437##2004-5-26##Determination of amino acid pairs sensitive to variants in human copper-transporting ATPase 2.##In this study, we use our probabilistic approach to analyze the amino acid pairs in human copper-transporting ATPase 2 (ATP7B) in order to determine which amino acid pairs are more sensitive to 125 variants from missense mutant human ATP7B. The results show 97.6% of 125 variants occur at randomly unpredictable amino acid pairs, which account for 80.9% of amino acid pairs in ATP7B, and the chance of occurring of variant is about 9 times higher in randomly unpredictable amino acid pairs than in predictable pairs. Thus, the randomly unpredictable amino acid pairs are more sensitive to variants in human ATP7B.
15078884##2004-4-14##A mutational study in the transmembrane domain of Ccc2p, the yeast Cu(I)-ATPase, shows different roles for each Cys-Pro-Cys cysteine.##Ccc2p is homologous to the human Menkes and Wilson copper ATPases and is herein studied as a model for human copper transport. Most studies to date have sought to understand how mutations in the human Menkes or Wilson genes impair copper homeostasis and induce disease. Here we analyze whether eight conserved amino acids of the transmembrane domain are important for copper transport. Wild-type Ccc2p and variants were expressed in a ccc2-Delta yeast strain to check whether they were able to restore copper transport by complementation. Wild-type Ccc2p and variants were also expressed in Sf9 cells using baculovirus to study their enzymatic properties on membrane preparations. The latter system allowed us to measure a copper-activated ATPase activity of about 20 nmol/mg/min for the wild-type Ccc2p at 37 degrees C. None of the variants was as efficient as the wild type in restoring copper homeostasis. The mutation of each cysteine of the (583)CPC(585) motif into a serine resulted in nonfunctional proteins that could not restore copper homeostasis in yeast and had no ATPase activity. Phosphorylation by ATP was still possible with the C583S variant, although it was not possible with the C585S variant, suggesting that the cysteines of the CPC motif have a different role in copper transport. Cys(583) would be necessary for copper dissociation and/or enzyme dephosphorylation and Cys(585) would be necessary for ATP phosphorylation, suggesting a role in copper binding.
14998371##2004-3-5##Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites.##The Wilson protein (ATP7B) is a copper-transporting CPx-type ATPase defective in the copper toxicity disorder Wilson disease. In hepatocytes, ATP7B delivers copper to apo-ceruloplasmin and mediates the excretion of excess copper into bile. These distinct functions require the protein to localize at two different subcellular compartments. At the trans-Golgi network, ATP7B transports copper for incorporation into apo-ceruloplasmin. When intracellular copper levels are increased, ATP7B traffics to post-Golgi vesicles in close proximity to the canalicular membrane to facilitate biliary copper excretion. In the present study, we investigated the role of the six N-terminal MBSs (metal-binding sites) in the trafficking process. Using site-directed mutagenesis, we mutated or deleted various combinations of the MBSs and assessed the effect of these changes on the localization and trafficking of ATP7B. Results show that the MBSs required for trafficking are the same as those previously found essential for the copper transport function. Either MBS 5 or MBS 6 alone was sufficient to support the redistribution of ATP7B to vesicular compartments. The first three N-terminal motifs were not required for copper-dependent intracellular trafficking and could not functionally replace sites 4-6 when placed in the same sequence position. Furthermore, the N-terminal region encompassing MBSs 1-5 (amino acids 64-540) was not essential for trafficking, with only one MBS close to the membrane channel, necessary and sufficient to support trafficking. Our findings were similar to those obtained for the closely related ATP7A protein, suggesting similar mechanisms for trafficking between copper-transporting CPx-type ATPases.
15182193##2004-6-9##Repair kinetics of trans-4-hydroxynonenal-induced cyclic 1,N2-propanodeoxyguanine DNA adducts by human cell nuclear extracts.##trans-4-Hydroxynonenal (HNE) is a major peroxidation product of omega-6 polyunsaturated fatty acids. The reaction of HNE with DNA produces four diastereomeric 1,N(2)-gamma-hydroxypropano adducts of deoxyguanosine (HNE-dG); background levels of these adducts have been detected in tissues of animals and humans. There is evidence to suggest that these adducts are mutagenic and involved in liver carcinogenesis in patients with Wilson's disease and in other human cancers. Here, we present biochemical evidence that in human cell nuclear extracts the HNE-dG adducts are repaired by the nucleotide excision repair (NER) pathway. To investigate the recognition and repair of HNE-dG adducts in human cell extracts, we prepared plasmid DNA substrates modified by HNE. [(32)P]-Postlabeling/HPLC determined that the HNE-dG adduct levels were approximately 1200/10(6) dG of plasmid DNA substrate. We used this substrate in an in vitro repair-synthesis assay to study the complete repair of HNE-induced DNA adducts in cell-free extracts. We observed that nuclear extracts from HeLa cells incorporated a significant amount of alpha[(32)P]dCTP in DNA that contained HNE-dG adducts by comparison with UV-irradiated DNA as the positive control. Such repair synthesis for UV damage or HNE-dG adducts did not occur in XPA cell nuclear extracts that lack the capacity for NER. However, XPA cells complemented with XPA protein restored repair synthesis for both of these adducts. To verify that HNE-dG adducts in DNA were indeed repaired, we measured HNE-dG adducts in the post-repaired DNA substrates by the [(32)P]-postlabeling/HPLC method, showing that 50-60% of HNE-dG adducts were removed from the HeLa cell nuclear extracts after 3 h at 30 degrees C. The repair kinetics indicated that the excision rate is faster than the rate of gap-filling/DNA synthesis. Furthermore, the HNE-dG adduct isomers 2 and 4 appeared to be repaired more efficiently at early time points than isomers 1 and 3.
14742317##2004-1-27##Immunohistochemical detection of 1,N6-ethenodeoxyadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis.##Increased oxidative stress and lipid peroxidation (LPO) are implicated in multistage carcinogenesis. Recent studies have shown that LPO-derived reactive hydroxyalkenals can form promutagenic exocyclic etheno-DNA adducts in vivo. Such DNA damage was found to be increased in the liver of patients with metal storage diseases and in colon adenomas of familial adenomatous polyposis patients. We now have investigated the levels of 1,N(6)-ethenodeoxyadenosine (epsilon dA) in human liver samples obtained from a group of patients diagnosed with hepatitis, fatty liver, fibrosis and cirrhosis, primary hemochromatosis and Wilson's disease. Using an immunohistochemical method, the relative mean pixel intensity of randomly selected nuclei was measured by imaging software; positively stained cell nuclei (arbitrary mean pixel intensity > or =0.5) were counted. Prevalence of epsilon dA (%) was calculated from the ratio of a number of positively stained cell nuclei over a total number of cells counted. When compared with normal livers (3.1%), the percent prevalence (means) was significantly higher in specimens of alcoholic fatty liver (15%) and fibrosis patients (50%) but not in samples with hepatitis (induced by various factors) (6.2%). The percent prevalence in alcohol fibrosis was as high as in the liver from Wilson's disease (50.7%) and hemochromatosis (33%) patients. This is the first demonstration of increased epsilon dA in human liver diseases due to alcohol abuse. We conclude that excessive hepatic DNA damage, as assessed by miscoding etheno-DNA adduct in the nuclei of liver biopsies, is probably caused by alcohol-induced oxidative stress and LPO. In cancer-prone liver diseases (fatty liver, cirrhosis/fibrosis) such damage may act as a driving force towards malignancy.
15163301##2004-5-28##Copper deficiency as an anti-cancer strategy.##Copper is a tightly regulated trace element. Disruptions of copper homeostasis are rare and they cause serious disorders such as Wilson's disease and Menkes disease. Copper also plays an important role in promoting physiological and malignant angiogenesis. Formation of new blood vessels by a tumor enables tumor growth, invasion and metastasis. The copper chelator tetrathiomolybdate (TM), which quickly and effectively depletes copper stores, is under investigation as an anti-angiogenic agent. Promising results in vitro, in pre-clinical animal models and in an early (phase I) clinical trial have led to ongoing phase II evaluation of TM in patients with advanced cancers.
15645960##2005-1-14##Wilson's disease.##
15278187##2004-7-28##Outcome predictors of fulminant hepatic failure in children.##
15192648##2004-6-12##Metal contents of liver parenchyma after percutaneous ethanol injection or radiofrequency ablation in patients with hepatocellular carcinoma before and after trientine hydrochloride therapy.##We administered trientine hydrochloride, a drug used in the treatment of Wilson's disease, to patients with hepatocellular carcinoma after radical treatment with percutaneous ethanol injection or radiofrequency ablation, and examined its effect on the reduction of liver-tissue copper content. We enrolled 24 patients with 3 or fewer primary lesions of Child class A or B hepatocellular carcinoma with diameters of 3 cm or less who had undergone radical treatment with percutaneous ethanol injection or radiofrequency ablation. Trientine hydrochloride was orally administered in a single daily dose of 250 mg to 12 patients before a meal (at fasting, group 1) or at a total daily dosage of 750 mg, divided into 3 doses, to 12 patients (group 2). This study was a randomized between-groups comparative study of 12 weeks' duration. We used the particle-induced x-ray-emission method to determine liver-tissue mineral content. Urine copper and serum mineral levels were also measured, and transaminase levels were examined. Liver-tissue copper content decreased significantly, to 160.1 microg/g dry weight, after treatment, compared with the pretreatment level of 306.8 microg/g dry weight (P <.05). We detected no significant difference in iron or zinc content before and after treatment. The copper content was significantly reduced after treatment in both groups (P <.05). The urine copper level was significantly increased after 1 week of treatment but decreased thereafter. Serum copper levels were significantly reduced after treatment (P <.01). We detected no significant difference in transaminase level before and after treatment. Iron-deficiency anemia in 1 patient after 12 weeks' treatment was the only adverse reaction, and it was improved by the administration of an iron product. We noted no other overt adverse reactions. In patients with hepatocellular carcinoma, trientine hydrochloride therapy may significantly reduce copper content in liver tissue.
15146013##2004-5-18##Wilson's disease: diagnostic errors and clinical implications.##
15524050##2004-11-5##[Late onset Wilson's disease].##
15166653##2004-5-29##Serum ceruloplasmin and ferroxidase activity are not decreased in hepatic failure related to alcoholic cirrhosis: clinical and pathophysiological implications.##
15122704##2004-5-4##Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo.##Wilson's disease results from mutations in the P-type Cu(2+)-ATPase causing Cu(2+) toxicity. We previously demonstrated that exposure of mixed neuronal/glial cultures to 20 microM Cu(2+) induced ATP loss and death that were attenuated by mitochondrial substrates, activators, and cofactors. Here, we show differential cellular sensitivity to Cu(2+) that was equalized to 5 microM in the presence of the copper exchanger/ionophore, disulfiram. Because Cu(2+) facilitates formation of oxygen radicals (ROS) which inhibit pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), we hypothesized that their inhibition contributed to Cu(2+)-induced death. Toxic CU(2+) exposure was accompanied by early inhibition of neuronal and hepatocellular PDH and KGDH activities, followed by reduced mitochondrial transmembrane potential, DeltaPsi(M). Thiamine (1-6 mM), and dihydrolipoic acid (LA, 50 microM), required cofactors for PDH and KGDH, attenuated this enzymatic inhibition and subsequent death in all cell types. Furthermore, liver PDH and KGDH activities were reduced in the Atp7b mouse model of Wilson's disease prior to liver damage, and were partially restored by oral thiamine supplementation. These data support our hypothesis that Cu(2+)-induced ROS may inhibit PDH and KGDH resulting in neuronal and hepatocellular death. Therefore, thiamine or lipoic acid may constitute potential therapeutic agents for Wilson's disease.
15202786##2004-6-19##Rapid detection of mutations in Wilson disease gene ATP7B by DNA strip technology.##Wilson disease leads to severe hepatic and neurological pathology resulting from cellular copper overload in the respective tissue. Although the affected gene, ATP7B, has been identified, genetic testing is challenging, time-consuming and expensive. Here we describe the development and use of a novel diagnostic test for four frequent mutations (M769V, W779X, H1069Q and P1134P-fs) found in Germany and many other countries in Europe. The test is based on multiplex polymerase chain reaction and DNA strip technology and was found to be highly sensitive and specific, as well as timely and cost-effective. We conclude that this test is a useful and reliable tool to screen Wilson disease patients and their family members for these mutations and may facilitate diagnosis in this complex disease.
15703644##2005-2-11##Inherited metabolic liver disease.##
15703643##2005-2-11##Hepatobiliary pathology.##
15213681##2004-6-24##[Severe hepatitis in Wilson's disease].##
15117609##2004-5-1##[Wilson's disease with severe neurological manifestations: response to trientine plus zinc therapy].##In patients with Wilson's disease and neurological manifestations, treatment with D-penicillamine can cause worsening of neurological symptoms, usually in the first few weeks of treatment. Because the neurological damage can be severe and irreversible, the use of D-penicillamine is controversial, and several authors believe that it should be avoided. Studies of the use of ammonium tetrathiomolybdate as an alternative chelating agent for the initial treatment of neurologic Wilson's disease are still in the experimental phase. Published experience on the simultaneous use of trientine, another chelating agent, and zinc, which blocks intestinal absorption of copper, is promising but limited. We present the case of a 17 year-old boy with severe neurologic Wilson's disease that had first presented six years previously. The patient showed a complete recovery after six months of treatment with a combination of trientine and zinc acetate.
15176379##2004-6-5##Gene symbol: ATP7B. Disease: Wilson's disease.##
15053929##2004-4-1##Copper-induced hepatotoxicosis with hepatic stellate cell activation and severe fibrosis in North Ronaldsay lambs: a model for non-Wilsonian hepatic copper toxicosis of infants.##Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.
15134922##2004-5-12##Copper transfer to the N-terminal domain of the Wilson disease protein (ATP7B): X-ray absorption spectroscopy of reconstituted and chaperone-loaded metal binding domains and their interaction with exogenous ligands.##The copper-transporting ATPases are 165-175 kDa membrane proteins, composed of 8 transmembrane segments and two large cytosolic domains, the N-terminal copper-binding domain and the catalytic ATP-hydrolyzing domain. In ATP7B, the Wilson disease protein, the N-terminal domain is made up of six metal-binding sub-domains containing the MXCXXC motif which is known to coordinate copper via the two cysteine residues. We have expressed the N-terminal domain of ATP7B as a soluble C-terminal fusion with the maltose binding protein. This expression system produces a protein which can be reconstituted with copper without recourse to the harsh denaturing conditions or low pH reported by other laboratories. Here we describe the reconstitution of the metal binding domains (MBD) with Cu(I) using a number of different protocols, including copper loading via the chaperone, Atox1. X-ray absorption spectra have been obtained on all these derivatives, and their ability to bind exogenous ligands has been assessed. The results establish that the metal-binding domains bind Cu(I) predominantly in a bis cysteinate environment, and are able to bind exogenous ligands such as DTT in a similar fashion to Atox1. We have further observed that exogenous ligand binding induces the formation of a Cu-Cu interaction which may signal a conformational change of the N-terminal domain.
15135151##2004-5-12##Dietary polyunsaturated fatty acids suppress acute hepatitis, alter gene expression and prolong survival of female Long-Evans Cinnamon rats, a model of Wilson disease.##In the Long-Evans Cinnamon rat, copper accumulates in the liver because of a mutation in the copper-transporting ATPase gene, and peroxidative stresses are supposed to be augmented. We examined the effects of dietary fatty acids on hepatitis, hepatic gene expression, and survival. Rats were fed a conventional, low-fat diet (CE2), a CE2 diet supplemented with 10 wt% of lard (Lar), high-linoleic soybean oil (Soy), or a mixture of docosahexaenoic acid (DHA)-rich fish oil and soybean oil (DHA/Soy). Among female rats, the mean survival times of the DHA/Soy and the Soy groups were longer by 17 approximately 20% than in the Lar and the CE2 groups. Among male rats, the survival times were much longer than in the females, but no significant difference in survival was observed among the dietary groups. Serum ceruloplasmin levels in female and male rats of all of the dietary groups were similar. Serum transaminase levels of the DHA/Soy group tended to be lower than in the CE2 group. Histological examinations revealed a marked degeneration in hepatic tissue integrity in the Lar and CE2 groups but not in the DHA/Soy group. Hepatic levels of metal-related genes, transferrin and ceruloplasmin, as well as those related to bile acid synthesis were up-regulated, and an inflammation-related gene (cyclooxygenase [COX]-2) was down-regulated in the DHA/Soy group. Some proliferation-related genes were also affected by the dietary fatty acids. These results indicate that polyunsaturated fatty acids suppress the development of acute hepatitis and prolong survival in females, regardless of whether they are of the n-6 or n-3 type, which are associated with altered gene expressions.
15161511##2004-5-27##[Copper metabolism after living related liver transplantation for Wilson's disease].##
15063339##2004-4-6##Plasma D-penicillamine redox state evaluation by capillary electrophoresis with laser-induced fluorescence.##D-Penicillamine (D-Pen) is a thiol drug used in the treatment of Wilson's disease, rheumatoid arthritis, metal intoxication and cystinuria. We have recently described a new capillary electrophoresis (CE) method to measure physiological thiols, in which separation of total plasma homocysteine, cysteine, cysteinylglycine, glutathione is achieved using the organic base N-methyl-D-glucamine in the run buffer. In this paper, we present an improvement of our method that allows a baseline separation of total plasma D-Pen from the physiological thiols. Moreover, reduced, free and protein-bound forms of drug are measured by varying the order of disulfide reduction with tributylphosphine and proteins precipitation with 5-sulphosalicylic acid (SSA). After derivatization with 5-iodoacetamidofluorescein (5-IAF), samples are separated and measured by capillary electrophoresis with laser-induced fluorescence in an uncoated fused-silica capillary (57 x 75 microm i.d.) using a phosphate/borate run buffer pH 11.4. In these conditions, the migration time of D-Pen is about 7 min and the time required for each analysis is roughly 10 min. The proposed method has been utilized to measure the various forms of the drug in a D-Pen administered Wilson's disease patient.
15102688##2004-4-23##Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy.##
14754885##2004-2-3##The N-terminal metal-binding site 2 of the Wilson's Disease Protein plays a key role in the transfer of copper from Atox1.##The Wilson's disease protein (WNDP) is a copper-transporting ATPase regulating distribution of copper in the liver. Mutations in WNDP lead to a severe metabolic disorder, Wilson's disease. The function of WNDP depends on Atox1, a cytosolic metallochaperone that delivers copper to WNDP. We demonstrate that the metal-binding site 2 (MBS2) in the N-terminal domain of WNDP (N-WNDP) plays an important role in this process. The transfer of one copper from Atox1 to N-WNDP results in selective protection of the metal-coordinating cysteines in MBS2 against labeling with a cysteine-directed probe. Such selectivity is not observed when free copper is added to N-WNDP. Similarly, site-directed mutagenesis of MBS2 eliminates stimulation of the catalytic activity of WNDP by the copper-Atox1 complex but not by free copper. The Atox1 preference toward MBS2 is likely due to specific protein-protein interactions and is not due to unique surface exposure of the metal-coordinating residues or higher copper binding affinity of MBS2 compared with other sites. Competition experiments using a copper chelator revealed that MBS2 retained copper much better than Atox1, and this may facilitate the metal transfer process. X-ray absorption spectroscopy of the isolated recombinant MBS2 demonstrated that this sub-domain coordinates copper with a linear biscysteinate geometry, very similar to that of Atox1. Therefore, non-coordinating residues in the vicinity of the metal-binding sites are responsible for the difference in the copper binding properties of MBS2 and Atox1. The intramolecular changes that accompany transfer of a single copper to N-WNDP are discussed.
15090321##2004-4-20##[Clinical experience with 13 cases of orthotopic liver transplantation].##
15499181##2004-10-23##Comparison of the disposition behavior of organic anions in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Long-Evans Agouti rats.##Long-Evans Cinnamon (LEC) rats have an abnormality similar to that observed in Wilson's disease in humans and are therefore a good animal model for the study of Wilson's disease. LEC rats develop hereditary hepatitis and severe jaundice. Mutant animals with hyperbilirubinemia have been widely used as animal models for human diseases. Among these mutant animals, Eisai hyperbilirubinemic rats (EHBR) have defective biliary excretion of organic anions. Thus, biliary excretion of sulfobromophthalein (BSP) and urinary excretion of phenolsulfonphthalein (PSP) in LEC rats were compared with those in Long-Evans Agouti (LEA) rats. In LEC rats, the excretion of BSP, a multidrug resistance-associated protein 2 (Mrp2/Abcc2) substrate, was significantly decreased compared to that in LEA rats. It has been reported that the transport function for organic anions on the kidney is maintained in EHBR. However, the urinary excretion of PSP is impaired in LEC rats. It is possible that organic anion transporters responsible for the urinary excretion of PSP in LEA rats and EHBR are impaired in LEC rats. It is important to elucidate the relationship between organic anion secretion and Wilson's disease.
15057754##2004-4-2##Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin.##
15057733##2004-4-2##A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis.##
15057922##2004-4-2##Persistence of elevated aminotransferases in Wilson's disease despite adequate therapy.##
15057900##2004-4-2##Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis.##Patients with Wilson's disease (WD), Indian childhood cirrhosis (ICC), and idiopathic copper toxicosis (ICT) develop severe liver disease morphologically characterized by ballooning of hepatocytes, inflammation, cytoskeletal alterations, and Mallory body (MB) formation, finally leading to mostly micronodular cirrhosis. The pathogenesis of MBs in copper toxicosis is still unresolved. Immunohistochemical analysis of MBs in different types of copper intoxication revealed that keratin, p62, and ubiquitin are integral components. Thus MBs associated with copper intoxication resemble those present in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). p62 is a multifunctional immediate early gene product that, on the one hand, is involved in stress-induced cell signaling (particularly that of oxidative stress) by acting as an adapter protein linking receptor-interacting protein (RIP) with the atypical protein kinase C. On the other hand, p62 binds with high affinity to polyubiquitin and ubiquitinated proteins. In conclusion, p62 accumulation in WD, ICC, and ICT and deposition in MBs indicates a central role of protein misfolding induced by oxidative stress in copper-induced liver toxicity. By sequestering potentially harmful misfolded ubiquitinated proteins as inert cytoplasmic inclusion bodies (e.g., as MBs), p62 may be a major player in an important cellular rescue mechanism in oxidative hepatocyte injury.
15024742##2004-3-17##Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients.##Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a defect in a metal transporting P-type ATPase, resulting in copper overload in various tissues and cells. The aim was to assess both the phenotype in Brazilian WD patients and the corresponding ATP7B genotype. Sixty subjects belonging to 46 pedigrees diagnosed as WD were included in this study. Direct sequencing of all 21 exons within ATP7B and their flanking introns was performed. Demographic, clinical, laboratory and histopathological data at the time of diagnosis were obtained. We identified twenty-five mutations, twelve of them reported for the first time. The c.3402delC mutation had the highest allelic frequency (30.8%), followed by the c.2123T>C (p.L708P) (16.7%). Exons 8 and 15 were the site of 62.5% of the mutations. The common European mutation c.3207C>A (p.H1069Q) was not present at all. Phenotype varied greatly among individuals with the same ATP7B genotype. Our data confirm the heterogeneity of ATP7B genotype in Brazilian WD patients. The mutational spectrum is compatible with the Brazilian history of Mediterranean immigration; however, new mutations, and different frequencies and phenotype associated with the previously known mutations characterize this population. Exons 8 and 15 should be preferentially screened in WD cases from Brazil. Phenotype variation among subjects with the same ATP7B genotype suggests that modifying factors play an additional role in the pathogenesis of WD.
15122050##2004-5-4##Effect of estrogen on plasma ceruloplasmin level in rats exposed to acute stress.##
21408049##2011-3-17##Wilson's disease Presenting with Neuropsychiatric Manifestations.##
15636330##2005-1-8##Cardiac involvement in Wilson's disease--an electrocardiographic observation.##
15060811##2004-4-3##Wilson's disease with Leu492Ser mutation and arylsulfatase A pseudodeficiency: just a coincidence?##Wilson's disease (WD) is an autosomal recessive disorder of copper transport, related to mutations of the ATP7B gene (McKusick 277900). Here we report a new case of WD in which a rare mutation, Leu492Ser expressed for the first time in homozygosity, is associated with neurological presentation of the disease and arylsulfatase A pseudodeficiency.
15125586##2004-5-6##Zinc sulphate release and morphology of matrices prepared for the individual therapy of Wilson's disease.##Hydrophobic zinc sulphate wax matrices with different drug loadings were prepared for the individual hospital therapy of Wilson's disease. The drug release parameters, scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) of the samples were analysed. The release mechanisms from matrices of 75% and 80% w/w zinc sulphate loadings were described with good correlation by the semi-empirical Fikkian diffusion based release model. Besides the zinc sulphate diffusion through the pores of the wax matrices, the parallel diffusion of zinc sulphate from the matrix surface is dominant in the case of samples of 83% and 90%w/w drug loadings. The combination of SEM and EDS analysis visualizes the morphology of the matrices and the related composition thus explaining the differences in the release characteristics.
14709553##2004-1-8##Binding of copper(I) by the Wilson disease protein and its copper chaperone.##The Wilson disease protein (WND) is a transport ATPase involved in copper delivery to the secretory pathway. Mutations in WND and its homolog, the Menkes protein, lead to genetic disorders of copper metabolism. The WND and Menkes proteins are distinguished from other P-type ATPases by the presence of six soluble N-terminal metal-binding domains containing a conserved CXXC metal-binding motif. The exact roles of these domains are not well established, but possible functions include exchanging copper with the metallochaperone Atox1 and mediating copper-responsive cellular relocalization. Although all six domains can bind copper, genetic and biochemical studies indicate that the domains are not functionally equivalent. One way the domains could be tuned to perform different functions is by having different affinities for Cu(I). We have used isothermal titration calorimetry to measure the association constant (K(a)) and stoichiometry (n) values of Cu(I) binding to the WND metal-binding domains and to their metallochaperone Atox1. The association constants for both the chaperone and target domains are approximately 10(5) to 10(6) m(-1), suggesting that the handling of copper by Atox1 and copper transfer between Atox1 and WND are under kinetic rather than thermodynamic control. Although some differences in both n and K(a) values are observed for variant proteins containing less than the full complement of six metal-binding domains, the data for domains 1-6 were best fitted with a single site model. Thus, the individual functions of the six WND metal-binding domains are not conferred by different Cu(I) affinities but instead by fold and electrostatic surface properties.
15049243##2004-3-31##[Wilson's disease in a 15-year-old boy diagnosed in connection with a febrile episode].##
15154620##2004-5-25##Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) in human hepatocellular carcinoma.##One of the major obstacles in the treatment of hepatocellular carcinoma (HCC) is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the expression of ATP7B has not previously been addressed in human liver and HCC. Our purpose was to investigate ATP7B expression in human liver and hepatocellular carcinoma and its clinical significance. We retrospectively examined the expression of ATP7B in primary hepatocellular carcinoma. Immunohistochemical analysis of ATP7B was performed using a monoclonal antibody against ATP7B in 19 surgically removed hepatocellular carcinomas. A variable degree of cytoplasmic staining of tumor cells was observed in 21.1% (4/19) of the analyzed carcinomas. ATP7B expression was not observed in normal hepatic cells. Strong expression of ATP7B was observed in all the analyzed bile ducts. These findings suggest that overexpression of ATP7B in hepatocellular carcinoma might be associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Further, ATP7B is expressed in bile duct epithelial cells, where it may mediate copper secretion into bile fluid.
14648017##2003-12-3##Cross-resistance to cisplatin in cells with acquired resistance to copper.##
14962673##2004-2-14##Functional assessment of the carboxy-terminus of the Wilson disease copper-transporting ATPase, ATP7B.##The carboxy-terminus of ATP7B, the protein defective in the copper-transport disorder Wilson disease, was investigated with respect to its role in copper delivery to the ferroxidase ceruloplasmin. We use yeast as a model system to assess the functional capabilities of ATP7B variants. The yeast ferroxidase, Fet3p, acquires copper from Ccc2p and cannot function if Ccc2p is impaired; expression of wild-type ATP7B in ccc2 yeast complements the iron-deficient phenotype. Our results demonstrate that the C-terminus of ATP7B is necessary for protein stability, as removal of the nonmembranous terminus leads to reduced protein levels and cessation of growth in iron-limited medium. Growth is partially restored when an additional three amino acids are present and is near wild-type levels when only one-third of the C-terminus is present. Measurement of ferroxidase activity is a more sensitive indicator of copper transport function and allowed identification of impaired variants not detected with the growth assay.
15176538##2004-6-5##Hepatitis E virus is responsible for decompensation of chronic liver disease in an endemic region.##
15636319##2005-1-8##Arthropathic presentation of Wilson's disease.##A patient is described who presented with polyarthritis involving small and large joints of limbs with later onset of tremors affecting all four extremities. Investigations including genetic study confirmed the diagnosis of Wilson's disease (WD). The case highlights the importance of considering the possibility of WD in young patient presenting with repetitive unexplained joint symptoms with or without tremor.
15088004##2004-4-17##Successful ECT in a patient with a psychiatric presentation of Wilson's disease.##
14748886##2004-1-30##ATP7b gene and Wilson's disease.##
15123354##2004-5-5##Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease.##
15129869##2004-5-8##Etiology of chronic liver disease in children.##
15125378##2004-5-6##[Large-droplet liver steatosis in celiac disease].##Authors monitored a case of a 25 years old woman who was admitted for swelling of lower limbs. Laboratory results showed hypoproteinemia, elevation of liver enzymes, and prolonged prothrombin time. Ultrasound examination proved hepatomegalia with diffusely hyperechogenic liver without central lesion. Computer tomography confirmed hepatomegalia with diffusely hyperechogenic liver and a suspicion of liver steatosis was expressed. Liver biopsy confirmed serious diffuse large droplet steatosis of unclear genesis. Carried out examinations excluded infectious and autoimmune liver diseases, metabolic diseases, and congenital liver diseases (Wilson's disease, porphyria, haemochromatosis etc.). Laboratory results showed gliadin, endomysin, and reticulin antibodies. An enteroscopy picture showed villi decrease. Histology examination of a biopsy specimen confirmed total villi atrophy with non-differentiated enterocytes and round-cell cellulisation of epithelium and proprium. Histology and histochemical findings were distinct proves of coeliac disease. A patient was prescribed a gluten free diet. Her metabolic parameters (normalisation of albumine levels, prothrombine time, and trace elements) and anino transferase levels gradually improved. This case documents development of a serious liver disorder as a result of malnutrition which developed in a young woman as a result of unrecognised coeliac disease.
14997456##2004-3-5##[Tourettism, hemiballism and juvenile Parkinsonism: expanding the clinical spectrum of the neurodegeneration associated to pantothenate kinase deficiency (Hallervorden Spatz syndrome)].##
14966923##2004-2-18##Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease.##
15272264##2004-7-24##Wilson's disease and hemochromatosis.##Wilson's disease (WD) and hereditary hemochromatosis (HH) are two inherited disorders with potentially devastating and life-threatening complications. Their eminent treatability makes diagnosis in adolescence or young adulthood critical. WD is the result of abnormal copper homeostasis, causing copper overload and end-organ damage. Chelation therapy can be highly efficacious in preventing manifestations of WD. HH is caused by inappropriate absorption of dietary iron, typically as the result of a specific mutation, C282Y, in the HFE gene. End-organ disease from iron accumulation is protean and includes progressive damage of the liver, pancreas, skin, heart, and pituitary. It is important to permit therapeutic phlebotomy to commence before the onset of complications.
15108772##2004-4-28##Long-term outcome of liver transplantation for autoimmune hepatitis.##
14748773##2004-1-30##A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations.##Wilson disease (WD) is a hereditary disorder, with recessive transmission and genetic heterogeneity. Several mutations of ATP7B, the gene underlying WD, were reported in many ethnic groups. In this study, mutation screening in ATP7B of 56 Saudi Arabian WD patients was undertaken. The clinical data of all patients were recorded. The entire ATP7B coding sequence, including intron-exon boundaries were screened for mutation by the polymerase chain reaction (PCR)-based mutation detection technique and DNA sequencing. Thirty-nine patients were symptomatic at presentation and 17 subjects were pre-symptomatic siblings of affected patients. Fourteen patients had neurological, 11 patients had mixed (hepatic and neurological), and 14 patients had hepatic presentations. Family history suggestive of WD was present in 72% of cases and 68% had consanguineous parents. Genetic analysis showed disease-causing mutations in three exons (exons 8, 19 and 21) of the ATP7B gene in 28 patients (50%). Mutations in exons 21 (18 cases) and 19 (one case) were unique for Saudis. This large series of Saudi patients with WD has shown wide variability in the genomic substrate of WD. There is no correlation between genotype and clinical presentation.
14768006##2004-2-10##Cancer-associated molecular signature in the tissue samples of patients with cirrhosis.##Several types of aggressive cancers, including hepatocellular carcinoma (HCC), often arise as a multifocal primary tumor. This suggests a high rate of premalignant changes in noncancerous tissue before the formation of a solitary tumor. Examination of the messenger RNA expression profiles of tissue samples derived from patients with cirrhosis of various etiologies by complementary DNA (cDNA) microarray indicated that they can be grossly separated into two main groups. One group included hepatitis B and C virus infections, hemochromatosis, and Wilson's disease. The other group contained mainly alcoholic liver disease, autoimmune hepatitis, and primary biliary cirrhosis. Analysis of these two groups by the cross-validated leave-one-out machine-learning algorithms revealed a molecular signature containing 556 discriminative genes (P <.001). It is noteworthy that 273 genes in this signature (49%) were also significantly altered in HCC (P <.001). Many genes were previously known to be related to HCC. The 273-gene signature was validated as cancer-associated genes by matching this set to additional independent tumor tissue samples from 163 patients with HCC, 56 patients with lung carcinoma, and 38 patients with breast carcinoma. From this signature, 30 genes were altered most significantly in tissue samples from high-risk individuals with cirrhosis and from patients with HCC. Among them, 12 genes encoded secretory proteins found in sera. In conclusion, we identified a unique gene signature in the tissue samples of patients with cirrhosis, which may be used as candidate markers for diagnosing the early onset of HCC in high-risk populations and may guide new strategies for chemoprevention. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
14731121##2004-1-21##Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease.##
12827356##2003-6-27##The SLC31 (Ctr) copper transporter family.##Copper is essential for many copper-dependent processes, including mitochondrial oxidative phosphorylation, free-radical detoxification, pigmentation, neurotransmitter synthesis, and iron metabolism. The identification of proteins for high affinity copper uptake and export has greatly expanded our understanding of cellular copper homeostasis. Copper export in human cells is mediated by the ATP7A and ATP7B P-type ATPases, which are, respectively, affected in the genetic disorders of copper metabolism, Menkes disease and Wilson disease. A different class of transporter known as the SLC31 or Ctr family of proteins mediates cellular copper uptake. These high-affinity copper transporters exist in all eukaryotes and their discovery has provided new insights into how cells acquire and regulate this essential nutrient. The following is a brief overview of the SLC31 copper transporter family with a focus on the human hCtr1 protein.
15099406##2004-4-22##Molecular regulation of copper excretion in the liver.##Cu is an essential nutrient that is required for a broad range of cellular and molecular processes. Mammals have efficient systems to control Cu homeostasis that operate at the level of controlling uptake, distribution, sequestration and excretion of Cu. The study of diseases associated with disturbed Cu homeostasis has greatly enhanced our understanding of the molecular mechanisms involved in Cu metabolism. In man the liver is responsible for excreting excess Cu from the body by means of biliary secretion. Wilson disease is a severe human disorder characterized by Cu accumulation in the liver as a result of a deficiency in biliary Cu secretion. This disorder is caused by mutations in the gene that encodes a Cu-transporting P-type ATPase (ATP7B). The MURR1 gene was identified recently, and it was hypothesized that this gene is also essential for biliary Cu excretion and is presumed to act downstream of ATP7B. MURR1 is mutated in canine Cu toxicosis, a disorder with phenotypic characteristics similar to those of Wilson disease. MURR1 encodes a protein that is of unknown function and is without detectable sequence homology to known proteins. MURR1 is readily detected in all tissues and cell types, suggesting that it may exhibit a pleiotropic function in different organs, which may or may not be exclusively linked to Cu homeostasis. The use of genetic, biochemical and genomic tools, as well as the development of appropriate models in organisms other than dog, will allow the elucidation of the molecular and cellular function of MURR1 in relation to hepatic Cu homeostasis and biliary Cu excretion.
15054912##2004-4-2##Zinc for prostate disease and other conditions: a little evidence, a lot of hype, and a significant potential problem.##Dietary and supplemental zinc, especially in excess, has received much attention in numerous alternative medicine resources. There is a small amount of medical evidence that zinc may alleviate some mostly rare medical conditions (such as Wilson's disease). However, in prostate conditions, such as BPH, large concentrations of zinc are found in the prostate gland. Excess intake of zinc, especially with individual supplements, has the potential to encourage the growth of prostate conditions from BPH to cancer. In fact, one large study found a significantly higher risk of advanced prostate cancer in men consuming large intakes of these supplements. Large doses of zinc can inhibit the benefits of bisphosphonate drugs, increase testosterone level, increase cholesterol, reduce levels of "good cholesterol" or HDL, and can promote immune dysfunction. More research is needed in this area, but in the meantime, the time seems more than ripe to discourage or immediately discontinue the intake of larger concentrations of zinc for most individuals until adequate research resolves this controversial issue.
14732483##2004-1-21##Identification of the "missing domain" of the rat copper-transporting ATPase, atp7b: insight into the structural and metal binding characteristics of its N-terminal copper-binding domain.##Wilson disease is an autosomal disorder of copper transport caused by mutations in the ATP7B gene encoding a copper-transporting P-type ATPase. The Long Evans Cinnamon (LEC) rat is an established animal model for Wilson disease. We have used structural homology modelling of the N-terminal copper-binding region of the rat atp7b protein (rCBD) to reveal the presence of a domain, the fourth domain (rD4), which was previously thought to be missing from rCBD. Although the CXXC motif is absent from rD4, the overall fold is preserved. Using a wide range of techniques, rCBD is shown to undergo metal-induced secondary and tertiary structural changes similar to WCBD. Competition 65Zn(II)-blot experiments with rCBD demonstrate a binding cooperativity unique to Cu(I). Far-UV circular dichroism (CD) spectra suggest significant secondary structural transformation occurring when 2-3 molar equivalents of Cu(I) is added. Near-UV CD spectra, which indicate tertiary structural transformations, show a proportional decrease in rCBD disulfide bonds upon the incremental addition of Cu(I), and a maximum 5:1 Cu(I) to protein ratio. The similarity of these results to those obtained for the Wilson disease N-terminal copper-binding region (WCBD), which has six copper-binding domains, suggests that the metal-dependent conformational changes observed in both proteins may be largely determined by the protein-protein interactions taking place between the heavy metal-associated (HMA) domains, and remain largely unaffected by the absence of one of the six CXXC copper-binding sites.
14723607##2004-1-16##Review article: diagnosis and current therapy of Wilson's disease.##Wilson's disease is an autosomal recessive inherited disorder of hepatic copper metabolism resulting in liver disease and/or neuropsychiatric disease. The diagnosis of neurological disease is straightforward if the following symptoms are present: Kayser-Fleischer rings, typical neurological symptoms and low serum ceruloplasmin levels. The diagnosis is more complex in patients presenting with liver diseases. None of the commonly used parameters alone allows a diagnosis with certainty. A combination of various laboratory parameters is necessary to firmly establish the diagnosis. In the future, limited mutation analysis may play an important diagnostic role. Recently, a group of international experts has proposed a score based on a variety of tests and clinical symptoms. The validity of this score needs to be assessed prospectively. Treatment requires life-long administration of copper chelators (d-penicillamine, trientine). A frequently used alternative is zinc. None of these treatments has been tested by prospective randomized controlled studies. Liver transplantation is reserved for severe or treatment-resistant cases with advanced liver disease, whilst experience with refractory neuropsychiatric disease is limited.
14675607##2003-12-17##Successful pregnancies and abortions in symptomatic and asymptomatic Wilson's disease.##
14510639##2003-9-27##The nucleotide-binding domain of the Zn2+-transporting P-type ATPase from Escherichia coli carries a glycine motif that may be involved in binding of ATP.##In P-type ATPases, the nucleotide-binding (N) domain is located in the middle of the sequence which folds into the phosphorylation (P) domain. The N domain of ZntA, a Zn2+-translocating P-type ATPase from Escherichia coli, is approx. 13% identical with the N domain of sarcoplasmic reticulum Ca2+-ATPase. None of the Ca2+-ATPase residues involved in binding of ATP are found in ZntA. However, the sequence G503SGIEAQV in the N domain of ZntA resembles the motif GxGxxG, which forms part of the ATP-binding site in protein kinases. This motif is also found in Wilson disease protein where several disease mutations cluster in it. In the present work, we have made a set of disease mutation analogues, including the mutants G503S (Gly503-->Ser), G505R and A508F of ZntA. At low [ATP], these mutant ATPases are poorly phosphorylated. The phosphorylation defect of the mutants G503S and G505R can, however, be partially (G503S) or fully (G505R) compensated for by using a higher [ATP], suggesting that these mutations lower the affinity for ATP. In all three mutant ATPases, phosphorylation by P(i) has become less sensitive to the presence of ATP, also consistent with the proposal that the Gly503 motif plays a role in ATP binding. In order to test this hypothesis, we have modelled the N domain of ZntA using the sarcoplasmic reticulum Ca2+-ATPase structure as a template. In the model, the Gly503 motif, as well as the residues Glu470 and His475, are located in the proximity of the ATP-binding site. In conclusion, the mutagenesis data and the molecular model are consistent with the idea that the two loops carrying the residues Glu470, His475, Gly503 and Gly505 play a role in ATP binding and activation.
15582261##2004-12-8##Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis.##
15690978##2005-2-5##The potential of bone marrow stem cells to correct liver dysfunction in a mouse model of Wilson's disease.##Metabolic liver diseases are excellent targets for correction using novel stem cell, hepatocyte, and gene therapies. In this study, the use of bone marrow stem cell transplantation to correct liver disease in the toxic milk (tx) mouse, a murine model for Wilson's disease, was evaluated. Preconditioning with sublethal irradiation, dietary copper loading, and the influence of cell transplantation sites were assessed. Recipient tx mice were sublethally irradiated (4 Gy) prior to transplantation with bone marrow stem cells harvested from normal congenic (DL) littermates. Of 46 transplanted tx mice, 11 demonstrated genotypic repopulation in the liver. Sublethal irradiation was found to be essential for donor cell engraftment and liver repopulation. Dietary copper loading did not improve cell engraftment and repopulation results. Both intravenously and intrasplenically transplanted cells produced similar repopulation successes. Direct evidence of functionality and disease correction following liver repopulation was observed in the 11 mice where liver copper levels were significantly reduced when compared with mice with no liver repopulation. The reversal of copper loading with bone marrow cells is similar to the level of correction seen when normal congenic liver cells are used. Transplantation of bone marrow cells partially corrects the metabolic phenotype in a mouse model for Wilson's disease.
15074475##2004-4-13##A new Olympus assay for the determination of ceruloplasmin.##Ceruloplasmin's main clinical importance is in the diagnosis of Wilson's disease, where plasma ceruloplasmin concentration is reduced. Increased levels are particularly notable in diseases of the reticuloendothelial system such as Hodgkin's disease as well as during pregnancy or use of contraceptive pills. This paper describes a new Olympus assay OSR6164 for the determination of ceruloplasmin on the Olympus AU640E, AU400E and AU2700 analytical systems. The turbidimetric assay has a linear measurable range of 60-2000 mg/l. Prozone hook effect greater than 9000 mg/l. Imprecision CV values < 5% for within-run and < 10% for between-day. Lipemic, hemolytic and icteric interference of < or = 5%. Traceability of recovery to CRM470 standardisation. Method comparison to Behring Nephelometry yielded a correlation (r) of 0.99 and a slope of 1.02. On-board and calibration stability of 60 days and 14 days, respectively. Serumor plasma (EDTA and lithium heparin anticoagulants) samples may be used.
14639035##2003-11-26##A rare homozygous missense mutation in ATP7B exon 19 in a case of Wilson disease.##
15266782##2004-7-23##Ultrastructural evaluation of activated forms of microglia in human brain in selected neurological diseases (SSPE, Wilson's disease and Alzheimer's disease).##Activated forms of microglia were ultrastructurally evaluated in three neurological diseases of different aetiology (subacute sclerosing panencephalitis--SSPE, Wilson's disease and Alzheimer's disease). The occurrence of activated rod, ramified and amoeboid microglia was found in the investigated diseases. The widest ultrastructural variability of microglia was in SSPE, including the presence of mitotic chromosomes or centrioles in its cytoplasm, which indicates microglia proliferation. In the nuclei of activated microglia, some nuclear bodies with different structures were frequently seen, whereas lamellar structures (similar to developing Birbeck's bodies--pathognomonic to Langerhans-type dendritic cells) were observed in the cytoplasm. The activated forms of microglia with apoptotic features were found only in SSPE cases. Some apoptotic nuclei were filled with nucleocapsids of measles virus. In Alzheimer's disease, activated microglia was most frequently bound to senile plaques. Ramified microglia was in contact with amyloid fibrils, which penetrated its cytoplasm and reached the nuclear membrane and channels of rough endoplasmic reticulum, or was situated among dystrophic neurites. Rod microglia was found predominantly at the edge of senile plaques. In Wilson's disease, the ultrastructure of activated microglia showed mostly indirect forms between rod, ramified and amoeboid microglia. The microglia ultrastructure suggests that its morphological form may express functional involvement in the pathogenesis of a given disease entity.
14579150##2003-10-28##A comparison of the mutation spectra of Menkes disease and Wilson disease.##The genes for two copper-transporting ATPases, ATP7A and ATP7B, are defective in the heritable disorders of copper imbalance, Menkes disease (MNK) and Wilson disease (WND), respectively. A comparison of the two proteins shows extensive conservation in the signature domains, with amino acid identities outside of the conserved domains being limited. The mutation spectra of MNK and WND were compared to confirm and refine further regions critical for normal function. Mutations were found to be relatively widespread; however, the majority was concentrated within defined functional domains and membrane-spanning segments, reinforcing the importance of these regions for protein function. Of the total published point mutations in ATP7A, 23.0% are splice-site, 20.7% nonsense, 17.2% missense, and 39.1% small insertions/deletions. There is a high prevalence (58.2%) of missense mutations in ATP7B. For the other mutations in ATP7B, 7.4% are splice-site, 7.4% nonsense, and 27.0% small insertions/deletions. A region of possible importance is the intervening sequence between the last copper-binding domain and the first transmembrane helix, as this region has a high percentage of MNK mutations. Similarly, the region containing the ATP-binding domain has 24.6% of all WND mutations. The study of mutation locations is useful for defining critical regions or residues and for efficient molecular diagnosis.
15368714##2004-9-17##Rare presentation of Wilson's disease: a case report.##A female presented with pain in left flank, detected to have bilateral renal calculi with deranged liver functions. On investigation found her to have Wilson's disease with hypercalciuria and incomplete distal renal tubular acidosis. Patient was started on penicillamine following which her hepatitis improved but hypercalciuria persisted after 10 weeks of follow up. The rarity of such presentation and literature review for the same is discussed.
14675255##2003-12-17##Wilson's disease with coexisting autoimmune hepatitis.##
15340310##2004-9-2##[Transplantation of the liver right lobe from a related donor].##From 1997 to 2003 transplantation of liver's right lobe from alive related donor was performed in 64 patients (28 men, 36 women) aged from 6 to 61 years (mean age was 22.6 +/- 3.2 years). Body weight of recipients ranged from 18 to 92 Kg (52.7 +/- 2.8 Kg on average). Indications for surgery were following: cirrhosis of liver due to Wilson's disease (34), primary sclerotic cholangitis (6), viral cirrhosis of liver (6), primary biliary cirrhosis (4), Bayler's disease (3), Caroly's disease (3), Budd-Chiary syndrome (3), secondary biliary cirrhosis (2), cirrhosis of liver due to deficient of alpha(1)-antitrypsin (1), hepatocellular carcinoma (1), total nodular transformation of liver (1). Intensive care before transplantation was needed for 68.75% potential recipients. Donors of liver's right lobe were relatives of patients similar to blood group. Age of donors ranged from 18 to 49 years, mean age was 37.9 +/- 1.4 years. Donors underwent right-sided hemihepatectomy, there were no complications. Lethal outcome in recipients was seen in 2 (3.1%) cases and was not associated with function of transplant. Lethal outcome in long-term period after transplantation was seen in 4 (6.5%) cases. All the others patients survived and followed from 1 to 73 months (23.8 +/- 2.4 months on average). Quality of life was good. Transplantation of liver's right lobe from related donor is the independent line in orthotopic transplantation of liver and ensure reliable results.
14994719##2004-3-5##Central pontine myelinolysis in Wilson's disease: MR spectroscopy findings.##
15224559##2004-7-1##[Wilson's disease: study of 6 neurologic forms observed at the University Hospital in Conakry].##This report describes 6 cases of Wilson's disease observed at the University Hospital Center in Conakry, Guinea. Presenting symptoms involved extrapyramidal syndrome in 4 cases, psychomotor epilepsy in 1, and confusional syndrome in 1 case. Diagnosis was based on neuropsychic manifestations, Kayser-Fleicher corneal ring, liver failure, and impaired copper metabolism. Brain CT-scan depicted normal features in 3 cases, symmetric hypodensity of the lenticular nucleus in one, discrete ventricular dilatation of in one a and cortico-subcoetical atrophy in one.
15042842##2004-3-27##[Human molecular genetics: study in the area of medical and ethnic genomics].##The review covers selected research topics in fields of medical and ethnic genomics tackled at the Department of Molecular Basis of Human Genetics, the Institute of Molecular Genetics. Primary concern is given to genetic causes of monogenic neurological disorders, among them hepatolenticular degeneration (Wilson's disease), torsion dystonia, and myotonic dystrophy. Results of polymorphic DNA marker surveys in Russia and neighboring countries are also presented.
15011394##2004-3-12##[Wilson disease].##
14763152##2004-2-7##[New method for analysis of target molecule in gastrointestinal carcinoma--from the choice of ATP7B as a target molecule for overcoming drug resistance through the development of an inhibitor against ATP7B].##
15666995##2005-1-26##Copper chelation as an antiangiogenic therapy.##Angiogenesis is now recognized as a crucial process in tumor development. Copper appears to act as an essential cofactor for several angiogenic growth factors, and both copper metabolism and ceruloplasmin expression are upregulated in many tumors. The role of copper chelators has been investigated in animal models with promising results. New therapies for Wilson's disease (a disease of copper accumulation) have enabled clinical trials of copper chelation to be undertaken. Here we discuss the evidence for a role of copper in angiogenesis and possible mechanisms of action of anticopper agents.
14738953##2004-1-24##Atypical childhood Wilson's disease.##Wilson's disease is a genetic disorder of copper metabolism with a hepatic or neurologic presentation. A hepatic presentation is more common in young children. Neurologic Wilson's disease often manifests as a movement disorder with dystonia, tremor, and dysarthria. Psychiatric or behavioral symptoms can also be a presenting feature of Wilson's disease. We describe an atypical neurologic presentation in a prepubertal child with minimal hepatic involvement; in which transient hemiparesis and encephalopathy dominated her initial neurologic presentation. Brain magnetic resonance imaging revealed extensive cortical and subcortical signal change, in addition to the classical basal ganglia signal abnormality observed in Wilson's disease. She was treated with oral tetrathiomolybdate anticopper therapy, followed by zinc maintenance. Her clinical status and brain imaging improved considerably at 1 year after treatment initiation. Neurologic Wilson's disease may have diverse presentations, and should be considered in children who present with cortical features and signal change on magnetic resonance imaging.
15379129##2004-9-24##[Wilson's disease and secondary copper hemochromatoses in hematological practice].##
14695788##2003-12-27##Rising plasma nociceptin level during development of HCC: a case report.##
14695766##2003-12-27##Increased nociceptin/orphanin FQ plasma levels in hepatocellular carcinoma.##
14974157##2004-2-21##[ATP7B gene mutations in Hungarian patients with Wilson disease--case reports to illustrate the diverse clinical presentations].##ATP7B gene mutations were examined in 70 Wilson patients from Hungary. 11 different mutations were found. In Hungary, similarly to other Central-Eastern European countries, the H1069Q was the most the frequent mutation, detected in 51 patients (73%) by semi-nested polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) assay. 10 further mutations have been found by sequencing as follows: P767P-fs, R778G, K844K-fs, I857T, R969Q, T977M, E1064K, M769L, Y715H and P1273S. These latter three mutations have not been described before. Among the 11 mutations there are five, which have been published only in patients of Turkish, Italian or Albanian origin. It might be the genetic consequence of the 150 years long occupation of Hungary in the 16th and 17th century by Turks. The genotype-phenotype analysis showed that the Kayser-Fleischer ring was more frequent (10/12 = 83%), and the age at the diagnosis was higher in H1069Q homozygous patients than in compound heterozygous or negative patients. Diverse clinical presentation of the disease was demonstrated by case reports giving messages for the practitioners. The gene mutation analysis is of particular importance in siblings of the index patient, since the detection of two mutant allels confirm the diagnosis of the disease even in absence of symptoms. The clinical manifestation of the disease can be preceded by the treatment.
15067983##2004-4-8##[Wilson disease in 2003].##The actuality of this review is based on the results of a recent international consensus conference on the diagnosis and phenotypic classification of Wilson disease published in 2003. The mechanism of the genetically determined copper elimination failure and the copper toxicity, the clinical presentation forms, the diagnosis and treatment of the disease is reviewed. Wilson disease should be taken into consideration in case of any liver disease of unknown origin or neuropsychiatric symptoms. The internationally accepted scoring system is presented.
14986826##2004-2-28##Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease.##Wilson's disease (WD), an autosomal recessive copper transport disorder, usually presents with symptoms involving the liver or central nervous system. The disease is caused by a large number of mutations in the ATP7B gene comprising 21 expressed exons. Some of the mutations appear to be population specific, whereas others are found in probands from a variety of different ethnic backgrounds. This paper presents the results of screening of the ATP7B gene by means of the direct sequencing of all exons in the gene in 39 Han and one Hui ethnic Chinese patients. Nineteen novel mutations were revealed along with nine others that have been previously described; 57.5% of the mutations were located in exons 8, 13, and 12. In particular, the Arg778Leu mutation in exon 8 was found in 55% of these Chinese patients in at least one allele. Five patients were homozygotes and 17 patients were heterozygotes for Arg778Leu. The detection rate on direct sequencing of the polymerase chain reaction products of all exons of the ATP7B gene in 40 unrelated patients was 83.8% of alleles. Seventeen polymorphisms were also identified in patients and healthy controls. We first reported the presence of ATP7B mutations in Chinese Hui ethnic patients and summarize our results here along with the previously reported findings. A significant correlation between genotype and phenotype was not found in 37 homozygotes and 52 heterozygotes for Arg778Leu.
15859921##2005-4-30##Outcome of mucormycosis in liver transplantation: four cases and a review of literature.##Mucormycosis is a rare but highly invasive fungal infection that occurs in transplant recipients. The literature contains descriptions of 12 cases of mucormycosis after orthotopic liver transplantation (OLT). This report describes the fatal courses in four patients at our center who developed mucormycosis after liver transplantation. Of 51 liver transplant recipients who received grafts between December 1993 and April 2003, 4 (7.8%; 3 males and 1 female) developed mucormycosis. The primary liver diseases in the four cases were Wilson's disease, autoimmune hepatitis, primary biliary cirrhosis, and cryptogenic cirrhosis. Three of the transplants were harvested by another team and shipped to our center. We concluded that selection of poor transplant candidates, prolonged antibiotic therapy and/or hospitalization prior to OLT, and breaks in aseptic technique during harvesting, shipping, and during operation are the main reasons for the high incidence of mucormycosis in our OLT patients.
14640923##2003-12-4##Current and future therapy in haemochromatosis and Wilson's disease.##There have been several new developments in the treatment of iron and copper overload disorders, such as haemochromatosis, thalassaemia and Wilson's disease. Clinical trials of orally administered iron chelators, both as monotherapy and in combination with deferoxamine, are in progress around the world. Several new chelators are now being introduced in clinical trials. Future therapies for iron overload may comprise of oral iron binding agents capable of preventing dietary iron absorption from the diet. The characterisation of specific iron transporters such as the divalent metallic transporter and ferroportin may hold promise for the development of 'smart' compounds capable of blocking iron transport. Several new agents are now available for the management of Wilson's disease, including trientine, zinc and tetrathiomolybdate. This review, will discuss the pathogenesis, and current and future therapies for iron and copper overload disorders.
14727626##2004-1-20##Where is the site that ATP7B transports copper within hepatocytes?##
14724838##2004-1-16##Wilson disease.##
14676457##2003-12-17##Idiopathic calcium pyrophosphate dihydrate (CPPD) crystal deposition disease in a young male patient: a case report.##Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a disease of the elderly and extremely rare in young individuals. If young people develop CPPD crystal deposition disease, it may be associated with metabolic diseases such as hemochromatosis, hyperparathyroidism, hypophosphatasia, hypomagnesemia, Wilson's disease, hypothyroidism, gout, acromegaly, and X-linked hypophosphatemic rickets. Therefore, in young-onset polyarticular CPPD crystal deposition disease, investigation for predisposing metabolic conditions is warranted. We report a case of a young male patient with idiopathic CPPD crystal deposition disease, who did not have any evidences of metabolic diseases after thorough evaluations. As far as we know, this is the first report of a young male patient presented with idiopathic CPPD crystal deposition disease.
14713890##2004-1-10##Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.##We have treated 9 patients who presented with hepatic decompensation resulting from Wilson's disease with a combination of trientine and zinc, generally for at least 4 months, followed by transition to zinc maintenance therapy. All of these patients had hypoalbuminemia, all but 1 had hyperbilirubinemia, and 7 had ascites. All of these patients would have been candidates for liver transplantation on the basis of their initial Child-Turcotte-Pugh (CTP) scores. The minimal listing criteria for transplant candidates is a score greater than 7. Eight of the 9 patients had demonstrated a CTP score of 10 or higher. The other scoring system that has been used in Wilson's disease to determine need for transplantation is the prognostic index of Nazer, in which a score over 6 indicates that the patient is unlikely to survive without a transplant if treated with penicillamine. Two of our patients had Nazer scores higher than 6. With our medical therapy, all 9 of these patients have recovered normal liver function as reflected by normalization of their CTP scores to 5. Because of coexisting neurologic disease, 1 of our 9 patients was initiated on a neurologic protocol and by chance randomized to receive tetrathiomolybdate (TM) and zinc after 2 weeks of trientine/zinc treatment. This patient's liver function recovered much more rapidly than did that of the other 8 patients, all of whom were treated with trientine/zinc, suggesting that TM therapy offers a further advantage. In summary, we were able to take 9 patients who presented with liver failure -8 of whom had CTP scores indicating a potential need for liver transplantation and 2 of whom had Nazer prognostic scores indicating that they were not likely to survive if treated only with penicillamine - and treat them medically, with recovery in all 9. We believe the trientine/zinc combination therapy should be the standard for initial treatment of liver failure in Wilson's disease because its efficacy is equal or slightly superior to that of penicillamine and because it has a much lower incidence of side effects. Moreover, TM warrants study to determine whether therapy for hepatic Wilson's disease can be further improved.
14725414##2004-1-17##Our experience with fulminant hepatic failure in Turkish children: etiology and outcome.##Fulminant hepatic failure is a rare and devastating event during childhood. The etiology of liver failure is reported to change according to age and geographical location. We aimed to investigate, retrospectively, causes and outcome of fulminant hepatic failure in Turkish children. Thirty-four children with fulminant hepatic failure were analysed by means of etiology and outcome. Etiological factor, clinical presentation, encephalopathy stage and biochemical parameters were correlated with outcome. Acute viral hepatitis was detected in 12 cases (35.2 per cent) and hepatitis A was the most commonly detected cause among cases with fulminant hepatic failure (n = 9, 26.4 per cent). Hepatitis B and non A-E infection were diagnosed in two (5.8 per cent) and one (2.9 per cent) cases, respectively. Wilson's disease was defined in four patients (12.5 per cent). Budd-Chiari syndrome (2.9 per cent), autoimmune hepatitis (2.9 per cent) and mushroom poisoning (2.9 per cent) were other detected causes of fulminant hepatic failure in this group. No viral, metabolic, toxic or anatomic reason could be detected in the remaining 15 (44.1 per cent) patients and they were evaluated as cryptogenic. Mortality was 67.6 per cent (23 cases). Encephalopathy grade, total and indirect bilirubin levels were found to be significantly higher in patients who died (p = 0.004, p = 0.03, p = 0.04). Seven patients could have been transplanted (two cadavaric, five living related) and the mortality of this group was 28.5 per cent (n = 2). It was concluded that fulminant hepatitis A virus (HAV) infection is the most common detectable cause of fulminant hepatic failure in Turkish children.
14676735##2003-12-17##Transient fetal myelosuppressive effect of D-penicillamine when used in pregnancy.##Normal fertility is sustained by progress in the medical therapy of Wilson's disease; however, pregnancy complications are encountered more frequently. The mother we present is a Wilson's disease patient who had been compliant with D-penicillamine for the preceding 13 years. She was admitted with unplanned pregnancy at the 16th gestational week. The dose of D-penicillamine could be reduced to 600 mg/d related to the underlying disease. Pregnancy ended with premature labor and delivery at the 29-30th weeks. The baby experienced type I respiratory distress and was treated by surfactant and mechanical ventilation. Neutropenia and leucopenia were documented at 6th postnatal hours. The baby showed neutropenia and leucopenia for 5 days and resolving without any further therapy. Intrauterine D-penicillamine was suspected to cause transient neonatal myelosuppression.
14602476##2003-11-7##Non-radioactive detection of five common microsatellite markers for ATP7B gene in Wilson disease patients.##Haplotype analysis using microsatellite markers is a useful indicator of specific mutations and is often exploited as the first large-scale screening technique to carry out the molecular characterization of the disease gene in probands from a specific population. However, the methodologies available are still cumbersome and require the use of either radioactive compounds or specialized equipment suitable to follow fluorescent dyes. Both these techniques may not be available for newly developing clinical laboratories. We have set up a sensitive and easy-to-use protocol to characterize five closely spaced, highly polymorphic microsatellite polymorphisms (CA repeats) that span the Wilson disease (WD) region, i.e. D13S316, D13S133, D13S301, D13S314, D13S315. The technique described here for the analysis of the WD gene microsatellite system relies on the quick detection method of silver staining, avoiding the use of toxic or sophisticated equipment. This approach could be the method of choice to implement molecular genetic testing in clinical laboratories, even those not especially equipped for DNA analysis and in particular in newly developed molecular genetics centers in countries whose population has not yet been characterized for WD-causing ATP7B gene mutations.
15048596##2004-3-30##The importance of iron and copper accumulation in the pathogenesis of non-alcoholic steatohepatitis.##
14669346##2003-12-12##Copper metabolism after living related liver transplantation for Wilson's disease.##
14617772##2003-11-18##In vivo reduction of amyloid-beta by a mutant copper transporter.##Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide.
14633694##2003-11-25##Evidence of alterations in base excision repair of oxidative DNA damage during spontaneous hepatocarcinogenesis in Long Evans Cinnamon rats.##The Long-Evans Cinnamon (LEC) rat, an animal model for Wilson's disease, is an inbred mutant strain, which because of the genetic copper metabolism disorder develops hepatitis approximately 4 months after birth, followed by chronic hepatitis later in life, and eventually all of the surviving animals from liver injury and hepatitis develop spontaneous hepatocellular carcinomas. This animal model also shows that the generation of reactive oxygen species and the accumulation of oxidative damage in the liver DNA has significantly increased over the lifetime of LEC versus the wild-type Long-Evans Agouti (LEA) rats. Thus, the LEC rats having this genetically induced oxidative condition are proved to be very useful model for the study of endogenous DNA lesions and their relation to spontaneous carcinogenesis. In this study, we tested the hypothesis that differences do exist between these two rat strains in respect to their capacity to repair oxidative DNA base modification, which could explain the elevation of endogenous oxidative damage in the LEC rat liver DNA. We found that both the activity and expression at the protein and RNA levels of major DNA glycosylases, endonuclease III and 8-oxoguanine DNA-glycosylase, which initiate the excision and repair of oxidized bases, were significantly altered during the acute (16-18 weeks) and early chronic (24 weeks) phases of hepatitis. Enzyme levels were restored in the later period of chronic hepatitis (week 40) in the LEC rat liver as compared with the age-matched LEA rats. This early reduction in the capacity to repair oxidative DNA base damage could have contributed to the accumulation of mutagenic adducts in liver DNA. These findings show for the first time in an animal model that acute hepatitis impairs the repair of oxidative DNA base damage and strongly suggest that the repair of endogenous DNA adducts plays a critical role in the development of spontaneous hepatocellular carcinoma in LEC rats.
14722976##2004-1-16##[Hepatic complications of pregnancy].##Liver diseases specific of pregnancy, the most common hepatic complications of pregnancy, are always associated with a sometimes asymptomatic increase in serum aminotransferase activity. The most frequent of the liver diseases specific of pregnancy in normotensive pregnant women is cholestasis of pregnancy, the cause of generalised pruritus, and, in those with pregnancy-induced hypertension, preeclampsia which requires short-term cessation of pregnancy. Similar treatment is required by acute fatty liver of pregnancy the diagnosis of which must be done in the third trimester when recent polydipsia, nausea or vomiting occurs. Moreover, pregnancy increases the incidence and/or the severity of herpes simplex hepatitis (for which acyclovir therapy is urgently required) and hepatitis type E. Pregnancy may also unmask untreated cases of autoimmune hepatitis, Wilson's disease or Budd-Chiari syndrome.
14625215##2003-11-20##MR features of diseases involving bilateral middle cerebellar peduncles.##
14652164##2003-12-4##Trace elements in human physiology and pathology. Copper.##Copper is a trace element, important for the function of many cellular enzymes. Copper ions can adopt distinct redox states oxidized Cu(II) or reduced (I), allowing the metal to play a pivotal role in cell physiology as a catalytic cofactor in the redox chemistry of enzymes, mitochondrial respiration, iron absorption, free radical scavenging and elastin cross-linking. If present in excess, free copper ions can cause damage to cellular components and a delicate balance between the uptake and efflux of copper ions determines the amount of cellular copper. In biological systems, copper homeostasis has been characterized at the molecular level. It is coordinated by several proteins such as glutathione, metallothionein, Cu-transporting P-type ATPases, Menkes and Wilson proteins and by cytoplasmic transport proteins called copper chaperones to ensure that it is delivered to specific subcellular compartments and thereby to copper-requiring proteins.
14616767##2003-11-18##Genetic variation in the promoter and 5' UTR of the copper transporter, ATP7B, in patients with Wilson disease.##ATP7B is a copper-transporting P-type ATPase defective in the copper transport disorder, Wilson disease (WND). We have sequenced the 5' UTR and promoter region of ATP7B in 37 unrelated WND patients in whom partial sequencing of the coding region and intron/exon boundaries of the gene had failed to identify one or both disease-causing mutations. Three patients were found to be heterozygous for a 15 bp deletion between nucleotides -424 and -441. This deletion had been previously identified as the most common mutation in Sardinian WND patients. Two novel single-nucleotide changes were also identified within the 5' UTR and promoter of ATP7B; however, these were found at a similar frequency in control chromosomes and are apparently normal variants. These results suggest that mutations in regulatory elements of ATP7B are uncommon in patients of European ancestry, except in Sardinia.
14723487##2004-1-16##DNA linkage based diagnosis of Wilson disease in asymptomatic siblings.##
12968035##2003-9-12##The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein.##Copper toxicosis in Bedlington terriers is an autosomal recessive disorder characterized by excessive hepatic copper accumulation in association with a marked decrease in biliary copper excretion. Recent genetic data have revealed that MURR1, a single copy gene on dog chromosome 10q26, is mutated in this disorder. This gene encodes a 190-amino acid open reading frame of unknown function that is highly conserved in vertebrate species. The Wilson disease protein is a copper transporting ATPase shown to play a critical role in biliary copper excretion. Here we demonstrate that the Wilson disease protein directly interacts with the human homologue of Murr1 in vitro and in vivo and that this interaction is mediated via the copper binding, amino terminus of this ATPase. Importantly, this interaction is specific for this copper transporter, a finding consistent with the observation that impaired copper homeostasis in affected terriers is confined to the liver. Our findings reveal involvement of Murr1 in the defined pathway of hepatic biliary copper excretion, suggest a potential mechanism for Murr1 function in this process, and provide biochemical evidence in support of the proposed role of the MURR1 gene in hepatic copper toxicosis.
14557570##2003-10-15##The "double panda sign" in Wilson's disease.##
12956859##2003-9-6##Potential c-fiber damage in Wilson's disease.##
14584759##2003-10-31##Reference limits for copper and iron in liver biopsies.##Using 141 liver biopsy results (103 adults, 38 children) and a rank-order approach, the following reference limits were found: copper 55 microg/g dry weight, iron 1800 microg/g dry weight (adults only), and iron index 1.0. The study was made feasible by the fact that both copper and iron were measured as standard practice in every liver biopsy received for either test. The added analyte tended to contribute more to normal results. Specimens with elevations of both were infrequent (7 of 141) and significant elevations of both (copper >200 microg/g, iron index >2.0) were suggestive of contamination. Advantages of using patient data included studying specimens of limited availability and acquiring information on the distribution of elevated results seen in clinical practice. Disadvantages included increased uncertainty in the reference limits relative to a normal population. Although most of the study population consisted of patients referred for diagnosis of Wilson's disease or hemochromatosis, the reference intervals were similar to those reported from autopsy studies.
14574444##2003-10-24##Gene expression in the liver of Long-Evans cinnamon rats during the development of hepatitis.##The Long-Evans cinnamon (LEC) rat, an authentic model for Wilson disease, is characterized by a mutation in the Atp7b gene leading to a defective copper excretion and, as a consequence, to an accumulation of the metal in the liver and copper-associated hepatotoxicity. In the present communication expression profiles of genes in the liver from wild-type Long-Evans agouti (LEA) and LEC rats at different stages of copper accumulation and liver disease were investigated. Disease states were defined according to serum aspartate aminotransferase activity and bilirubin levels in serum and from histopathology of the liver. Gene expression was determined with the Affymetrix RTU34 oligonucleotide array covering 1031 genes. Compared to the LEA rat, the nondiseased LEC rat with already increased hepatic copper level showed an enhanced expression of genes, particularly related to oxidative stress and DNA damage. During the progression of the liver disease, in particular genes related to oxidative stress, DNA damage, apoptosis and inflammation with acute-phase reaction were upregulated.
14669425##2003-12-13##[Pregnancy, delivery and puerperium in patients after liver transplantation].##We report two cases of successful pregnancies in women after liver transplantation for end-stage liver dysfunction caused in one case by Wilson disease and in the second one by lupoid hepatitis. For woman with the Wilson disease it was a second pregnancy and for woman with lupoid hepatitis it was the first pregnancy. Mothers continued immunosuppressive therapy during their pregnancies. Labours started spontaneously at 39th and 36th week's of gestation. As a result the healthy two female infants weighing 3600 g and 2420 g respectively were born. The first woman with her baby was discharged from hospital on the third day after delivery and the second one and her baby on the sixth day after delivery. Both were in good condition.
21206869##2011-1-6##Wilson's Disease : A Case Report.##Wilson's disease is a rare metabolic disorder involving copper metabolism may present with hepatic, neurological and psychiatric manifestations. We present a case of Wilson's disease with behavioral symptoms, which responded to risperidone.
14636015##2003-11-26##Role of intensive PEX in a patient with fulminant hepatic failure due to Wilson's disease (WD) in preparation for orthotopic liver transplantation (OLT).##
14606709##2003-11-11##Bridging use of plasma exchange and continuous hemodiafiltration before living donor liver transplantation in fulminant Wilson's disease.##A 15-year-old girl presented with acute hepatic failure showing ascites and hepatic encephalopathy, accompanied by hemolytic anemia. She was diagnosed as having fulminant Wilson's disease (FWD). Plasma exchange (PE), continuous hemodiafiltration (CHDF) and D-penicillamine administration were started immediately. Copper [24,000 microg] was removed by PE and CHDF over three days, which relieved the jaundice and the consciousness disorder. A successful liver transplant followed. FWD progresses rapidly and often liver transplantation is the only possible therapy. In this case, PE and CHDF were an effective therapy bridge until liver transplantation.
14689090##2003-12-23##[44-year-old patient with fulminant liver failure].##The 44-year old female patient was admitted with acute hepatic failure and extensive haemolysis under the preliminary diagnosis of Wilson's disease. General characteristic criteria of Wilson's disease as Kayser-Fleischer ring, low serum copper and low ceruloplasmin levels were not observed. The preliminary diagnosis of acute Wilson's disease was established on the basis of the characteristic laboratory values with an AP/bilirubin ratio <2, an AST/ALT ratio >4, accompanying hemolysis and a highly elevated cupruresis. The definitive diagnosis of Wilson's disease was verified after orthotopic liver transplantation by quantitative copper evaluation in the explanted liver. The case represents the yet oldest patient reported with an acute manifestation of Wilson's disease.
14514926##2003-9-30##4193delC, a common mutation causing Wilson's disease in Saudi Arabia: rapid molecular screening of patients and carriers.##
14551693##2003-10-11##[Electrophysiological impairment profile of patients with Wilson's disease].##In addition to hepatic and extrapyramidal motor clinical symptoms, Wilson's disease patients also exhibit subclinical disorders of other central nervous pathways. In this study, an impairment profile is described by means of eight electrophysiological tests (EAEP, MSEP, TSEP, T-VEP, MEP, EEG, heart frequency variability, and SSR) for 37 patients (28 with neurological, nine with tnon-neurological form) undergoing long-term drug therapy. The occurrence in 64.3% of a delayed wave III and/or IPL III-V prolongation in patients with the neurological form makes pathological FAEP the most common form of the disorder, followed by disorders in MSEP, TSEP, MEP, and T-VEP. Patients with the non-neurological form usually have normal values, although latency prolongations occur in isolated cases. The range of evoked potential findings is characterised primarily by latency prolongations, i.e. a demyelinising impairment type, and significant losses of potential hardly occur (except in the MEP). The electrophysiological impairment profile does not include EEG changes or vegetative disorders.
14635519##2003-11-26##[Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura].##In this study we report an individual of Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura. The initial symptom of this female patient was olfactory paranoia at age 17. Although that psychiatric symptom was well controlled under pharmacological treatment for two years, she developed olfactory paranoia as well as sialorrhea, dysarthria and finger tremor at age 20. A year later rigidity was also present in the extremities. At age 23, idiopathic thrombocytopenic purpura was found based on hematological examinations. Because her extrapyramidal symptoms were progressive, she was referred to our department to evaluate her neurologic condition. She was diagnosed as having Wilson's disease based on (1) the presence of Kayser-Fleischer rings, (2) extrapyramidal signs, and (3) a decreased level of serum copper and ceruloplasmin. T2 and FLAIR images of brain MRI showed hyperintense lesions in the putamen, thalamus and pontine tegmentum. Diffusion-weighted images also showed hyperintense lesions in the thalamus and pontine tegmentum. The biopsy specimen of the liver revealed chronic hepatitis with copper accumulation. Since D-penicillamine treatment was initiated, she has shown no olfactory paranoia and exacerbation of ITP. Her gait disturbance has also improved. Olfactory paranoia and ITP are rare clinical complications of Wilson's disease. Further analysis may warrant consideration of the pathophysiological mechanism of the psychiatric, hematological and neuroradiological condition seen in Wilson's disease.
14572346##2003-10-24##[Acute severe hepatitis and hemolytic anemia appeared firstly in a Wilson's disease patient].##
14642110##2003-12-3##[Living donor liver transplantation treatment of Wilson's disease complicated with neuropathy].##
12974640##2003-9-17##Functional roles of metal binding domains of the Archaeoglobus fulgidus Cu(+)-ATPase CopA.##CopA, a thermophilic membrane ATPase from Archaeoglobus fulgidus, drives the outward movement of Cu(+) or Ag(+) [Mandal et al. (2002) J. Biol. Chem. 277, 7201-7208]. This, as other P(IB)-ATPases, is characterized by a putative metal binding sequence (C(380)PC(382)) in its sixth transmembrane fragment and cytoplasmic metal binding sequences in its NH(2)- and COOH-terminal ends (C(27)AMC(30) and C(751)HHC(754)). Using isolated CopA, we have studied the functional role of these three putative metal binding domains. Replacement of transmembrane Cys residues by Ala results in nonfunctional enzymes that are unable to hydrolyze ATP. However, the CPC --> APA substituted enzyme binds ATP, indicating its correct folding and suggesting that enzyme turnover is prevented by the lack of metal binding to the transmembrane site. Replacement of C-terminal Cys by Ala (C(751,754)A) has no significant effect on ATPase activity, enzyme phosphorylation, apparent binding affinities of ligands, or E1-E2 equilibrium. In contrast, replacement of Cys in the N-terminal metal binding domain (N-MBD) (C(27,30)A) leads to 40% reduction in enzyme turnover. The C(27,30)A enzyme binds Cu(+), Ag(+), and ATP with the same high apparent affinities as the wild-type CopA. Evidence that N-MBD disruption has no effect on the E1-E2 equilibrium is provided by the normal interaction of ATP acting with low affinity and the unaffected IC(50) for vanadate inhibition observed in the C(27,30)A-substituted enzyme. However, replacement C(27,30)A slowed the dephosphorylation of the E2P(metal) form of the enzyme, suggesting a reduction in the rate of metal release. Other investigators have shown the Cu-dependent interaction of isolated N-MBDs from the Wilson disease Cu-ATPase with the ATP binding cytoplasmic domain [Tsivkovskii et al. (2001) J. Biol. Chem. 276, 2234-2242]. Therefore, the data suggest a regulatory mechanism in which the Cu-dependent N-MBD/ATP binding domain interaction would accelerate cation release, the enzyme rate-limiting step, and consequently Cu(+) transport.
14626805##2003-11-25##A case of penicillamine-induced dermopathy.##
14595502##2003-11-5##[Neuropsychiatric disturbances in Wilson's disease and use of electroconvulsive therapy: case report].##Wilson's disease consists in a inborn error of metabolism with marked neuropsychiatric manifestations. These manifestations need to be correctly identified and treated. There are four neuropsychiatric symptoms clusters established for Wilson's disease patients: behavior and/or personality disorders, mood disorders, cognitive deficits, and psychotic manifestations. Although such patients are more commonly seen in neurological and hepatological settings, mental health professionals must keep in mind a high level of suspicion, once first presentations may be of psychiatric nature. This study presents a review of literature about neuropsychiatric aspects of Wilson's disease, emphasizing diagnostic issues. It is presented the case of a 26 years old male patient initially with psychiatric polimorfic symptoms. The treatment of this patient with electroconvulsive therapy is presented, adding a report of this therapeutic modality, applied to that case, to the two only previous records in the literature.
13129463##2003-9-18##Excess dietary histidine decreases the liver copper level and serum alanine aminotransferase activity in Long-Evans Cinnamon rats.##Long-Evans Cinnamon (LEC) rats spontaneously develop fulminant hepatitis, associated with excess Cu accumulation in the liver: thus, they are considered an animal model of Wilson's disease. In the present study, we investigated the ability of excess dietary histidine to reduce the excess accumulation of liver Cu in LEC rats by comparing them with Fischer rats. The results clearly showed that the excess-histidine diet markedly stimulated the Cu excretion in urine, and significantly decreased the liver Cu content in LEC rats by 47.5%. The serum Cu content in LEC rats was not influenced by excess dietary histidine. We also compared the effects of excess dietary histidine on some liver antioxidant enzyme activities, liver and serum lipid levels and serum alanine aminotransferase activity of LEC and Fischer rats. Dietary histidine decreased the activities of total and Cu,Zn-superoxide dismutase in the liver of both strains. In LEC rats, the liver cholesterol content decreased, and serum cholesterol and phospholipids levels increased on feeding the excess-histidine diet. When fed on the basal diet, the serum alanine aminotransferase activity was higher in LEC rats than in Fischer rats, but a significant decrease in serum alanine aminotransferase activity of LEC rats was observed on feeding the excess-histidine diet. These results suggest that excess dietary histidine is effective in removing Cu ions from the liver of LEC rats. Thus, it may be of benefit in the prevention or treatment of liver injury in LEC rats and in patients with Wilson's disease.
14527081##2003-10-7##Death receptor activation-induced hepatocyte apoptosis and liver injury.##The TNFalpha receptor super-family consists of several members sharing a sequence homology in a unique function domain, the death domain, which is located in the intracellular portion of the receptor. These so-called death receptors, including Fas, TNF-R1 and TRAIL-R1/TRAIL-R2, are expressed on hepatocytes. When stimulated by their ligands, FasL, TNFalpha or TRAIL, respectively, the death receptors can activate multiple death domain-initiated apoptosis programs, including both extrinsic and intrinsic pathways. A cascade of caspases is activated, which cleave proteins important for the cell structure and function. Activation of the intrinsic pathway also leads to mitochondrial release of several apoptotic proteins and mitochondrial dysfunction, which kill the cell through both caspase-dependent and caspase-independent mechanisms. Death receptor-induced hepatocyte apoptosis contributes to the development of a number of liver diseases, including viral hepatitis, inflammatory hepatitis, Wilson's disease, alcoholic liver disease, endotoxiemia-induced liver failure and ischemia/reperfusion-induced liver damage. This article comprehensively reviews the mechanisms of induction and regulation of death receptor-initiated apoptosis in hepatocytes, examines how these molecular events affect our understanding of the pathogenesis of these diseases and further discusses the potential therapeutic application of the knowledge. We hope we can provide a cohesive and integrated perspective on the many aspects of these complicated processes.
12963867##2003-9-10##Spontaneously T1-hyperintense lesions of the brain on MRI: a pictorial review.##In this work, the brain lesions that cause spontaneously hyperintense T1 signal on MRI were studied under seven categories. The first category includes lesions with hemorrhagic components, such as infarct, encephalitis, intraparenchymal hematoma, cortical contusion, diffuse axonal injury, subarachnoid hemorrhage, subdural and epidural hematoma, intraventricular hemorrhage, vascular malformation and aneurysm, and hemorrhagic neoplasm. The second category includes protein-containing lesions, such as colloid cyst, craniopharyngioma, Rathke's cleft cyst, and atypical epidermoid. The third category includes lesions with fatty components, such as lipoma, dermoid, and lipomatous meningioma. Lesions with calcification or ossification, such as endocrine-metabolic disorder, calcified neoplasm, infection, and dural osteoma, constitute the fourth category, whereas the fifth category includes lesions with other mineral accumulation, such as acquired hepatocerebral degeneration and Wilson disease. The sixth category includes melanin-containing lesions, such as metastasis from melanoma and leptomeningeal melanosis. The last category is the miscellaneous group, which includes ectopic neurohypophysis, chronic stages of multiple sclerosis, and neurofibromatosis type I. The above-mentioned lesions are presented with their typical T1-hyperintense images, and the underlying reasons for those appearances in magnetic resonance imaging are discussed.
12940844##2003-8-28##MR imaging of the brain in patients with hepatic form of Wilson's disease.##The aim of this study was to detect the sites and frequency of possible lesions by brain magnetic resonance imaging (MRI; 1,5T) in a group of 16 neurologically asymptomatic patients with hepatic form of Wilson's disease (WD; seven untreated and nine under treatment). Abnormal MR findings of the brain were found in 75% of patients. Lesions in brain parenchyma were detected in all untreated, drug-naive patients and in 44% of treated patients. Abnormal signal in globus pallidus, putamen, and caudate nucleus was revealed in 86, 71 and 71% of treated and in 33, 33 and 22% of untreated patients, respectively. In five of eight patients with putaminal pathology (62.5%) and in four of seven patients with caudate nuclei involvement (57%), only proton density 2-weighted sequence (PDW) exhibited sensitivity for lesion detection, with both T1W and long echo T2W sequences being insensitive. This superiority of PDW sequence was even more pronounced in the group of untreated patients in whom 80% of putaminal pathology was visible exclusively on this sequence. The lower frequency of lesions in the group of treated in comparison with untreated patients indicated that they might be reversible in the course of chronic chelating therapy.
14563227##2003-10-18##Clinical, histologic and serologic evaluation of patients with acute non-A-E hepatitis in north-eastern Brazil: is it an infectious disease?##Non-A-E hepatitis and acute cryptogenic hepatitis are the names given to the disease of patients with clinical hepatitis, but in whom serologic evidence of A-E hepatitis has not been found. Over a period of 8 years, we evaluated in Brazil 32 patients who fulfilled the criteria for this diagnosis in order to determine patterns of the clinical illness, laboratory parameters, or histologic features. Each patient was subjected to virologic tests to exclude A-E hepatitis and cytomegalovirus/Epstein-Barr virus infection. Drug-induced hepatitis and autoimmune disease were also excluded. Wilson's disease was excluded in young patients. The course of the disease was clinical/biochemical recovery in 3 months in 25 patients and persistent alanine aminotransferase (ALT) elevation in 7 patients. Three of these had chronic hepatitis, and one had severe fibrosis on liver biopsy. During the acute illness, mean peak ALT was 1267 IU/L, bilirubin was 4.0 mg/dL, and ferritin was 1393 IU/mL. GB virus type C (GBV-C) was found in six patients, and TT virus (TTV) in five patients. We conclude that, in Brazil, non-A-E hepatitis probably originates from still unidentified viruses. The course of the disease and the histologic patterns are similar to those recorded for known viruses. Continuous survey for the specific etiologic agents is needed.
12933917##2003-8-23##Mitochondria.##Following the discovery in the early 1960s that mitochondria contain their own DNA (mtDNA), there were two major advances, both in the 1980s: the human mtDNA sequence was published in 1981, and in 1988 the first pathogenic mtDNA mutations were identified. The floodgates were opened, and the 1990s became the decade of the mitochondrial genome. There has been a change of emphasis in the first few years of the new millennium, away from the "magic circle" of mtDNA and back to the nuclear genome. Various nuclear genes have been identified that are fundamentally important for mitochondrial homeostasis, and when these genes are disrupted, they cause autosomally inherited mitochondrial disease. Moreover, mitochondrial dysfunction plays an important role in the pathophysiology of several well established nuclear genetic disorders, such as dominant optic atrophy (mutations in OPA1), Friedreich's ataxia (FRDA), hereditary spastic paraplegia (SPG7), and Wilson's disease (ATP7B). The next major challenge is to define the more subtle interactions between nuclear and mitochondrial genes in health and disease.
12962167##2003-9-10##Wilson disease.##Wilson disease is a rare disorder of copper metabolism that results in accumulation of copper in the liver and subsequently in other organs, mainly the central nervous system and the kidneys. Advances in the diagnosis and treatment of Wilson disease are discussed, with the emphasis that this is a disease of children, adolescents, and young adults. The myriad manifestations of Wilson disease make its diagnosis dependent on a high index of suspicion, and determination of its genetic background is helping to elucidate the genotype-phenotype correlation and the diversity of presentations. Treatment of Wilson disease has progressed from chelation therapy using D-penicillamine and trientine to the more recent use of zinc and finally to the establishment of liver transplantation as an urgent but excellent modality for fulminant presentation. The evolution of Wilson disease from a uniformly fatal disease to an eminently treatable disease during the past century is an example of the remarkable advances of modern medicine.
12930977##2003-8-22##Parallel gene analysis with allele-specific padlock probes and tag microarrays.##Parallel, highly specific analysis methods are required to take advantage of the extensive information about DNA sequence variation and of expressed sequences. We present a scalable laboratory technique suitable to analyze numerous target sequences in multiplexed assays. Sets of padlock probes were applied to analyze single nucleotide variation directly in total genomic DNA or cDNA for parallel genotyping or gene expression analysis. All reacted probes were then co-amplified and identified by hybridization to a standard tag oligonucleotide array. The technique was illustrated by analyzing normal and pathogenic variation within the Wilson disease-related ATP7B gene, both at the level of DNA and RNA, using allele-specific padlock probes.
12954924##2003-9-5##Quetiapine for mania with Wilson's disease.##
12925721##2003-8-20##Abdominal malignancies in patients with Wilson's disease.##
14529909##2003-10-8##Results of liver transplantation according to indications for orthotopic liver transplantation.##
14529845##2003-10-8##Role of genetic testing in liver transplantation for Wilson's disease.##
12794172##2003-6-10##The distinct roles of the N-terminal copper-binding sites in regulation of catalytic activity of the Wilson's disease protein.##Wilson's disease protein (WNDP) is a copper-transporting ATPase essential for normal distribution of copper in human cells. Recent studies demonstrate that copper regulates WNDP through several mechanisms. Six metal-binding sites (MBS) at the N terminus of WNDP are predicted to be involved in copper-dependent regulation of WNDP; however, specific roles of MBS remain poorly understood. To address this issue, we generated WNDP variants with mutations or truncation in the N-terminal region and characterized their functional properties. We show that copper cooperatively stimulates catalytic activity of WNDP and that this effect requires the presence of both MBS5 and MBS6. Mutations of MBS6 or MBS1-5 result in non-cooperative activation of the enzyme by copper, whereas the deletion of MBS1-4 does not abolish cooperativity. Our data further suggest that MBS5 and MBS6 together regulate the affinity of the intramembrane-binding site(s) for copper. Analysis of the copper-dependent stimulation of catalytic phosphorylation demonstrate that the MBS6 and MBS1-5 mutants have a 7-8-fold lower EC50 for copper activation, suggesting that their affinity for copper is increased. This conclusion is confirmed by a markedly decreased inhibition of these mutants by a copper chelator bathocuproine disulphonate. In contrast, deletion of MBS1-4 does not affect the affinity of sites important for catalytic phosphorylation. Rather, the MBS1-4 region appears to control access of copper to the functionally important metal-binding sites. The implications of these findings for intracellular regulation of WNDP are discussed.
14562189##2003-10-17##Status epilepticus in a case with wilson's disease during D-pencillamine treatment.##
14704886##2004-1-6##Self-rated emotional functioning of patients with neurological or asymptomatic form of Wilson's disease.##Psychopathology was assessed in 50 patients with the neurological form of Wilson's disease (WD-N) and in 17 asymptomatic patients (WD-A) compared to matched healthy controls and to rheumatoid arthritis (RA) control patients using The Hopkins Symptom Checklist. As hypothesized, WD-N patients had significantly lower interpersonal sensitivity and aggression/hostility scores than had healthy controls, but did not differ from them either in depression or anxiety levels. Retarded depression and anxiety were higher among RA patients than in WD-N patients. This nondistressed response to the chronic disabling disease was even more salient in 19 WD patients with lesions in basal ganglia only. WD-A patients did not differ from their healthy peers, which suggests a tendency towards hypercompensation and denial in the former. WD-N patients' limited awareness of their deficits (including impaired control of affective behavior) seems to result from their brain damage implicating the basal ganglia.
12898347##2003-8-5##Regional serotonin transporter availability and depression are correlated in Wilson's disease.##In patients with Wilson's disease (WD), depression is a frequent psychiatric symptom. In vivo neuroimaging studies suggest that depression and other neuropsychiatric disorders are associated with central serotonergic deficits. However, in vivo measurements of serotonergic neurotransmission have not until now been performed in patients with this copper deposition disorder. The present prospective study revealed that depressive symptomatology is related to an alteration of presynaptic serotonin transporters (SERT) availability as measured by [123I]-2beta-carbomethoxy-3beta-(iodophenyl)tropane ([123I]beta-CIT) and high-resolution single-photon emission computed tomography (SPECT). SERT imaging with [123I]beta-CIT-SPECT could therefore become a useful tool for diagnosis and therapy monitoring in depressed WD patients.
15156603##2004-5-26##Results of treatment of Wilson's disease--own observations.##
15156602##2004-5-26##Treatment of Wilson's disease.##On the basis of literature review and own experience we presented the method of treatment of Wilson's disease. Causative treatment has been impossible so far, although gene therapy could be real in the future. Nowadays the principle of treatment is the elimination of the excess of easily mobilized copper by chelating agents or blocking the intestinal absorption of copper. Chelation therapy, aimed at mobilizing copper from the affected organs and promoting its excretion in the urine or stool is the most important. The major chelating agent is d-penicillamine, which is quite effective but not without some side effects. Alternative chelating agents such as trientine and tetrathiomolybdate have also been successfully employed. Zinc salts are also of therapeutic value. They promote copper excretion by inducing the synthesis of metallothionein in the intestine, thereby blocking copper absorption from the gut. Zinc salts have almost no side effects. They cannot be used as an initial treatment, but are very effective for maintenance therapy. The chelation therapy is ineffective in patients with acute liver failure with encephalopathy and hemolysis. In these cases, liver transplantation is the only hope for survival. Liver transplantations in patients with dominating psychoneurological symptoms are open to discussion.
12869652##2003-7-19##The copper export pump ATP7B modulates the cellular pharmacology of carboplatin in ovarian carcinoma cells.##Human tumor cells lines with acquired resistance to cisplatin (DDP) and carboplatin (CBDCA) are often cross-resistant to copper and vice versa, and some DDP-resistant cells overexpress the copper export pump ATP7B. We sought to demonstrate that ATP7B directly mediates resistance to DDP and CBDCA by stably transfecting human carcinoma cells with a vector designed to express ATP7B. Increased expression of ATP7B rendered all three cell lines tested more resistant to a 1-h exposure to DDP (1.6-2.6-fold), CBDCA (1.5-1.6-fold), and copper (1.2-1.4-fold). The effect of ATP7B on the cellular pharmacology of 64Cu and [14C]CBDCA was investigated in more detail using one cell pair (2008 cells transfected with an empty vector or an ATP7B-expressing vector). In the 2008/ATP7B subline, steady-state copper levels were decreased under both basal and copper-supplemented conditions, as was steady-state CBDCA content upon exposure to 50 microM [14C]CBDCA. Over the first 5 min, the average rate of accumulation of copper and CBCDA in the 2008/ATP7B cells was reduced by 37 and 61%, respectively. Efflux was more rapid from 2008/ATP7B cells for both copper and CBDCA. Two-compartment modeling indicated that the second phase of efflux was increased by a factor of 3.9-fold for CBCDA and to an even greater extent for copper. We conclude that expression of ATP7B regulates sensitivity to CBDCA as well as to DDP and copper and that a transporter that normally mediates copper homeostasis modulates the cellular pharmacology of CBDCA.
12973662##2003-9-16##Frontal N30 of median nerve SSEPs for evaluation of movement disorders with destructive basal ganglia deficits.##This study was performed to show the usefulness of N30 and N20 of median nerve SSEPs for evaluating the pathogenesis of central nervous system movement disorders. The subjects were 14 patients, consisting of 7 patients with an extrapyramidal lesion, 3 patients with suspicion of hypoxic-ischemic cerebral injury before birth period (H-I group), 3 patients with kernicterus during the neonatal period (kernicterus group), and 1 patient having Wilson's disease. Seven patients had spastic hemiplegia. Patients with athetotic CP had the ability to handle an electric wheelchair alone, and those with spastic hemiplegia could walk alone. Thirty control subjects were included in this study for clinical investigation. The characteristic finding of a predominant absence or amplitude reduction of frontal N30 compared with that of parietal N20 (4 and 1, respectively, out of 6 examinations) was obtained in athetotic CP patients of the H-I group. The predominant absence of N30 compared with N20 did not appear in the kernicterus group, hemiplegic patients or a patient with Wilson's disease. Therefore, frontal N30 might sensitively reflect destructive damage in the frontal basal ganglia in children.
14580665##2003-10-29##Familial pediatric rapidly progressive extrapyramidal syndrome: is it Hallervorden-Spatz disease?##The clinical features of two children of a family with rapidly progressive extrapyramidal-pyramidal-dementia complex have been described. Inheritance seems most likely to be autosomal recessive. Magnetic resonance imaging results of brain were negative. Even so, the authors argued in favor of a diagnosis of Hallervorden-Spatz disease because the cases fulfilled the clinical criteria for diagnosis of this disease. Apart from the negative magnetic resonance findings, the other unusual feature was the early development of levodopa-induced dyskinesia. Few conditions need to be considered in the differential diagnosis of a childhood-onset rapidly progressive extrapyramidal syndrome. Such conditions include Wilson's disease, Hallervorden-Spatz disease (HSD), juvenile form of Huntington's disease, juvenile neuronal ceroid lipofuscinosis, early-onset Machado-Joseph disease neuroacanthocytosis, storage disorders, and variant form of dopa-response dystonias (DRD). Rarer conditions are Leigh's disease, Lafora body disease, and dentato-rubro-pallido-luysian atrophy. HSD is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Onset is most commonly in late childhood or early adolescence. The disease can be familial or sporadic. When familial, it is inherited recessively and has been linked to chromosome 20. Recently, a mutation in the pantothenate kinase (PANK2) gene on band 20pl3 has been described in patients with typical HSD. HSD produces typical magnetic resonance imaging (MRI) changes in brain, aiding in antemortem diagnosis. The typical finding is of bilaterally symmetrical hyperintense signal changes in the external segment of globus pallidus, with surrounding hypointensity on T(2)-weighted image. These imaging features are fairly diagnostic and have been termed the "eye-of-the tiger sign". The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is caused by loss of signal secondary to iron deposition. Described herein are the clinical aspects of a family with autosomal recessive inheritance with rapidly progressive extrapyramidal-pyramidal-dementia complex but with negative brain MRI results. The diagnosis should be considered a variant form of HSD.
12892020##2003-8-2##[From gene to disease; Wilson disease: copper storage due to mutations in ATP7B].##
12810447##2003-6-18##Polymicrobial septic arthritis in a patient with Wilson's disease.##
12860252##2003-7-16##Copper induces the expression of cholesterogenic genes in human macrophages.##Accumulation of lipids and cholesterol by macrophages and subsequent transformation into foam cells are key features in development of atherosclerosis. Serum copper concentrations have been shown to be associated with cardiovascular disease. However, the mechanism behind the proatherogenic effect of copper is not clear. We used DNA microarrays to define the changes in gene expression profile in response to copper exposure of human macrophages. Expression monitoring by DNA microarray revealed 91 genes that were regulated. Copper increased the expression of seven cholesterogenic genes (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, IPP isomerase, squalene synthase, squalene epoxidase, methyl sterol oxidase, H105e3 mRNA and sterol-C5-desaturase) and low-density lipoprotein receptor (LDL-R), and decreased the expression of CD36 and lipid binding proteins. The expression of LDL-R and HMG CoA reductase was also investigated using real time PCR. The expression of both of these genes was increased after copper treatment of macrophages (P<0.01 and P<0.01, respectively). We conclude that copper activates cholesterogenic genes in macrophages, which may provide a mechanism for the association between copper and atherosclerosis. The effect of copper on cholesterogenic genes may also have implications for liver steatosis in early stages of Wilson's disease.
12791196##2003-6-7##Torsion Dystonia in Children.##Medical treatment of childhood-onset dystonia can lead to substantial improvement of the condition, often with much more pronounced benefit than in adults. The authors give every patient a trial of levodopa to assess the possible diagnosis of dopa-responsive dystonia, followed-up with centrally acting anticholinergics such as trihexiphenydil. If needed, baclofen or clonazepam is added or substituted. In focal dystonia or segmental and generalized dystonia with prominent involvement of specific muscle groups, botulinum toxin injections are often used. Pallidal deep brain stimulation is offered to selected patients with medically refractory dystonia. Treatment of secondary dystonias, caused by such conditions as Wilson's disease, requires therapy for the underlying disorder. Physical therapy, splints, and occupational therapy can be useful in some patients. The authors do not use intrathecal baclofen unless there is evidence of accompanying spasticity.
14703896##2004-1-6##Anticopper efficacy of captopril and sodium dimercaptosulphonate in patients with Wilson's disease.##The aim of this study was to explore and compare initial treatment effects of captopril (Tensiomin) and sodium dimercaptosulphonate (DMPS) on a relatively large series of Wilson's disease inpatients. Two important markers of anticopper efficacy: serum sulphydryl and 24 h urinary copper levels in the patients were evaluated before and after treatment. The patients were randomly subdivided into 4 groups to allow statistical analysis (ANOVA) of the values recorded. The protocol was an open-label study of all the patients treated for 8 weeks (i.e., all the patients except those in the no-drug group), and a further six-month follow-up (post hospitalization) of the 14 patients administered captopril. Several copper-related variables were studied to evaluate the effect of the drugs on copper, and several biochemical and clinical variables were studied to evaluate potential toxic effects. Captopril was found to have a significant anticopper effect and did not markedly raise serum sulphydryl levels within this limited patient sample; the anticopper efficacy of captopril was, however, found to be markedly lower than that of DMPS; DMPS was found to raise the patients' serum sulphydryl and urinary copper levels. Evaluation of data from individual patients revealed evidence of a toxic side effect in only 1 patient, treated with DMPS, who exhibited transiently raised serum alanine aminotransferases, while no serious adverse events, upstanding syncope, irritating cough and leukopenia induced by captopril were noted. The results obtained in this four-group sample suggest that captopril might be a mild anticopper agent for Wilson's disease, possibly relieving the hepatic portal hypertension, but that DMPS has a greater field of anticopper efficiency than captopril. The authors also discuss recent experience of the overall treatment in China.
12885331##2003-7-30##Characterization of the molecular defect in the ATP7B gene in Wilson disease patients from Yugoslavia.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from the absence or dysfunction of a copper transporting P-type ATPase (ATP7B). Approximately 150 mutations of the ATP7B have been identified to date. In this paper, we report the results of molecular characterization and genotype-phenotype analysis, which we have carried out on 35 patients from Yugoslavia affected by WD. Using single-strand conformational polymorphism (SSCP) followed by direct sequencing, we characterized the molecular defect in 80% of WD chromosomes and found 11 different mutations, three of which are novel. The most common mutations that accounted for the molecular defect in 71.3% of WD chromosomes were H1069Q (48.9%), 2304-2305insC (11.4%), R616Q (5.7%), and A1003T (5.7%). The results produced in this paper indicate that the best strategy for mutation detection in Yugoslavian patients with WD is an SSCP analysis of exons 14, 8, 5, and 13, where most of the defects (73.1%) lie, followed by mutation analysis of the remaining exons in ATP7B in patients in whom the mutation was not detected by the finitial screening. These data can be used to develop straightforward genetic testing in this population or in other countries composed of a genetically mixed population like the United States, where a significant number of immigrants came from Central and Eastern Europe.
12940376##2003-8-28##Congenital and inherited ophthalmologic abnormalities.##
12894051##2003-8-2##A case report on Wilson's disease.##A case of Wilson's disease, a rare autosomal recessive disorder of copper metabolism is reported here. The patient was presented with the difficulty in speech and writing for 4 years and also on walking for 1 year. He also noticed difficulty to perform any work by hands for 6 months. He had splenomegaly and bilateral gynaecomastia. His speech was low volume slurred and monotonous, muscle tone was mildly increased, and gait was limping. Slit lamp examination of eye revealed bilateral Kayser-Fleischer ring with normal visual acuity. Investigations revealed low serum albumin(26 gram/L), increased alanine trans-aminase ( A.L.T=57 U/L). Ultrasonogram of hepatobiliary system revealed coarse hepatic tissue echotexture with splenomegaly. Liver scan showed slightly nonuniform radiotracer distribution in the liver, there was slight increased bony uptake. Serum caeruloplasmin level was 11.51 mg/dl. 24 hours urinary copper excretion was 150 microgram per day. Liver biopsy revealed cirrhotic change. Now he was advised for taking copper chelating agent (penicillamine) in a dose of 1 gram/day.
12831417##2003-7-2##Fulminant Wilson's disease in children: appraisal of a critical diagnosis.##
13679120##2003-9-19##The diagnostic value of sensory evoked potentials in pediatric Wilson disease.##We studied the sensory evoked potentials in pediatric Wilson disease to verify their subclinical neurologic involvement and to elucidate the role of cirrhosis in abnormal evoked potentials in non-neurologic Wilson disease. Thirty children (17 male, 13 female), diagnosed with Wilson disease before 18 years, were enrolled. The mean age during studies was 15.8 +/- 6.3 years, and disease duration since diagnosis was 3.0 +/- 3.3 years. In 12 neurologic Wilson disease cases, there were prolonged interpeak latencies of brainstem auditory evoked potentials III-V, I-V, somatosensory evoked potentials N13-N20 (P < 0.01 vs controls and non-neurologic cases), and P100 latency (P < 0.01 vs controls). All 12 patients had at least one abnormal evoked potential, including 91.7% brainstem auditory, 58.3% somatosensory, and 25% visual evoked potentials. In 18 non-neurologic Wilson disease cases, there were still prolonged interpeak latencies for brainstem auditory evoked potentials I-V and somatosensory evoked potentials N13-N20 (P < 0.05 vs controls), with 27.8% of them having at least one abnormal evoked potential, including 16.6% brainstem auditory, 5.6% somatosensory, and 11.1% visual evoked potentials. In those with non-neurologic Wilson disease, there were no significant differences in all the evoked potential parameters between the cirrhotic and non-cirrhotic patients.
12881597##2003-7-26##Apolipoprotein E genotypes in Chinese patients with Wilson's disease.##
12783576##2003-6-5##Antiangiogenic therapy through copper chelation.##As new compounds are being evaluated for use in clinical trials involving antiangiogenic therapies, two important factors must be considered. Independent of clinical efficacy, the potential drug must be cost-effective and have reasonable ease of production. The compound endostatin (Entremed, Inc.) has recently completed two Phase I trials with minimal toxicity to the patients treated [1,2]. However, due to the difficulty and expense of producing large quantities of a recombinant protein, Entremed Inc. has experienced financial difficulties [3]. As this company's fate indicates, a drug must not only be clinically effective, but must also possess reasonable production economics. Another interesting component of compound development is selectivity. Highly selective antiangiogenic compounds such as the tyrosine kinase inhibitor SU-5416 are being replaced by less selective compounds such as SU-6668, which acts on a broader spectrum of tyrosine kinase receptors [4]. This move towards using less selective antiangiogenic compounds is based on preclinical models that demonstrate both better clinical efficacy when using less specific molecules and low response rates from the more selective compounds. With the aim of further examining broadly-acting antiangiogenic agents, the authors are currently evaluating new classes of agents that preferentially bind copper and inhibit angiogenesis. Copper has been known to be a significant target for antiangiogenic therapy for a number of years [5]. Recently, through the use of molecular techniques, the target enzymes that utilise copper as a cofactor are being elucidated. This review will describe the historical use of anticopper therapy for the treatment of Wilson's disease and evaluate some of the new anticopper compounds currently under consideration for use in antiangiogenic therapy.
12782122##2003-6-5##Genomic studies of gene expression: regulation of the Wilson disease gene.##Bacterial artificial chromosomes (BACs) have many advantages over other large-insert cloning vectors and have been used for a variety of genetic applications, including the final contigs of the human genome. We describe the utilization of a BAC construct to study gene regulation in a tissue culture-based system, using a 170-kb clone containing the entire Wilson disease (WND) locus as a model. A second BAC construct that lacked a putative negatively regulating promoter sequence was created. A nonviral method of gene delivery was applied to transfect three human cell lines stably with each construct. Our results show correct WND gene expression from the recombinant locus and quantification revealed significantly increased expression from the clone lacking the negative regulator. Comparison with conventional methods confirms the reliability of the genomic approach for thorough examination of gene expression. This experimental system illustrates the potential of BAC clones in genomic gene expression studies, new gene therapy strategies, and validation of potential molecular targets for drug discovery.
12774027##2003-5-30##A practice guideline on Wilson disease.##
12819634##2003-6-24##Zinc treatment prevents lipid peroxidation and increases glutathione availability in Wilson's disease.##Oxidative and reductive mechanisms are important in Wilson's disease. In this study, we sought to evaluate tissue levels of glutathione and cysteine, an important detoxification system, and of malondialdehyde, a marker of lipoperoxidation, in patients with Wilson's disease receiving penicillamine or zinc treatment, in comparison with patients with chronic liver disease of different origin. Concentrations of cysteine, reduced/oxidized glutathione, malondialdehyde, zinc, and copper were determined (with the use of high-pressure liquid chromatography, fluorimetry and atomic-absorption spectrophotometry) in liver-biopsy specimens from 24 patients with Wilson's disease (18 treated with zinc, 6 with penicillamine), 34 patients with chronic viral hepatitis, and 10 patients with alcoholic liver disease. In patients with Wilson's disease, the concentration of reduced glutathione was lower than that in patients with viral hepatitis and as high as that in subjects with alcoholic liver damage. The cysteine level was significantly lower than those in the control groups, and the percentage of oxidized glutathione/total glutathione was higher than that in viral or alcoholic disease. Malondialdehyde levels were low, but when zinc- and penicillamine-treated patients were considered separately, only the former had low malondialdehyde levels. Zinc-treated patients had higher concentrations of reduced glutathione and a lower percentage of oxidized glutathione. In summary, patients with Wilson's disease have relevant glutathione depression, with low levels of reduced glutathione and cysteine and high concentrations of oxidized glutathione: This is prevented by zinc administration, which inhibits lipid peroxidation and increases glutathione availability.
12955875##2003-9-6##Diagnosis and phenotypic classification of Wilson disease.##Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.
12718440##2003-4-30##A mutation in the ATP7B copper transporter causes reduced dopamine beta-hydroxylase and norepinephrine in mouse adrenal.##The copper-transporting ATPases Atp7A and Atp7B play a major role in controlling intracellular copper levels. In addition, they are believed to deliver copper to the copper-requiring proteins destined for the secretory vesicles. One cuproprotein, dopamine beta-hydroxylase (DBH) functions in the biosynthesis of norepinephrine and epinephrine, neurohormones in endocrine and nervous tissue. To evaluate the consequences of loss of Atp7B on the function of DBH, the level of proteins in adrenal gland were compared between normal mice and mice containing a null mutation in the ATP7B gene. The levels of DBH, as well as another vesicular protein, chromogranin A, are reduced in the ATP7B -/- mice. In addition to the lower level of enzyme, the products of DBH catalytic activity, norepinephrine and epinephrine, are also decreased. Although these changes are a consequence of ATP7B gene function, Atp7B mRNA is not normally expressed in the adrenal gland. Instead, Atp7A mRNA is present. The levels of copper and DBH RNA within adrenals of the ATP7B -/- mice are not different from the wild type. The results of these experiments suggest that copper-requiring enzymes are affected by a loss of ATP7B even in tissue not normally expressing this protein. Therefore the multisystemic effects observed in Wilson disease, the human disorder characterized by mutation in ATP7B, may be a secondary consequence of the major accumulation of copper in liver.
14570999##2003-10-23##Parkinsonism plus syndrome--a review.##Parkinsonism plus syndrome is a group of heterogeneous degenerative neurological disorders, which differ from the classical idiopathic Parkinson's disease in certain associated clinical features, poor response to levodopa, distinctive pathological characteristics and poor prognosis. Associated clinical features include symmetrical onset, infrequent or atypical tremor, prominent rigidity in axial musculature, bradykinesia, early postural instability, supranuclear gaze palsy, early autonomic failure, pyramidal affection, cerebellar involvement, alien limb phenomenon, apraxia and significant early cognitive dysfunction in some cases. Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and dementia with Lewy body disease (DLB) are commoner disorders. Less frequent disorders are cortico-basal ganglionic degeneration (CBGD), frontotemporal dementia with chromosome 17 (FTDP-17), Pick's disease, parkinsonian-dementia complex of Guam, Pallidonigral degeneration, Wilson's disease and a rigid variant of Huntington's disease. During the last 3 decades, major progress has been made in understanding PSP, CBGD and FTDP-17, which are tau disorders. MSA and DLB together with idiopathic Parkinson's disease are called alpha-synucleinopathies. Recent studies show that the diagnosis of these Parkinsonism plus syndromes improves when strict diagnostic criteria are used. However, unusual presentations may pose a diagnostic challenge. The shortcomings of the current studies demand the need for further research to identify biologic markers that may allow earlier diagnosis, and understanding of the factors leading to alpha-synuclein or tau aggregation. Identification of therapeutic strategies that may prevent the aggregation of these proteins and rescue dysfunctional cells has been stressed. This review focuses on the advances in the clinical, neuroimaging, pathologic, genetic and management aspects of these disorders.
12826186##2003-6-27##Liver transplantation for hepatic and neurological Wilson's disease.##Wilson's disease (WD) is an autosomal-recessive inherited disorder of copper metabolism characterized by excessive deposition of copper throughout the body. If medical treatment fails in cases of fulminant hepatic failure and progressive hepatic dysfunction due to advanced cirrhosis, liver transplantation (OLTx) has been demonstrated to be a valuable treatment option. Between December 1993 and December 2002, 225 OLTxs in 198 patients were performed in our institution. In this consecutive series six patients (three females and three males) were liver grafted for WD. The follow-up ranged from 3 to 7 years. All patients are alive with well-functioning grafts at present. The ceruloplasmin levels increased after transplantation and remained normal. The Kayser-Fleischer ring disappeared in all patients, and urinary copper excretion normalized. The neurological manifestations in the two patients with severe neurological symptoms showed after 2 to 5 years a downward tendency; in one the ataxic movements disappeared completely. The psychiatric disorder in one patient disappeared as well the mild neurological symptoms in the patient with CHILD A cirrhosis. These two patients are fully recovered and returned to work. OLTx should be considered as a treatment option in patients with severe progressive neurological deficits even in cases with stable liver function since liver grafting definitely cures the underlying biochemical defect. In such cases an early decision for liver transplantation is justified because neurological deficits may become irreversible.
12826183##2003-6-27##A case of electrical storm in a liver transplant patient.##Electrical storm has not been well described in liver transplant patients. We present a case of sympathetically mediated recurrent ventricular fibrillation in a young patient transplanted for acute Wilson's disease. This case highlights the role of the sympathetic nervous system in causing electrical storm and it demonstrates the ability of beta-blocking agents to terminate the event. In young liver transplant patients, beta-blocking agents should be considered for therapy of perioperative electrical storm if there is no known structural or coronary heart disease and when there are no risk factors for, or evidences of, torsades de pointes.
12748103##2003-5-16##Diffusion MR imaging changes associated with Wilson disease.##We herein report the case of a patient with Wilson disease. The patient underwent echo-planar diffusion MR imaging twice, 1.5 years apart. The lesions were in the putamina and caudate nuclei. At the first examination, undertaken after onset of extrapyramidal symptoms, a restricted diffusion pattern was evident. It is likely that this corresponded to cell swelling caused by the accumulation of copper. On the images obtained 1.5 years later, an opposite pattern (an elevated diffusion pattern) was noted. It is likely that this reflected necrosis, spongiform degeneration, and demyelination, which are among the known histopathologic changes associated with Wilson disease.
12756138##2003-5-21##Molecular diagnosis and prophylactic therapy for presymptomatic Chinese patients with Wilson disease.##
12774959##2003-5-31##Dopamine transporter binding in Wilson's disease.##
12839386##2003-7-4##Neurologic deterioration in a child with Wilson's disease on penicillamine therapy.##Penicillamine is the standard therapy for Wilson's disease in children. We report an 8-year-old-girl with liver disease due to Wilson's disease who developed extrapyramidal symptoms following administration of penicillamine. Symptoms resolved within 20 hours of stopping the drug but recurred within 24 hours when gradually increasing small doses were recommenced.
12974446##2003-9-17##Wilson's disease in late adulthood presenting with ascites.##
12736737##2003-5-9##The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease.##
12700322##2003-4-18##Faces of the giant panda and her cub: MRI correlates of Wilson's disease.##
12730458##2003-5-6##Genetic defects in copper metabolism.##Genetic defects in copper metabolism highlight the delicate balance mammalian systems have developed to maintain normal copper homeostasis. Menkes disease, the mottled mouse, the Atox-1-deficient mouse and the ctr1 knockout mouse reveal the importance of adequate copper intake during embryogenesis and early development, especially in the central nervous system. The toxicity associated with excess copper as manifest in Wilson disease, the toxic milk mouse, the LEC rat and copper toxicosis in the Bedlington terrier demonstrate the profound cellular susceptibility to copper overload, in particular, in the brain and liver. Ceruloplasmin (Cp) contains 95% of the copper found in human serum, and inherited loss of this protein results in diabetes, retinal degeneration and neurodegeneration. Despite normal copper metabolism, aceruloplasminemic patients and the Cp knockout mouse have disturbed iron homeostasis and mild hepatic copper retention. These genetic disorders of copper metabolism provide valuable insight into the mechanisms regulating copper homeostasis and models to further dissect the role of this essential metal in health and disease.
12730448##2003-5-6##Molecular and cellular aspects of copper transport in developing mammals.##Copper is an essential trace element that requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects because of the ability of the metal ion to catalyze the formation of free radicals. The Cu-ATPases, ATP7A and ATP7B, play an important role in the physiological regulation of copper. Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood. In contrast, mutations in ATP7B result in the genetic toxicosis, Wilson disease. We propose that the physiological regulation of copper is accomplished mainly by the intracellular copper-regulated trafficking of the Cu-ATPases. This process allows the overall copper status in the body to be maintained when levels of copper in the diet alter. A study of the defects in mouse models of Menkes and Wilson diseases has demonstrated that both ATPases play an important role in supplying copper to the developing fetus and neonate.
12730405##2003-5-6##Soy protein isolate enhances hepatic copper accumulation and cell damage in LEC rats.##In a series of experiments, the effects of soy protein isolate (SPI), defatted soy (DFS) or SPI supplemented with L-methionine (SPIM) were examined in the Long-Evans rat with a cinnamon coat color (LEC rat), a model animal of Wilson's disease with a hereditary defect in the Atp7b gene resulting in defective copper metabolism and copper accumulation in hepatocytes. Milk casein in the control AIN-93G diet (20 g/100 g) was totally or 60% replaced by the soy products, SPI, DFS or SPIM (L-Met added to be equal to that in the control diet) beginning when rats were 6 wk old. Copper and iron concentrations in SPI and DFS were measured and the concentrations of these metals in the salt mix were adjusted so that test and the control diets had the same final concentrations. Food intake did not differ among groups. Rats were euthanized when they became moribund with jaundice. Survival time in the SPI diet group was shorter (14.0 +/- 0.8 wk) than in the control group (19.1 +/- 1.7 wk) (P < 0.001), and that in the DFS diet group was intermediate (16.0 +/- 1.7 wk). Survival time in the SPIM diet group did not differ from that of the SPI diet group. Copper concentrations in the livers of rats in the SPI and SPIM diet groups were approximately 80% higher than in rats fed the control diet. Liver iron concentrations did not differ among the groups. The results, including histological analyses, indicate that SPI enhances copper uptake into the liver cells and promotes liver cell damage in LEC rats. However, this did not occur in the livers of F344 rats with wild-type Atp7b. Recommendations to individuals suffering from Wilson's disease to avoid consuming soy protein may be warranted.
12717088##2003-4-30##Early occurrence of hypertransaminasemia in a 13-month-old child with Wilson disease.##
12809272##2003-6-18##Palatal lift prosthesis for palatopharyngeal closure in Wilson's disease.##This is a report of our work on a female patient with Wilson's disease who was treated for speech improvement. A palatal lift prosthesis was constructed to displace the soft palate superiorly and posteriorly and partially restore the functional deficiencies of palatopharyngeal insufficiency. Cephalometric radiographs confirm the association between the displacement of the soft palate and speech improvement.
12698088##2003-4-17##Liver transplantation for Wilson's disease: long-term results and quality-of-life assessment.##
12551905##2003-1-29##The role of the invariant His-1069 in folding and function of the Wilson's disease protein, the human copper-transporting ATPase ATP7B.##The copper-transporting ATPase ATP7B is essential for normal distribution of copper in human cells. Mutations in ATP7B lead to Wilson's disease, a severe disorder with neurological and hepatic manifestations. One of the most common disease mutations, a H1069Q substitution, causes intracellular mislocalization of ATP7B (the Wilson's disease protein, WNDP). His-1069 is located in the nucleotide-binding domain of WNDP and is conserved in all copper-transporting ATPases from bacteria to mammals; however, the specific role of this His in the structure and function of WNDP remains unclear. We demonstrate that substitution of His-1069 for Gln, Ala, or Cys does not significantly alter the folding of the WNDP nucleotide-binding domain or the proteolytic resistance of the full-length WNDP. In contrast, the function of WNDP is markedly affected by the mutations. The ability to form an acylphosphate intermediate in the presence of ATP is entirely lost in all three mutants, suggesting that His-1069 is important for ATP-dependent phosphorylation. Other steps of the WNDP enzymatic cycle are less dependent on His-1069. The H1069C mutant shows normal phosphorylation in the presence of inorganic phosphate; it binds an ATP analogue, beta,gamma-imidoadenosine 5'-triphosphate (AMP-PNP), and copper and undergoes nucleotide-dependent conformational transitions similar to those of the wild-type WNDP. Although binding of AMP-PNP is not disrupted by the mutation, the apparent affinity for the nucleotide is decreased by 4-fold. We conclude that His-1069 is responsible for proper orientation of ATP in the catalytic site of WNDP prior to ATP hydrolysis.
12529325##2003-1-17##Supplying copper to the cuproenzyme peptidylglycine alpha-amidating monooxygenase.##We explored the role of known copper transporters and chaperones in delivering copper to peptidylglycine-alpha-hydroxylating monooxygenase (PHM), a copper-dependent enzyme that functions in the secretory pathway lumen. We examined the roles of yeast Ccc2, a P-type ATPase related to human ATP7A (Menkes disease protein) and ATP7B (Wilson disease protein), as well as yeast Atx1, a cytosolic copper chaperone. We expressed soluble PHMcc (catalytic core) in yeast using the yeast pre-pro-alpha-mating factor leader region to target the enzyme to the secretory pathway. Although the yeast genome encodes no PHM-like enzyme, PHMcc expressed in yeast is at least as active as PHMcc produced by mammalian cells. PHMcc partially co-migrated with a Golgi marker during subcellular fractionation and partially co-localized with Ccc2 based on immunofluorescence. To determine whether production of active PHM was dependent on copper trafficking pathways involving the CCC2 or ATX1 genes, we expressed PHMcc in wild-type, ccc2, and atx1 mutant yeast. Although ccc2 and atx1 mutant yeast produce normal levels of PHMcc protein, it lacks catalytic activity. Addition of exogenous copper yields fully active PHMcc. Similarly, production of active PHM in mouse fibroblasts is impaired in the presence of a mutant ATP7A gene. Although delivery of copper to lumenal cuproproteins like PAM involves ATP7A, lumenal chaperones may not be required.
12769823##2003-5-29##Animal models of copper-associated liver disease.##Recent advances in molecular biology have made possible the identification of genetic defects responsible for Wilson's disease, Indian childhood cirrhosis and copper toxicosis in Long Evans Cinnamon rats, toxic milk mice, and Bedlington terriers. The Wilson's disease gene is localized on human chromosome 13 and codes for ATP7B, a copper transporting P-type ATPase. A genetic defect similar to that of Wilson's disease occurs in Long Evans Cinnamon rats and toxic milk mice. Familial copper storage disorders in Bedlington and West Highland white terriers are associated with early subclinical disease, and copper accumulation with subsequent liver injury culminating in cirrhosis. The canine copper toxicosis locus in Bedlington terriers has been mapped to canine chromosome region CFA 10q26. Recently, a mutated MURR1 gene was discovered in Bedlington terriers affected with the disease. Idiopathic childhood cirrhosis is biochemically similar to copper toxicosis in Bedlington terriers, but clinically much more severe. Both conditions are characterized by the absence of neurologic damage and Kayser-Fleisher rings, and normal ceruloplasmin levels. A recent study added North Ronaldsay sheep to the list of promising animal models to study Indian childhood cirrhosis. Morphologic similarities between the two conditions include periportal to panlobular copper retention and liver changes varying from active hepatitis to panlobular pericellular fibrosis, and cirrhosis. Certain copper-associated disorders, such as chronic active hepatitis in Doberman pinschers and Skye terrier hepatitis are characterized by copper retention secondary to the underlying disease, thus resembling primary biliary cirrhosis in humans. Copper-associated liver disease has increasingly being recognized in Dalmatians. Copper-associated liver diseases in Dalmatians and Long Evans Cinnamom rats share many morphologic features. Fulminant hepatic failure in Dalmatians is characterized by high serum activities of alanine aminotransferase and aspartate aminotransferase, and severe necrosis of centrilobular areas (periacinar, zone 3) hepatocytes. Macrophages and surviving hepatocytes contain copper-positive material. Liver disease associated with periacinar copper accumulation has also been described in Siamese cats. Many questions regarding copper metabolism in mammals, genetic background, pathogenesis and treatment of copper-associated liver diseases remain to be answered. This review describes the similarities between the clinico-pathological features of spontaneous copper-associated diseases in humans and domestic animals.
12763797##2003-5-24##Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1.##Wilson's disease protein (WNDP) is a copper-transporting P(1)-type ATPase which plays a key role in normal distribution of copper in a number of tissues, particularly in the liver and the brain. Copper has numerous effects on WNDP, altering its structure, activity, and intracellular localization. To better understand the function of this copper-transporting ATPase and its regulation by copper, we have recently developed the functional expression systems for WNDP and for Atox1, a cytosolic protein that serves as an intracellular donor of copper for WNDP. Here we summarize the results of our experiments on characterization of the enzymatic properties of WNDP and the effects of Atox1 on the WNDP activity.
12676121##2003-4-5##Metabolic liver disease in the young adult.##This chapter describes the gene mutations, phenotypes, diagnosis and therapy of the common metabolic liver diseases in young adulthood: haemochromatosis, Wilson disease, alpha(1)-anti-trypsin deficiency and cystic fibrosis. The remarkable variability of the phenotypical expression of the mutated genotypes makes screening recommendations and the establishment of prognosis for these liver disorders in young adults problematical. The diagnosis and therapy of the young adult with metabolic liver disease is discussed, with an emphasis on maintaining quality-of-life and balancing the importance of early intervention with the stigmatization of the diagnosis of potentially life-threatening liver disease. There is a critical need for the development of biochemical markers that would predict the risk of expression of clinical phenotypes and prognosis.
23267555##2012-12-27##Wilson's Disease--Diagnosis and Treatment.##
12701394##2003-4-19##[From gene to disease; Wilson disease: copper storage due to mutations in ATP7B].##Wilson disease is an autosomal recessive disorder of copper metabolism. The gene defective in Wilson disease encodes a copper transporting P-type ATPase expressed in the liver. The disturbed export of copper into bile results in accumulation of copper in liver and secondarily in other organs such as the brain. These patients generally present with either hepatic or neurological symptoms.
12604341##2003-2-27##Effects of soy protein isolate on LEC rats, a model of Wilson disease: mechanisms underlying enhancement of liver cell damage.##Soy-protein isolate (SPI) enhances liver cell damage in Long-Evans rats with a cinnamon-like coat color (LEC rats), which have a defect in Atp7b, the Wilson disease gene. Animals administered an SPI-diet from an age of six weeks died significantly earlier than those administered a control-diet, AIN-93G, from severe liver cell damage associated with jaundice. Since the liver copper level was higher with the SPI-diet than the control-diet, one of the reasons for SPI-toxicity to LEC rats might be due to the higher uptake of copper into liver cells. In the present study, liver levels of glutathione, and liver and intestinal mRNA and protein levels were determined for metallothionein, MT-1 and MT-2. Furthermore, liver and intestinal mRNA expression for the high affinity copper transporter, Ctr1, was determined. None of the parameters showed any significant differences between the SPI-diet and control-diet groups, except for Ctr1 mRNA levels in the liver. It is thus suggested that SPI enhances liver cell copper uptake through induction of Ctr1 expression and this might be the mechanism underlying increased liver damage in LEC rats.
12662398##2003-3-29##Wilson's disease: the importance of measuring serum caeruloplasmin non-immunologically.##Wilson's disease should be considered as a possible diagnosis in any child, adolescent or young adult with liver damage without other explanation, especially when haemolysis is present. However, it may also present in adolescents or young adults with neurological signs confined to the motor system. The first diagnostic screening test is the estimation of the serum caeruloplasmin and total serum copper concentrations, with calculation of the serum non-caeruloplasmin-bound ('free') copper. Serum caeruloplasmin, which contains copper, is best determined by measurement of its oxidase activity, as the immunonephelometric method measures both caeruloplasmin and the biologically inactive apo-form. Diagnosis may be confirmed by an elevated urinary copper excretion. All close relatives of an identified patient must be screened and, where doubt persists, investigation of the Wilson's gene at chromosome 13q14.3 can be employed. Lifelong follow-up studies are best conducted in a specialist centre. Compliance with chelating therapy (penicillamine or trientine) or administration of the metal antagonist tetrathiomolybdate or zinc is monitored by determination of the serum 'free' copper, which should be maintained at or near 1.6 micromol/L (10 microg/100 mL). Side-effects of therapy are detected by the estimation of urinary total protein, full blood count and erythrocyte sedimentation rate, clotting factors and liver function tests.
12605205##2003-2-28##British anti-Lewisite (dimercaprol): an amazing history.##Emergency physicians are familiar with British anti-Lewisite (BAL) because it is a heavy metal-chelating agent that is recommended in some cases of metal poisoning, especially arsenic. Although there are more modern chelating agents, the fact that BAL is still recommended and stocked by hospital pharmacies more than 60 years after its initial synthesis is itself remarkable. During World War II, BAL minimized the risk to the Allied infantry of injury or death from Lewisite, a very potent arsenic-based chemical warfare agent. Once developed, BAL revolutionized the treatment of heavy metal poisonings, both accidental and iatrogenic (eg, toxicity from treatment of arthritis with gold salts). In 1951, BAL was used to treat Wilson's disease with striking success. Today, BAL might again become prominent should terrorists or governments use Lewisite against civilians or military forces.
12820478##2003-6-25##Mutation analysis of copper-transporting P-type adenosine triphosphatase (ATP7B) in human solid carcinomas.##A major obstacle in the treatment of human solid carcinomas is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. ATP7B is overexpressed in human solid carcinomas such as breast, gastric and oral squamous cell carcinomas. ATP7B expression has an influential effect on some subsets of patients with cisplatin-treated carcinomas. ATP7B mutation is well-known as a cause of Wilson's disease. In addition, the six copper-binding domain and ATP-binding domain of ATP7B are important for the transportation of metals. Therefore, we performed the mutation analysis at the six copper-binding domain and ATP-binding domain of ATP7B. No mutation at the six copper-binding domain and ATP-binding domain was observed in breast, gastric and oral squameous cell carcinomas. These results indicate that the analysis of the ATP7B gene and/or protein will be helpful for the choice of chemotherapy in patients with human solid carcinomas.
12633149##2003-3-14##Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy.##
12572677##2003-2-8##Copper-induced trafficking of the cU-ATPases: a key mechanism for copper homeostasis.##The Menkes protein (MNK) and Wilson protein (WND) are transmembrane, CPX-type Cu-ATPases with six metal binding sites (MBSs) in the N-terminal region containing the motif GMXCXXC. In cells cultured in low copper concentration MNK and WND localize to the transGolgi network but in high copper relocalize either to the plasma membrane (MNK) or a vesicular compartment (WND). In this paper we investigate the role of the MBSs in Cu-transport and trafficking. The copper transport activity of MBS mutants of MNK was determined by their ability to complement a strain of Saccharomyces cerevisiae deficient in CCC2 (delta ccc2), the yeast MNK/WND homologue. Mutants (CXXC to SXXS) of MBS1, MBS6, and MBSs1-3 were able to complement delta ccc2 while mutants of MBS4-6, MBS5-6 and all six MBS inactivated the protein. Each of the inactive mutants also failed to display Cu-induced trafficking suggesting a correlation between trafficking and transport activity. A similar correlation was found with mutants of MNK in which various MBSs were deleted, but two constructs with deletion of MBS5-6 were unable to traffic despite retaining 25% of copper transport activity. Chimeras in which the N-terminal MBSs of MNK were replaced with the corresponding MBSs of WND were used to investigate the region of the molecules that is responsible for the difference in Cu-trafficking of MNK and WND. The chimera which included the complete WND N-terminus localized to a vesicular compartment, similar to WND in elevated copper. Deletions of various MBSs of the WND N-terminus in the chimera indicate that a targeting signal in the region of MBS6 directs either WND/MNK or WND to a vesicular compartment of the cell.
12600964##2003-2-26##Efficient strategy for molecular diagnosis of Wilson disease in the sardinian population.##
12619106##2003-3-6##TP53 and liver carcinogenesis.##Primary hepatocellular carcinoma (HCC) is one of the most common malignancies and has the fourth highest mortality rate worldwide. The major risk factors, including chronic infections with the hepatitis B or C virus, are exposure to dietary aflatoxin B1(AFB1), vinyl chloride, or alcohol consumption. Southern China and sub-Saharan Africa have the highest dietary AFB1 exposure, making it and hepatitis B virus (HBV) the major causes of cancer mortality in these geographic areas. Recent studies have discovered genetic and epigenetic changes involved in the molecular pathogenesis of HCC, including somatic mutations in the p53 tumor suppressor gene (TP53). AFB1 induces typical G:C to T:A transversions at the third base in codon 249 of p53. Chronic active hepatitis B and C (HCV) infection, and further inflammatory and oxyradical disorders including Wilson disease (WD) or hemochromatosis, generate reactive oxygen/nitrogen species that can damage DNA and mutate the p53 gene. The X gene of HBV (HBx) is the most common open reading frame integrated into the host genome in HCC. The integrated HBx is frequently mutated and has a diminished ability to function as a transcriptional cotransactivator and to activate the NF-kappa B pathway. However, the mutant HBx proteins still retain their ability to bind to and abrogate p53-mediated apoptosis. In summary, both viruses and chemicals are implicated in the etiology and molecular pathogenesis of HCC. The resultant molecular changes in the ras and Wnt signal-transduction pathways, and the p53 and Rb tumor suppressor pathways significantly contribute to liver carcinogenesis
12579336##2003-2-13##Expression of copper-transporting P-type adenosine triphosphatase in human esophageal carcinoma.##A major obstacle in the treatment of esophageal carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphatase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate if ATP7B is expressed in esophageal carcinoma and whether its expression correlates with reduced responsiveness to cisplatin treatment. We retrospectively examined the expression of ATP7B in primary esophageal carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 17 esophageal carcinoma patients. Twelve of them received cisplatin-based chemotherapy before surgery. We performed immunohistochemical analysis of ATP7B using a monoclonal antibody against ATP7B in 17 esophageal carcinomas. A variable degree of cytoplasmic staining of tumor cells was observed in 76.5% (13/17 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent non-neoplastic tissues. ATP7B positivity was not significant in gender, age, histopathological grading or TNM categories. Patients with ATP7B-positive tumors tended to have an inferior response to chemotherapy compared with the patients with ATP7B-negative tumors. These findings suggest that overexpression of ATP7B in esophageal carcinoma could be associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B gene expression might be considered as a chemoresistance marker for cisplatin in the patients of esophageal carcinoma and provider of important information on the strategy against esophageal carcinoma.
12579329##2003-2-13##Wilson disease protein ATP7B is localized in the late endosomes in a polarized human hepatocyte cell line.##Wilson disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion. The gene responsible for Wilson disease has been cloned, however, the precise localization of this gene product ATP7B, a copper-transporting ATPase, is still controversial. We examined the localization of ATP7B by expressing a chimeric protein, ATP7B-tagged with green fluorescent protein (GFP) (GFP-ATP7B), in HEK293, Hep3B and a highly polarized human hepatocyte line (OUMS29). Intracellular organelles were visualized by immunofluorescence microscopy. The effects of bathocuproine disulfonate, a copper chelator, and copper sulfate were examined. GFP-ATP7B colocalized with a late endosome marker, but not with endoplasmic reticulum, Golgi, or lysosome markers in a copper-depleting condition. Treatment with copper sulfate did not affect the localization of ATP7B. ATP7B is localized in the late endosomes in both copper-depleting and copper-loaded conditions. ATP7B seems to translocate copper from the cytosol into the late endosomes, and copper may be excreted to bile via lysosomes. We believe that the disturbed incorporation of copper into the late endosomes caused by mutated ATP7B is the main defect in Wilson disease.
12624602##2003-3-8##Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice.##Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson's disease, produces an antiangiogenic effect by reducing systemic copper levels. Several angiogenic cytokines appear to depend on normal levels of copper for activity. In both animal tumor models and in cancer patients, TM therapy has proved effective in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic and inflammatory cytokines are also subject to modulation by the availability of copper in a manner similar to angiogenic cytokines. As a first step in evaluating whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we studied the effects of TM on a murine model of bleomycin-induced pulmonary fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin, a surrogate marker of systemic copper levels. Significant decreases in systemic copper levels were associated with marked reduction in lung fibrosis as determined on the basis of histopathologic findings and a biochemical measure of fibrosis. The protection afforded by TM was also reflected in significantly reduced bleomycin-induced body-weight loss. In the next phase of this work, we will seek to determine the mechanisms by which TM brings about this therapeutic benefit.
12785748##2003-6-6##Childhood dystonia.##Childhood dystonias are a heterogeneous group of disorders with strong inherited basis. This review describes the clinical characteristics, classification, genetic basis, pathophysiology, biochemistry, pathology, and treatment of dystonias, including the primary dystonias, the dystonia-plus syndromes, secondary dystonias, and heredodegenerative disorders. Conditions discussed in detail include idiopathic torsion dystonia, dopa-responsive dystonia, Wilson's disease, myoclonus dystonia, rapid-onset dystonia parkinsonism, neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome), mitochondrial dystonias, Niemann-Pick type C, and neuroacanthocytosis.
12812649##2003-6-19##[Genotype-phenotype correlation of patients with wilson disease in Chinese population].##
12580588##2003-2-13##Tetrathiomolybdate causes formation of hepatic copper-molybdenum clusters in an animal model of Wilson's disease.##Wilson's disease is an autosomal recessive human illness in which large quantities of copper accumulate in various organs, including the brain and the liver. If left untreated, it results in hepatitis, neurological complications, and death. Long-Evans Cinnamon (LEC) rats have a homologous mutation to Wilson's disease and thus provide an animal model. Liver lysosomes from tetrathiomolybdate-treated LEC rats were isolated and analyzed by Cu and Mo K-edge X-ray absorption spectroscopy. The lysosomes contained a Cu-Mo-S cluster in which the Mo is coordinated by four sulfurs at 2.24 A with approximately three copper neighbors at 2.70 A. Each Cu is coordinated to 3-4 sulfurs at 2.28 A with approximately one Mo neighbor at 2.70 A. These results indicate the formation of a biologically novel molybdenum-copper-sulfur cluster.
12565888##2003-2-5##Mutational analysis of the Menkes copper P-type ATPase (ATP7A).##The Menkes protein (ATP7A; MNK) is a ubiquitous human copper-translocating P-type ATPase and it has a key role in regulating copper homeostasis. Previously we characterised fundamental steps in the catalytic cycle of the Menkes protein. In this study we analysed the role of several conserved regions of the Menkes protein, particularly within the putative cytosolic ATP-binding domain. The results of catalytic studies have indicated an important role of 1086His in catalysis. Our findings provide a biochemical explanation for the most common Wilson disease-causing mutation (H1069Q in the homologous Wilson copper-translocating P-type ATPase). Furthermore, we have identified a unique role of 1230Asp, within the DxxK motif, in coupling ATP binding and acylphosphorylation with copper translocation. Finally, we found that the Menkes protein mutants with significantly reduced catalytic activity can still undergo copper-regulated exocytosis, suggesting that only the complete loss of catalytic activity prevents copper-regulated trafficking of the Menkes protein.
12591639##2003-2-20##Concordant pre- and postsynaptic deficits of dopaminergic neurotransmission in neurologic Wilson disease.##
12557139##2003-1-31##Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines.##
14599926##2003-11-6##Rheumatologic manifestations of hepatic diseases.##A possible link is suggested between hepatic diseases and rheumatic disease. Polyarthralgia and polyarthritis may be seen during the prodromal period of acute viral hepatitis, especially in hepatitis B virus (HBV). The symptoms of arthritis, mild, localized or generalized, mostly involve the small joints of hands. Joint symptoms frequently precede the onset of jaundice, no residual joint deformities. Circulating immune complexes are believed to play a causative role in the development of vasculitis and arthritis. Hemochromatosis is an antosomal recessive disorder of iron. About 43%-81% of patients with hemochromatosis have arthritis. The common extrahepatic manifestations of autoimmune hepatitis are arthralgia and skin rash. The reported prevalence of symptomatic inflammatory arthropathy in patients with primary biliary cirrhosis ranges from 4% to 50%. Skeletal involvement with Wilson's disease is common. Such patients may complain of pain and stiffness, mainly in the knee, wrist, or other large joints. Shwachman's syndrome is a disorder of pancreatic exocrine. Symmetric bone lesions have been reported in 10% to 15% of patients. They are involved predominantly at the femoral neck. Rheumatic symptoms are seen in one third of adult patients with cystic fibrosis and arthritis in 2.5% to 12% of patients. The arthritis caused by pancreatic panniculitis is usually symmetrical and involves the small joints of the hand, wrist, and feet, but may involve such larger joints as the elbow, ankle, and knee.
12725264##2003-5-3##Wilson's disease.##
12624714##2003-3-8##Investigation of fine-motor disturbances in Wilson's disease.##Patients suffering from Wilson's disease (WD) can be divided into two main subgroups: neurologic and nonneurologic WD. We measured passive and active fine-motor abilities of 37 WD patients and 24 randomly selected volunteers. The measurement was based on a standardized test set in a defined environment for detection of disturbed finemotor control. The set contains 5 tests comprising rest tremor, postural tremor, target tapping, forefinger tapping and spiral painting, reflecting different aspects of movement disorders. The tests showed significant differences between neurologic WD and volunteers, especially for tasks defining active control. In neurologic WD we found no differences between subgroups whereas for non-neurologic WD we often detected slight movement disorders. The detected movement disorders cam be interpreted as persistent disorders after long-term therapy.
12509969##2003-1-3##Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin.##An important clinical problem in the treatment of oral squamous cell carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro (Komatsu et al., Cancer Res 60, 1312-1316,2000). However, the clinical significance of this transporter has not previously been addressed. Our aim of this study was to investigate if ATP7B is expressed in oral squamous cell carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment. Biopsy tissues were obtained from the tumors of 70 patients with oral SCC, and 51 patients received cisplatin-based preoperative chemotherapy. We performed immunohistochemical analysis of ATP7B using monoclonal antibody against ATP7B in 51 oral SCC and adjacent neoplastic tissues. The significance of ATP7B in the prognosis of patients with oral SCC was also examined in the survival analysis of mortality follow-up data covering the period 1991 through 2000. We retrospectively examined the expression of ATP7B in primary oral SCC carcinoma and its association with chemotherapeutic effect. A variable degree of cytoplasmic staining of tumor cells was observed in 54.9% (28/51 cases) of the analyzed carcinomas. Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.03). The patients who received cisplatin-based chemotherapy with ATP7B-positive carcinomas had a significantly poorer overall survival than those with ATP7B-negative tumors (P = 0.015). These findings suggest that high levels of ATP7B expression in oral SCC are associated with unfavorable clinical outcome in patients with oral SCCs treated with cisplatin-based chemotherapy. ATP7B expression may be a preoperative indicator for a choice of cisplatin in some patients.
12591452##2003-2-20##Recovery of severe neurologic manifestations of Wilson's disease after living-related liver transplantation: a case report.##
14759316##2004-2-5##[Treatment of Wilson's disease with penicillamine and zinc salts: a follow-up study].##
12648406##2003-3-22##[Expression characters of ATP7B mRNA in liver tissue of patients with Wilson's disease].##
12527412##2003-1-16##Effect and possible role of Zn treatment in LEC rats, an animal model of Wilson's disease.##The effect of oral zinc (Zn) treatment was studied in the liver, kidneys and intestine of Long-Evans Cinnamon (LEC) rats in relation to metals interaction and concentration of metallothionein (MT) and glutathione (GSH). We also investigated the change in the activity of antioxidant enzymes and determined the biochemical profile in the blood and metal levels in urine. We showed that the Zn-treated group had higher levels of MT in the hepatic and intestinal cells compared to both untreated and basal groups. Tissue Zn concentrations were significantly higher in the Zn-treated group compared to those untreated and basal, whereas Cu and Fe concentrations decreased. The antioxidant enzyme activities in the Zn-treated group did not change significantly with respect to those in the basal group, except for hepatic glutathione peroxidase activity. Moreover, the biochemical data in the blood of Zn-treated group clearly ascertain no liver damage. These observations suggest an important role for Zn in relation not only to its ability to compete with other metals at the level of absorption in the gastrointestinal tract producing a decrease in the hepatic and renal Cu and Fe deposits, but also to MT induction as free radical scavenger.
12445675##2002-11-26##Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human gastric carcinoma.##This study describes the first report that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in human gastric carcinomas. Herein, we investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain gastric carcinomas. To test this hypothesis, ATP7B expression level was examined in 51 gastric carcinomas by immunohistochemistry. ATP7B protein could be detected in 41.2% (21/51) of gastric carcinoma by immunohistochemical analysis. In ATP7B-positive tumors, adjacent non-neoplastic tissue was similarly analyzed, revealing that ATP7B is upregulated in gastric carcinoma. ATP7B expression in poorly differentiated/undifferentiated carcinoma was significantly higher than that in well/moderately-differentiated carcinoma (P=0.0278). These findings suggested that ATP7B expression might be a chemoresistance marker against cisplatin in some patients with poorly differentiated/undifferentiated gastric carcinoma.
14582469##2003-10-30##[Wilson's disease].##Wilson's disease is an autosomal recessive disorder of copper metabolism. The Wilson disease protein is a copper-transporting P-type ATPase, ATP7B, the malfunction of which results in the toxic accumulation of copper in the liver and brain, causing the hepatic and/or neurological symptoms accompanying this disease. Patients present, generally between the ages of 10 and 40 years, with liver disease, neurological disease of a movement disorder type, or behavioral abnormalities, and often with a combination of these. Because Wilson's disease is effectively treated, it is extremely important for physicians to learn to recognize and diagnose the disease. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 200 unique mutations have been identified and most individuals are compound heterozygotes. The treatment of Wilson's disease must be life long. Copper chelation with penicillamine is an effective therapy in most patients. Another chelating agent which has been used successfully as the initial therapy is trientine. The search for new anticopper drugs for Wilson's disease is culminating in two excellent new drugs: zinc for maintenance therapy and ammonium tetrathiomolybdate (which is to date still an experimental drug) for initial therapy. Liver transplantation is indicated for the fulminant form and in those patients with severe disease not responding to optimal medical management. This paper reviews the pathogenesis, pathology, clinical presentation and diagnosis of the Wilson's disease as well as the most recent views on the molecular genetics and the treatment of this disease.
15279036##2004-7-29##[Pathogenesis and treatment of Wilson's disease].##Authors review the pathogenesis, symptoms and diagnosis of Wilson's disease. Wilson's disease or hepatolenticular degeneration is an autosomal recessive disorder. It is caused by defective hepatic excretion of copper. The disease is fatal without treatment. The prevention of severe permanent damage depends upon early recognition and diagnosis followed by appropriate lifelong anticopper treatment. The purpose of the therapy of Wilson's disease is to eliminate the copper by chelators (D-penicillamine, triethylene tetramine, ammonium tetrathiomolibdate) and to inhibit the absorption and accumulation of copper by zinc salts (zinc sulphate, zinc acetate, zinc gluconate).
12784049##2003-6-5##Liver support--a task for nephrologists? Extracorporeal treatment of a patient with fulminant Wilson crisis.##
12573885##2003-2-8##Diffusion MRI findings in Wilson's disease.##Six patients having Wilson's disease were studied with diffusion MRI in order to characterize cerebral lesions. Diffusion MRI was obtained using the spin-echo, echo-planar sequence with a gradient strength of 30 mT/m. The trace protocol was used in the axial imaging plane. Heavily diffusion-weighted (b=1000s/mm(2)) images, and the ADC (apparent diffusion coefficient) values from automatically generated ADC maps were studied. The ADC values of the normal brain parenchyma were available in 17 age-matched cases for comparison (ADC values, 0.85+/-0.11 x 10(-3)mm(2)/s). In Wilson's disease two distinct diffusion MRI patterns were observed by quantitative evaluations of the ADC maps; cytotoxic edema-like (ADC values, 0.52+/-0.03 x 10(-3)mm(2)/s), and vasogenic edema-like (ADC values, 1.42+/-0.17 x 10(-3)mm(2)/s) patterns. Diffusion imaging appears to be a promising sequence to evaluate the changes in the brain tissue in Wilson's disease at least by revealing two different patterns.
12640330##2003-3-18##[Catatonia de novo, report on a case: immediate vital prognosis and psychiatric prognosis in longer term].##We report on the case of a 20 year old woman with no previous psychiatric history, who displayed a first episode of catatonia with acute onset. Symptoms started plainly with sudden general impairment, intense asthenia, headache, abdominal pain and confusion. After 48 hours, the patient was first admitted to an emergency unit and transferred to an internal medicine ward afterwards. She kept confused. Her behaviour was bizarre with permanent swinging of pelvis, mannerism, answers off the point and increasingly poor. The general clinical examination was normal, except for the presence of a regular tachycardia (120 bpm). The paraclinical investigations also showed normal: biology, EEG, CT Scan, lumbar puncture. Confusion persisted. The patient remained stuporous, with fixed gazing and listening-like attitudes. She managed to eat and move with the help of nurses but remained bedridden. The neurological examination showed hypokinaesia, extended hypotonia, sweating, urinary incontinence, bilateral sharp reflexes with no Babinski's sign and an inexhaustible nasoorbicular reflex. The patient was mute and contrary, actively closed her eyes, but responded occasionally to simple instructions. For short moments, she suddenly engaged in inappropriate behaviors (wandering around) while connecting back to her environment answering the telephone and talking to her parents. The patient's temperature rose twice in the first days but with no specific etiology found. During the first 8 days of hospitalization, an antipsychotic treatment was administered: haloperidol 10 mg per os daily and cyamemazine 37.5 mg i.m. daily. Despite these medications, the patient worsened and was transferred to our psychiatric unit in order to manage this catatonic picture with rapid onset for which no organic etiology was found. On admission, the patient was stuporous, immobile, unresponsive to any instruction, with catalepsy, maintenance of postures, severe negativism and refusal to eat. A first treatment by benzodiazepine (clorazepate 20 mg i.v.) did not lead to any improvement. The organic investigations were completed with cerebral MRI and the ruling out of a Wilson's disease. Convulsive therapy was then decided. It proved dramatically effective from the first attempt; 4 shocks were carried out before the patient's relatives ask for her discharge from hospital. The patient revealed she had experienced low delirium during her catatonic state. The clinical picture that followed showed retardation with anxiety. She was scared with fear both for the other patients and the nursing team. She kept distant and expressed few affects. The treatment at the time of discharge was olanzapine 10 mg per os. She was discharged with a diagnosis of catatonia but with no specific psychiatric etiological diagnosis associated. She discontinued her follow-up a few weeks later. After one year, we had no information about her. Catatonia has now become rare but remains a problem for clinicians. We reviewed data concerning short term vital prognosis and psychiatric long term prognosis in catatonia. Lethal catatonia is associated with acute onset, both marked psychomotor and neurovegetative symptoms. In the light of literature, there is no proband clinical criterion during the episode that is of relevant diagnostic value to ascertain the psychiatric etiology.
12544701##2003-1-25##Kayser-Fleischer like rings in alcoholic liver disease: a case report.##Kayser-Fleischer rings are brown pigmented rings that run along the periphery of the cornea. Situated in Descemet's membrane and being comprised of granules of deposited copper they have traditionally been thought of as pathognomic of Wilson's disease. However, they can also be seen in other forms of liver disease. We document a case of Kayser-Fleischer like rings occurring in alcoholic liver disease--a previously unreported association.
14530621##2003-10-8##Movement disorders possibly induced by traditional chinese herbs.##The authors describe the neurological presentation and CT/MRI findings in 4 patients exposed to overdoses of decoctions of two different Chinese herbs. Case 1, a 15-year-old boy, ingested herba serissae along with the safe-dosage Salvia miltiorrhiza for treating a left renal stone. Sophora subprostrata root (SSR) was primarily used for treating three other diseases: viral B hepatitis in case 2, a 9-year-old boy; infection of the throat and a low fever in case 3, a 11-year-old girl, and a minor facial infection in case 4, a 12-year-old boy. All patients showed complex neurological manifestations primarily including convulsions, mental changes and dystonia syndromes. Their CT and/or MRI revealed abnormal density lesions in the striatum and globus pallidus bilaterally. They excluded the possibility of Wilson's disease in each of the 4 patients and suggested that overdosage of SSR and herba serissae could cause intoxications of the central nervous system, particularly damage to the basal ganglia. Chemically, coumarin (case 1) and matrine and oxymatrine (cases 2-4) in the two medicinal herbs are suggested to be possibly responsible for the morbidity.
12824712##2003-6-26##Clinical presentation and treatment of Wilson's disease: a single-centre experience.##Thirty patients with Wilson's disease (WD) were observed at a movement disorder clinic between 1970 and 2000. Disease onset was at the mean age (SD) of 14.5 (+/-5.9) years. Presentation with hepatic disease occurred in 12 of 30 patients and with neurologic disease in 15. Three patients were asymptomatic at the time of diagnosis. The mean (SD) delay to diagnosis was 5.9 (+/-5.7) years. Five patients diagnosed in an advanced stage of disease died before initiating treatment. Eighteen patients were followed and treated with D-penicillamine alone or in combination with zinc sulphate. Treatment improved most of neurological symptoms. Dystonic postures, behavioural disturbances and dysarthria were the most resistant neurological signs. 'Pseudo-sclerotic' neurologic involvement predicted a good outcome, whereas hepatic onset and 'classic' neurologic involvement were associated with a poorer prognosis. Two of the 18 treated patients died of hepatic failure due to voluntary discontinuation of therapy. Both D-penicillamine and zinc sulphate were well tolerated. No teratogenic effect of D-penicillamine was observed throughout 5 pregnancies. Our results suggest that D-penicillamine or a combination of D-penicillamine and zinc sulphate is a safe and effective long-term treatment in patients with WD.
12594382##2003-2-21##[Late presentation of Wilson's disease as cirrhosis complicating hepatocellular carcinoma].##
12525328##2003-1-15##[Wilson's disease: physiopathological, clinical and therapeutic considerations].##
12617443##2003-3-6##Evaluation of diagnostic parameters of Wilson's disease in childhood.##
12617442##2003-3-6##Wilson's disease--a diagnostic dilemma?##
12767257##2003-5-28##Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation.##The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines.
12872841##2003-7-23##Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes.##The trace metal copper is an essential cofactor for a number of biological processes, including mitochondrial oxidative phosphorylation, free-radical eradication, neurotransmitter synthesis and maturation, and iron metabolism. Consequently, copper transport at the cell surface and the delivery of copper to intracellular proteins are critical events in normal cellular homeostasis. Four genes have been reported to influence the cellular uptake and the delivery of copper to specific cell compartments and proteins. These include hCTR1, which regulates cellular copper uptake; HAH1, which mediates the transfer of copper to the Menkes and Wilson disease transporters; CCS, which is related to the transfer of copper to superoxide dismutase; and hCOX17, which directs trafficking of copper to mitochondrial cytochrome-c oxidase. At present, no genetic disorders have been associated with defects in these four copper transporter genes. In this study, we test the possibility that defective copper uptake or intracellular translocation represents the basic defect in three categories of candidate phenotypes among 22 patients: ethylmalonic encephalopathy; mitochondriopathies of unknown aetiology; and neurodevelopmental abnormalities with clinical and chemical evidence of copper deficiency. Mutation analyses of the copper uptake protein, hCTR1, and the three copper chaperones were performed by direct sequencing of the whole coding regions. No causative mutations were identified for the four copper transporter genes in 22 patients. A heterozygous polymorphism (847G>A) for CCS was detected in 7 patients. For the distinct disease entity ethylmalonic encephalopathy, we additionally show normal mRNA levels for each of the four genes. The negative results notwithstanding, we encourage ongoing study of additional patients with candidate phenotypes. Further, our results are consistent with the notion that other unknown copper-related transporters could be involved in diseases.
12532272##2003-1-18##Function and regulation of the mammalian copper-transporting ATPases: insights from biochemical and cell biological approaches.##Copper is an essential trace element that plays a very important role in cell physiology. In humans, disruption of normal copper homeostasis leads to severe disorders, such as Menkes disease and Wilson's disease. Recent genetic, cell biological, and biochemical studies have begun to dissect the molecular mechanisms involved in transmembrane transport and intracellular distribution of copper in mammalian cells. In this review, we summarize the advances that have been made in understanding of structure, function, and regulation of the key human copper transporters, the Menkes disease and Wilson's disease proteins.
12645521##2003-3-21##[Case no 5. Wilson's disease].##
16340261##2005-12-13##A case report of Wilson's disease.##Wilson's disease (hepatolenticuler degeneration), an inborn error of copper metabolism, is an autosomal recessive disorder characterized by degenerative changes in brain, liver disease and Kayser Fleisher (KF) rings in the cornea. It is due to a defect of p-type ATPase which is probably required for normal extrusion of copper from cells. In this case report, we present a seven and half year old male who presented with complaints of slurring of speech, drooling of saliva, intentional tremor and dark pigmentation over face and trunk for last 9 months. On examination KF ring was present, spleen was palpable and intentional tremor was present. Laboratory investigations confirmed the diagnosis.
12518296##2003-1-9##State of the art review: molecular diagnosis of inherited movement disorders. Movement Disorders Society task force on molecular diagnosis.##This review is designed to provide practical help for the clinical neurologist to make appropriate use of the possibilities of molecular diagnosis of inherited movement disorders. Huntington's disease, Parkinson's disease and parkinsonian syndromes, ataxias, Wilson disease, essential tremor, dystonias, and other genetic diseases associated with a variety of movement disorders are considered separately.
12559147##2003-2-1##Impairment of recognition of disgust in Chinese with Huntington's or Wilson's disease.##The selective involvement of the basal ganglia in recognition of the facial expression of disgust was investigated by examining a group of six symptomatic Huntington's disease patients and 32 Wilson's disease patients in China. Morphed photographs of facial expressions covering happiness-surprise-fear-sadness-disgust-anger were used and the patients were asked to label each photo. Other measures assessed basic cognitive functions and perception of non-emotion facial information, such as perception of gender, age, gaze direction, and recognition of unfamiliar as well as famous people. There was dissociation between the perception of emotions and other facial information, and between impairment of recognition of disgust and other emotions. The basal ganglia are the overlapping substrate involved in both Huntington's and Wilson's disease, although each has its own other lesions. The differentially severe impairment of recognition of disgust in the Chinese Huntington's disease and Wilson's disease patients strengthens the view that basal ganglia are selectively involved in processing the emotion of disgust.
12760731##2003-5-23##D-penicillamine and plasmapheresis in acute liver failure secondary to Wilson's disease.##We report a case of a 19-year-old woman with acute liver failure, Coombś negative hemolytic anemia, and renal failure as initial manifestations of Wilsoń disease with recovery following medical treatment. The clinical picture and low serum transaminase and alkaline phosphatase levels gave us a clue to suspect Wilsoń disease and to initiate plasmapheresis and D-penicillamine soon after admission. The serum and urinary copper levels were elevated with low serum ceruloplasmin. We proceeded to ambulatory follow-up with medical treatment with D-penicillamine. A few months later, during the course of a laparoscopic cholecystectomy because of symptomatic gallstone disease, a liver biopsy sample was obtained that showed histological liver fibrosis and strongly elevated levels of liver tissue copper.
14626136##2003-11-25##[Wilson disease].##
15906702##2005-5-24##Newborn screening in Japan.##In the 1970's, the government began to take steps for the treatment of congenital diseases. Mass newborn screening was started in October 1977 throughout Japan in order to detect five inborn errors of metabolism including phenylketonuria, maple syrup urine disease, homocystinuria, histidinemia, and galactosemia. In 1979, mass screening for congenital hypothyroidism was added to the original program. In 1989, screening for congenital adrenal hyperplasia was added and in 1992, screening of histidinemia was discontinued. Currently, screening covers six diseases. The government paid half the cost of screening tests initially and in 2001 this was raised to the full cost (approximately 3000 yen). Parents pay for sample collection. The program is carried out according to law. A new activity involving screening for Wilson disease now necessitates taking dried blood specimens from children 1-3 years old.
14761325##2004-2-6##[Genotype and phenotype correlation in Chinese patients with Wilson's Disease].##
12505283##2002-12-31##Molecular pathogenesis of human hepatocellular carcinoma.##Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the viral-chemical etiology as well as molecular mechanisms of HCC pathogenesis remains largely unknown. Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC. Oxidative stress and chronic inflammation have been linked to an increased risk of liver cancer. For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumor suppressor gene. The Hepatitis B virus X gene (HBx), a viral transactivator with oncogenic potentials, has been shown to bind to and inactivate p53-mediated apoptosis. HBx mutants derived from HCC have a diminished ability to act as a transactivator. However, they still retain the ability to bind to and abrogate p53-mediated apoptosis. The comparison of gene expression profiles between HBx-expressing primary human hepatocytes and HBV-infected liver samples by cDNA microarrays indicate a unique alteration of a subset of oncogenes and tumor suppressor genes including p53. Our studies implicate both viral and endogenous chemical processes in the etiology of HCC, and p53 may be a common target for the inactivation during liver carcinogenesis.
12405529##2002-10-31##A kinetic study on the copper-albumin catalyzed oxidation of ascorbate.##Serum albumin can specifically bind one Cu(II)-ion, and is proposed to function as a copper transport protein in vivo. Cu(II)-albumin is rapidly reduced by ascorbate. A second order rate constant of 0.54 mM(-l) x min(-1) was estimated for the reaction. The oxidation process is catalytic, the Cu(I)-albumin molecule being reoxidized by molecular oxygen. The reaction was found to follow Michaelis-Menten kinetics, characterized by an apparent Km-value of 0.89 mM, and a catalytic constant of 0.066 microM O2/min. An apparent inhibition of oxygen uptake was obtained with catalase (but not with superoxide dismutase), suggesting the formation of H2O2 in the system. Wilson's disease patients usually have increased amounts of non-ceruloplasmin copper in plasma. The low level of plasma ascorbate observed in such patients could possibly be due, at least in part, to an oxidation by Cu(II)-albumin.
12441847##2002-11-21##Cataracts associated with systemic disorders and syndromes.##This review article examines the ophthalmic literature published on cataracts and systemic disease during the past year. Epidemiologically, the association between alcohol consumption and lens opacification is reviewed. Cataracts continue to be strongly associated with systemic diseases such as diabetes mellitus. Clinical, basic science reports and the results of the Blue Mountains Eye Study group on the morphology of diabetes-related cataracts are presented. Patients with neurologic disorders such as Wilson disease may first present with decreased vision and cataracts. Cataracts are now associated with syndromes such as Cohen syndrome, Degos disease, and Dubowitz syndrome. A recent study suggests earlier mortality in middle-age patients undergoing cataract surgery.
12522607##2003-1-11##Unusual imaging findings in Wilson's disease.##We present unusual imaging findings in the liver of a patient with Wilson's disease. On US, the liver contours were irregular and its echogenicity was increased with multiple, small hypo- and hyperechoic nodules. Prominent perihepatic fat layer was noted to be increased in thickness. On CT and MR, multiple, small, enhancing nodules were detected in the liver in the early arterial phase after administration of intravenous contrast material. Biopsy was consistent with chronic parenchymal liver pathology with dysplastic changes but without evidence of hepatocellular carcinoma. To our knowledge, dysplastic nodules enhancing at the arterial phase and thickened perihepatic fat layer have not been previously reported in patients with Wilson's disease.
12575461##2003-2-11##[A simple and rapid method for detection of the 106Gln mutation in Wilson-Konovalov disease].##A simple and rapid method for detecting the 1069Gln mutation in gene ATP7B based on a PCR specific for this allele has been developed. The 1069Gln mutation is the main cause of Wilson disease (WD) in Russia and accounts for approximately 40% of all mutant alleles of gene ATP7B. Therefore, the method proposed makes the postnatal and prenatal diagnosis of Wilson disease in Russia considerably more rapid and less expensive.
14664727##2003-12-11##Cancer therapy with tetrathiomolybdate: antiangiogenesis by lowering body copper--a review.##A new anticopper drug, tetrathiomolybdate (TM), developed for Wilson's disease, is a very promising antiangiogenic agent. Copper levels lowered into an antiangiogenic window by TM have shown efficacy against cancer in a variety of animal models as well as in patients. The only significant toxicity so far results from overtreatment and excessive bone marrow depletion of copper. The resulting anemia and/or leukopenia is easily treatable by dose reduction or drug holiday. The underlying concept for TM efficacy as an anticancer agent is that when the body's copper status is in the window, cellular copper needs are met and toxicity is avoided. Copper status is relatively easily monitored by following serum ceruloplasmin, a copper-containing protein secreted by the liver at a rate dependent upon the amount of copper in the liver available to incorporate into the protein. The authors speculate that the copper level is a primitive angiogenesis and growth-signaling regulator that has been retained throughout evolution.
12472971##2002-12-11##Copper metabolic defects and liver disease: environmental aspects.##Copper (Cu) is an essential trace element for many biological processes. Cu homeostasis is generally well maintained by inbuilt controls in intestinal absorption, biliary excretion and intrahepatic storage. Copper deficiency disorders are rare. Acute Cu toxicity occurs occasionally in accidental poisoning with Cu sulfate. Chronic Cu toxicity in the form of liver cirrhosis and damage to other organs is seen classically in Wilson's Disease (genetic abnormality of Cu metabolism) and in the presumed environmental disorder Indian Childhood Cirrhosis (ICC). The clinical, epidemiological and treatment aspects of ICC are described. The evidence linking ICC to environmental Cu is (i) greatly increased hepatic Cu; (ii) early introduction of Cu contaminated milk boiled or stored in brass vessels; (iii) dramatic decline in ICC throughout the country coincident with change in feeding vessels; and (iv) continued long-term remission in d-penicillamine-treated patients after withdrawal of the drug. The nature and role of a second factor in the causation of ICC remains unclear, although a genetic predisposition is strongly suspected. Scattered reports of an ICC-like illness from the West (Idiopathic Cu Toxicosis, Endemic Tyrolean Infantile Cirrhosis), suggest that different mechanisms (environmental, genetic or both) can lead to the same end stage liver disease-'ecogenetic' disorders.
12529799##2003-1-17##The indication for liver transplant to improve neurological symptoms in a patient with Wilson's disease.##
12445172##2002-11-26##HFE gene mutations and iron metabolism in Wilson's disease.##
12473395##2002-12-11##Movement disorders in the tropics.##The spectrum of movement disorders in the tropics is different from that seen in the industrialized nations of the west. This is not surprising given the unique combination of environmental and population characteristics in the tropics. Infections seldom encountered in the west such as tuberculous meningitis, typhoid fever, Japanese encephalitis, malaria, trypanosomiasis or cysticercosis are often seen in the tropics and with global patterns of travel and immigration these conditions are becoming more common worldwide. Movement disorders associated with these infections, HIV, slow virus and prion disease are discussed. Taking into account the diverse etiologies of movement disorders in the tropics, movement disorders with a nutritional basis such as the infantile tremor syndrome, seasonal ataxia and tropical ataxic neuropathy, and manganese neurotoxicity are also reviewed. Finally, certain special characteristics of ubiquitous disorders such as Parkinson's disease, and disorders with a genetic basis such as Wilson's disease and spinocerebellar degeneration are described.
12485310##2002-12-18##Wilson's disease in psychiatric patients.##
12459093##2002-12-3##[Ceruloplasmine and iron metabolism: their implications in hemochromatosis, Wilson's disease and aceruloplasminemia].##
12228238##2002-9-14##Copper-regulated trafficking of the Menkes disease copper ATPase is associated with formation of a phosphorylated catalytic intermediate.##The Menkes protein (MNK; ATP7A) is a copper-transporting P-type ATPase that is defective in the copper deficiency disorder, Menkes disease. MNK is localized in the trans-Golgi network and transports copper to enzymes synthesized within secretory compartments. However, in cells exposed to excessive copper, MNK traffics to the plasma membrane where it functions in copper efflux. A conserved feature of all P-type ATPases is the formation of an acyl-phosphate intermediate, which occurs as part of the catalytic cycle during cation transport. In this study we investigated the effect of mutations within conserved catalytic regions of MNK on intracellular localization and trafficking from the trans-Golgi network (TGN). Our findings suggest that mutations that block formation of the phosphorylated catalytic intermediate also prevent copper-induced relocalization of MNK from the TGN. Furthermore, mutations in the phosphatase domain, which resulted in hyperphosphorylation of MNK, caused constitutive trafficking from the TGN to the plasma membrane. A similar effect on trafficking was observed with a phosphatase mutation in the closely related copper ATPase, ATP7B, affected in Wilson disease. These findings suggest that the copper-induced trafficking of the Menkes and Wilson disease copper ATPases is associated with the phosphorylated intermediate that is formed during the catalysis of these pumps. Our findings describe a novel mechanism for regulating the subcellular location of a transport protein involving the recognition of intermediate conformations during catalysis.
12508671##2003-1-2##[Rare, but important chronic liver diseases].##The presence of steatosis and inflammatory infiltrate in liver biopsies is essential for the diagnosis of non-alcoholic steatohepatitis (NASH). These findings are similar to those with alcoholic liver disease. However, in the NASH-situation alcohol doesn't play an important role. Risk factors for the development of NASH are obesity and diabetes. Most of the patients are clinically asymptomatic. This means, that a diagnosis of NASH is a diagnosis of exclusion: Viral induced, autoimmune, metabolic and toxic liver disease have to be excluded. The disease has a benign clinical course. The risk of cirrhosis is low. So far, there is no established treatment. Preliminary reports suggest a positive effect of weight-loss and ursodeoxycholic acid. Wilson's disease, a copper storage disorder, in which biliary copper excretion is reduced, is inherited as an autosomal recessive trait. Most patients with Wilson disease become symptomatic between the ages of 6 and 15. In about 90% of patients serum ceruloplasmin levels and serum copper concentrations are reduced. Copper excreation is increased. Histologic examination of liver biopsy specimens reveals fatty infiltration, Mallory bodies and ballooned glycogen nuclei, abnormalities which are also found in alcoholic liver disease. The definitive diagnostic parameter is the quantitative determination of liver copper content (> 250 micrograms/g dryweight). Untreated Wilson disease is always fatal. Lifelong treatment with anti-copper drugs are essential, D-penicillamine being the firstline therapy. Hereditary hemochromatosis (HH) is an iron overload disease inherited as an autosomal recessive trait. The frequency of the disease is high. The first symptoms usually can be found at the age of 20-50 years. Arthralgia develops in up to 50% of the patients. Many organs are involved, most often the liver. The organ is usually enlarged, transaminases are always moderately elevated. Laboratory findings disclose a marked elevation in serum ferritin and transferrin saturation. More than 80% of HH-patients are homozygous for the C282Y-mutation in the HFE-gene. The firstline treatment of HH is phlebotomy. Treatment is lifelong. When serum ferritin drops below 50 micrograms/l, the frequency of phlebotomy should be reduced (4-12 per year). If the patient already has cirrhosis, the risk of HCC is very high.
12385784##2002-10-19##Correction of the copper transport defect of Menkes patient fibroblasts by expression of two forms of the sheep Wilson ATPase.##The Wilson disease (WD) protein (ATP7B) is a copper-transporting P-type ATPase that is responsible for the efflux of hepatic copper into the bile, a process that is essential for copper homeostasis in mammals. Compared with other mammals, sheep have a variant copper phenotype and do not efficiently excrete copper via the bile, often resulting in excessive copper accumulation in the liver. To investigate the function of sheep ATP7B and its potential role in the copper-accumulation phenotype, cDNAs encoding the two forms of ovine ATP7B were transfected into immortalised fibroblast cell lines derived from a Menkes disease patient and a normal control. Both forms of ATP7B were able to correct the copper-retention phenotype of the Menkes cell line, demonstrating each to be functional copper-transporting molecules and suggesting that the accumulation of copper in the sheep liver is not due to a defect in the copper transport function of either form of sATP7B.
12438251##2002-11-20##Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper.##Impaired uptake of cisplatin (DDP) consistently accompanies the acquisition of resistance to the platinum drugs. The pathways by which DDP enters or exits from cells remain poorly defined. Using three pairs of human ovarian carcinoma cell lines, each consisting of a sensitive parental line and a stably DDP-resistant subline derived by in vitro selection, resistance to DDP was found to be accompanied by cross-resistance to Cu. Accumulation of DDP in the resistant sublines ranged from 38 to 67% of that in the parental line at 1 h, and DNA adduct formation varied from 10 to 38% of that in the sensitive cells. The DDP-resistant cells had 22-56% lower basal levels of copper, and the copper levels were only 27-46% of those observed in the sensitive parental lines after a 24-h exposure to medium supplemented with copper. The initial influx rate for DDP in the three resistant cell lines ranged from 23 to 55% of that in the sensitive cells of each pair; the initial influx rate for copper in the resistant cells varied from 56 to 75% of control. Studies performed using one pair of cell lines demonstrated that for both copper and DDP the initial efflux rate was lower, whereas the terminal efflux rate was higher in the resistant cells. On Western blot analysis all three resistant lines exhibited increased expression of one or the other of the two copper export pumps (ATP7A or ATP7B) with no change in the HAH1 chaperone. We conclude that the acquisition of DDP resistance in ovarian carcinoma is accompanied by alterations in the cellular pharmacology of DDP that are paralleled by similar changes in the uptake and efflux of copper. These results are consistent with the concept that DDP enters and exits from the cell via transporters that normally mediate copper homeostasis.
12443926##2002-11-22##Transport and detoxification systems for transition metals, heavy metals and metalloids in eukaryotic and prokaryotic microbes.##Transition metals, heavy metals and metalloids are usually toxic in excess, but a number of transition metals are essential trace elements. In all cells there are mechanisms for metal ion homeostasis that frequently involve a balance between uptake and efflux systems. This review will briefly describe ATP-coupled resistance pumps. ZntA and CadA are bacterial P-type ATPases that confers resistance to Zn(II), Cd(II) and Pb(II). Homologous copper pumps include the Menkes and Wilson disease proteins and CopA, an Escherichia coli pump that confers resistance to Cu(I). For resistance to arsenicals and antimonials there are several different families of transporters. In E. coli the ArsAB ATPase is a novel system that confers resistance to As(III) and Sb(III). Eukaryotic arsenic resistance transporters include Acr3p and Ycf1p of Saccharomyces cerevisiae. These systems provide resistance to arsenite [As(III)]. Arsenate [As(V)] detoxification involves reduction of As(V) to As(III), a process catalyzed by arsenate reductase enzymes. There are three families of arsenate reductases, two found in bacterial systems and a third identified in S. cerevisiae.
12544487##2003-1-25##Identification of novel mutations and the three most common mutations in the human ATP7B gene of Korean patients with Wilson disease.##
12412803##2002-11-5##Decreased bone density, elevated serum osteoprotegerin, and beta-cross-laps in Wilson disease.##Osteopathia has been reported in Wilson disease (WD), but bone density has not been measured; therefore, we performed bone mineral density (BMD), bone mineral content (BMC), and quantitative bone ultrasound (QUS) assessments, as well as measured the serum levels of osteocalcin (OCN), beta-cross-laps (beta-CTx's), and the recently discovered osteoprotegerin (OPG) and its ligand RANKL to investigate the underlying mechanism of osseous disorders. Serum OCN, beta-CTx, OPG, and RANKL levels were measured by ELISA in 21 WD patients and in 20 age- and gender-matched healthy subjects. BMD, BMC, and QUS parameters were also determined. Osteoporosis was present in 9/21 (43%) WD patients. Abnormal QUS parameters were found in 7 (33%) of the patients. Although serum OCN levels were similar in patients and controls (29.93 +/- 24.65 mg/ml vs. 29.84 +/- 6.89 mg/ml), beta-CTx and OPG levels were significantly increased in WD compared with the healthy controls (625.4 +/- 312.3 pg/ml vs. 423.6 +/- 144.3 pg/ml and p = 0.022 and 7.2 +/- 3.4 pM vs. 3.5 +/- 1.0 pM and p < 0.001, respectively). No difference was observed in the RANKL level. There was a positive correlation between OCN and beta-CTx (r = 0.55; p = 0.01). We proved high occurrence of osteoporosis in WD. Negative bone remodeling balance is a consequence of increased bone resorption, which is indicated by elevated beta-CTx. The novel finding of elevated serum OPG may reflect a compensatory reaction to enhanced osteoclast activity, despite the normal OCN level.
12399241##2002-10-26##The eye in Wilson's disease: sunflower cataract associated with Kayser-Fleischer ring.##
12515040##2003-1-8##[Molecular analysis of Wilson disease].##
12216079##2002-9-7##Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP.##Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorly-differentiated ovarian carcinomas treated with cisplatin-based chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy.
12406443##2002-10-31##Steatohepatitis in children.##Steatohepatitis in children occurs in the childhood version of non-alcoholic fatty liver disease (NAFLD), as a result of hepatotoxicity and with certain genetic/metabolic diseases. Until recently, NAFLD was considered to be rare in children. It is now recognized as an important childhood liver disease, especially because childhood obesity is much more common. Children with NAFLD may present as young as 4 years old; males tend to predominate; fibrosis is often found on liver biopsy and cirrhosis has been reported. Treatment for childhood NAFLD currently consists of weight reduction plus regular aerobic exercise; vitamin E may be an effective adjunctive therapy. Drug hepatotoxicity and genetic/metabolic diseases that can cause fatty liver, such as Wilson's disease and cystic fibrosis, must be excluded since treatment is radically different. Other causes of chronic hepatitis, such as chronic viral hepatitis, must also be excluded. Multisystemic inherited diseases with hyperinsulinaemia plus insulin resistance may have NAFLD as hepatic involvement and should be identified.
12426114##2002-11-12##Molecular mechanism of copper transport in Wilson disease.##Wilson disease is an autosomal recessive disorder of copper metabolism. The Wilson disease protein is a putative copper-transporting P-type ATPase, ATP7B, whose malfunction results in the toxic accumulation of copper in the liver and brain, causing the hepatic and/or neurological symptoms accompanying this disease. The cytosolic N-terminal domain (approximately 70 kDa) of this ATPase comprises six heavy metal-associated domains, each of which contains the conserved metal-binding motif GMTCXXC. The N-terminal domain (Wilson disease copper-binding domain [WCBD]) has been expressed, purified, and characterized using various techniques. The WCBD binds six atoms of copper in the +1 oxidation state competitively, and with a greater affinity than all other metals. The copper atom is coordinated by two cysteines in a distorted linear geometry. Copper binds the WCBD in a cooperative manner and induces secondary and tertiary conformation changes. Zinc binding to the WCBD has also been characterized by circular dichroism spectroscopy and shown to produce conformational changes that are completely different from those induced by copper. The phosphorylation/nucleotide-binding domain of ATP7B has also been expressed and characterized and shown to be capable of binding ATP but lacking ATPase activity. A peptide corresponding to the sixth transmembrane domain of ATP7B has been constructed and shown to undergo secondary conformational changes upon binding a single atom of copper. Finally, a chimeric protein consisting of the WCBD and truncated ZntA, a zinc-transporting ATPase lacking the N-terminal domain, has been constructed and analyzed for metal ion selectivity. These results suggest that the core determines the metal ion specificity of P-type ATPases, and the N-terminal metal-binding domain may play a regulatory role.
12325021##2002-9-27##Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B.##More than 200 Wilson disease (WD) disease-causing mutations have been defined to date. Missense mutations are largely prevalent while splice-site mutations are limited in number. Most reside in the splice donor or acceptor sites and only a minority are detected in splicing consensus sequences. Furthermore, only a few splicing mutations have been studied at the RNA level to date. In this study, using the RT-PCR method we performed the molecular characterization of four consensus splice-site mutations identified by DNA analysis in patients with WD. One of them, previously described 1707+3insT, occurred at position 3 in the donor splice site of intron 4, while the other three, 2122-8T>G, 2866-6T>G, and 3061-12T>A, are novel and occurred in the acceptor splice sites of introns 7, 12, and 13, respectively. Analysis revealed a prevalently abnormal splicing in the samples carrying the mutations compared to the normal controls. Comparison of RNA splicing with normal controls in liver and lymphocytes further suggests that abnormal splicing of the WD gene is also present and differentially regulated in normal tissues. The results produced in this study strongly suggest that DNA mutations residing in the consensus sequence of WD gene splice sites result in the WD phenotype by interfering with the production of the normal WD protein. Further studies are necessary to better quantify the amount of different transcripts produced by these mutations, and establish their correlation with the disease phenotype.
12412992##2002-11-5##Genetic disorders affecting proteins of iron and copper metabolism: clinical implications.##Iron and copper are essential transition metals that permit the facile transfer of electrons in a series of critical biochemical pathways. Recent work has identified the specific proteins involved in the absorption, transport, utilization, and storage of iron and copper. Remarkable progress is being made in understanding the molecular basis of disorders of human iron and copper metabolism. This review describes these proteins and examines the clinical consequences of new insights into the pathophysiology of genetic abnormalities affecting iron and copper metabolisms. Hereditary hemochromatosis is the most common genetic disorder of iron metabolism caused by mutations in the HFE gene. Aceruloplasminemia is a rare iron metabolic disorder that results from deficiency of ceruloplasmin ferroxidase activity as a consequence of mutations in the ceruloplasmin gene. Menkes disease and Wilson's disease are inherited disorders of copper metabolism resulting from the absence or dysfunction of homologous copper-transporting ATPases.
12359384##2002-10-3##Wilson disease manifested primarily as amenorrhea and accompanying thrombocytopenia.##
12539962##2003-1-24##Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation.##Wilson's disease protein (WNDP) is a product of a gene ATP7B that is mutated in patients with Wilson's disease, a severe genetic disorder with hepatic and neurological manifestations caused by accumulation of copper in the liver and brain. In a cell, WNDP transports copper across various cell membranes using energy of ATP-hydrolysis. Copper regulates WNDP at several levels, modulating its catalytic activity, posttranslational modification, and intracellular localization. This review summarizes recent studies on enzymatic function and copper-dependent regulation of WNDP. Specifically, we describe the molecular architecture and major biochemical properties of WNDP, discuss advantages of the recently developed functional expression of WNDP in insect cells, and summarize the results of the ligand-binding studies and molecular modeling experiments for the ATP-binding domain of WNDP. In addition, we speculate on how copper binding may regulate the activity and intracellular distribution of WNDP, and what role the human copper chaperone Atox1 may play in these processes.
12539961##2003-1-24##Structural and functional insights of Wilson disease copper-transporting ATPase.##Wilson disease is an autosomal recessive disorder of copper metabolism. The gene for this disorder has been cloned and identified to encode a copper-transporting ATPase (ATP7B), a member of a large family of cation transporters, the P-type ATPases. In addition to the core elements common to all P-type ATPases, the Wilson copper-transporting ATPase has a large cytoplasmic N-terminus comprised six heavy metal associated (HMA) domains, each of which contains the copper-binding sequence motif GMT/HCXXC. Extensive studies addressing the functional, regulatory, and structural aspects of heavy metal transport by heavy metal transporters in general, have offered great insights into copper transport by Wilson copper-transporting ATPase. The findings from these studies have been used together with homology modeling of the Wilson disease copper-transporting ATPases based on the X-ray structure of the sarcoplasmic reticulum (SR) calcium-ATPase, to present a hypothetical model of the mechanism of copper transport by copper-transporting ATPases.
12539960##2003-1-24##Copper transporting P-type ATPases and human disease.##Copper transporting P-type ATPases, designated ATP7A and ATP7B, play an essential role in mammalian copper balance. Impaired intestinal transport of copper, resulting from mutations in the ATP7A gene, lead to Menkes disease in humans. Defects in a similar gene, the copper transporting ATPase ATP7B, result in Wilson disease. This ATP7B transporter has two functions: transport of copper into the plasma protein ceruloplasmin, and elimination of copper through the bile. Variants of ATP7B can be functionally assayed to identify defects in each of these functions. Tissue expression studies of the copper ATPases and their copper chaperone ATOX1 indicate that there is not complete overlap in expression. Other chaperones may be important for the transport of copper into ATP7A and ATP7B.
12555942##2003-1-31##Niemann-Pick disease type C in adults.##Although it is often perceived as a paediatric disorder, significant numbers of patients with Niemann-Pick disease type C present for the first time in adult life or survive into adult life. The presentation in these patients differs from that seen in the classical juvenile form of the disease. Adult patients are often referred to clinicians with psychosis or other major psychiatric problems. The dystonia with preserved intellectual functioning can be mistaken for other basal ganglia disorders such as Wilson disease. The presence of vertical gaze palsy is an important clinical clue and, in the presence of a modest increase in plasma chitotriosidase activity, can be very helpful in the differential diagnosis. The diagnosis should be confirmed in suspected cases by filipin staining of cultured fibroblasts, as well as cholesterol esterification studies and DNA mutation analysis.
12360442##2002-10-3##Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease.##Wilson's disease presenting as acute liver failure (ALF) is potentially fatal, and liver transplantation (LTx) is the only option. We report two patients with Wilson's disease and ALF treated with the Molecular Adsorbents Recirculating System (MARS). Both patients fulfilled criteria for poor prognosis. Because LTx was not available immediately in either case, MARS was used as a bridge to LTx. In Case 1, serum bilirubin decreased from 803 to 425 micromol/L after 3 treatments, but increased to 656 micromol/L during a break, decreasing again to 457 micromol/L with further treatment. Serum copper decreased from 53.7 micromol/L, to 35.8 micromol/L after first treatment session, and 17.4 micromol/L at treatment completion. In Case 2, MARS treatment over 2 weeks reduced serum bilirubin from 1200 to 450 micromol/L and copper from 35 to 13 micromol/L with marked improvement in encephalopathy and reduction in ammonia (59 to 34 micromol/L). Both patients were successfully bridged to LTx (days 9 and 28, respectively). Analysis of albumin-dialysate from the MARS circuit suggested that copper removal occurred mostly in the first few hours of treatment, partly being adsorbed by albumin and partly by the MARSFlux membrane (Teraklin AG, Rostock, Germany). These data suggest that MARS removes copper efficiently and can be used to bridge patients with Wilson's disease and ALF to LTx.
12420134##2002-11-7##Tissue localization of the copper chaperone ATOX1 and its potential role in disease.##ATOX1 is a cytoplasmic copper chaperone that interacts with the copper-binding domain of the membrane copper transporters ATP7A and ATP7B. ATOX1 has also been suggested to have a potential anti-oxidant activity. This study investigates the tissue-specific localization of the mouse homolog, Atox1, in mouse liver and kidney. Immunohistochemical studies in the liver localize the copper chaperone to hepatocytes surrounding both hepatic and central veins. In the kidney, Atox1 is localized to the cortex and the medulla. Cortex immunostaining is specific to glomeruli in both the juxtamedullary and cortical nephrons. Expression in the medulla appears to be associated with the loops of Henle. These data suggest that localized regions in the liver and kidney express Atox1 and have a role in copper homeostasis and/or anti-oxidant protection. Twenty-seven patients with Wilson disease-like phenotypes and two patients with Menkes disease-like phenotypes were screened for ATOX1 mutations with no alterations detected. The human phenotype resulting from mutations in ATOX1 remains unidentified.
12395188##2002-10-24##clap1, a gene encoding a copper-transporting ATPase involved in the process of infection by the phytopathogenic fungus Colletotrichum lindemuthianum.##A screen for insertional mutants of Colletrichum lindemuthianum, the causative agent of common bean anthracnose, led to the identification of a non-pathogenic, lightly colored transformant. This mutant is unable to induce disease symptoms on intact or wounded primary leaves of seedlings and plantlets of Phaseolus vulgaris. In vitro, it exhibits normal vegetative growth, sporulation and conidial germination, but the cultures remain beige instead of becoming black. Microscopic examination revealed that this mutant forms fewer appressoria than the wild-type strain, and these are misshapen and poorly melanized. Molecular analyses indicated that the mutagenic plasmid had targeted clap1, a gene encoding a putative copper-transporting ATPase sharing 35% identity with the human Menkes and Wilson proteins and the product of the CCC2 gene of Saccharomyces cerevisiae. Complementation of the non-pathogenic beige mutant with a wild-type allele of clap1 restored both pathogenicity and pigmentation. Conversely, replacement of the wild-type allele with a disrupted clap1 gene gave rise to non-pathogenic beige transformants. Compared with the wild-type strain, extracts from clap1 mutants were found to have very low levels of phenol oxidase activity. These observations suggest that the clap1 gene product may be involved in the pathogenicity of C. lindemuthianum strains because of its role in delivering copper to secreted cuproenzymes, such as the phenol oxidases that mediate the polymerization of 1,8-dihydroxynaphthalene to melanin.
12392630##2002-10-24##[Comparative effects of tensiomin and sodium dimercaptosulphonate on the serum sulfydryl and anticopper of the patients with Wilson's disease].##
12487879##2002-12-19##[Multimodal approach to clinical liver transplantation].##
12297577##2002-9-26##Denny-Brown, Wilson's disease, and BAL (British antilewisite [2,3-dimercaptopropanol]).##In 1951 Denny-Brown and Porter described the successful treatment of Wilson's disease using the chelating agent British antilewisite. The presentation of their results both at meetings and in print changed the traditional view of neurology from a descriptive to an interventional discipline using treatments based on the underlying biochemical disorder. The authors review the importance of these reports and provide edited digital versions of the films Denny-Brown made of the five patients described in the initial reports.
12221184##2002-9-11##Copper genes are not implicated in the pathogenesis of focal dystonia.##
12242608##2002-9-21##Metallothionein and antioxidant enzymes in Long-Evans Cinnamon rats treated with zinc.##The Long-Evans Cinnamon (LEC) rat is a mutant animal model for Wilson's disease. It is known that an abnormal accumulation of Cu and Fe in the liver and low concentrations of both ceruloplasmin and Cu in the serum occur in these rats. The accumulation of Cu is explained by the defective expression of the Cu-transporting P-type ATPase gene, homologous to the gene for Wilson's disease (ATP7B). The aim of this work was to clarify the action mechanism of Zn, and to verify the role that this metal plays in LEC rats in short-term treatment experiments (1 and 2 weeks) on concentrations of Cu, Zn, Fe, metallothionein (MT), 8-hydroxy-2'-deoxyguanosine (oh(8)dG) and on the activity of antioxidant enzymes. It is well known that Zn induces MT and has the ability to prevent redox-active metals, Cu and Fe, binding to and causing oxidative damage at active sites of Zn metalloenzymes and nonspecific binding sites on proteins. Zn administration reduces Cu and Fe transport from mucosal to serosal intestinal sides through competitive mechanisms. Our findings show that treatment with zinc acetate increases tissue Zn and MT contents and decreases Cu and Fe concentrations in the liver and kidneys, even if hepatic Zn and MT concentrations decrease with treatment period. Induction of MT synthesis by Zn contributes to the reduction in free radicals produced by Cu and Fe. We also observed that the superoxide dismutase (SOD)activity in liver decreases with treatment duration in association with the Cu and Fe liver decrease. However, the SOD activity in kidney increases in untreated rats at 2 weeks relative to those untreated for 1 week.
12242607##2002-9-21##Copper balance and ceruloplasmin in chronic hepatitis in a Wilson disease animal model, LEC rats.##In an animal model of Wilson disease, Long-Evans rats with cinnamon-colored coat (LEC rats), copper (Cu) accumulates in the liver with age up to the onset of acute hepatitis owing to a hereditary defective transporter for the efflux of Cu, ATP7B. The plasma Cu concentration is low in LEC rats because of the excretion of apo-ceruloplasmin (apo-Cp). However, toward and after the onset of chronic hepatitis, plasma Cu concentration increases in the form of holo-Cp, while the liver Cu concentration is maintained at a constant level without the occurrence of fulminant hepatitis. In the present study, the material balance of Cu was studied in LEC rats with chronic hepatitis in order to elucidate the mechanisms underlying the increase of holo-Cp in plasma and the maintenance of Cu at a constant level in the liver. The relationship between the Cu concentration and ferroxidase activity of Cp was analyzed in the plasma of LEC rats of different ages and of Wistar rats fed a Cu-deficient diet for different durations. Cu was suggested to be delivered to Cp in an all-or-nothing manner, resulting in the excretion of fully Cu-occupied holo-Cp (Cu(6)-Cp) or totally Cu-unoccupied Cu(0)-Cp (apo-Cp), but not partially Cu-occupied Cu(n)-Cp (where n = 1-5). The increase of holo-Cp in acute and chronic hepatitis in LEC rats was explained by the delivery of Cu, accumulating in the non-metallothionein-bound form, to Cp outside the Golgi apparatus of the liver. The plasma Cu concentration and ferroxidase activity were proposed to be specific indicators of the appearance of non-metallothionein-bound Cu in the liver of LEC rats.
12439848##2002-11-20##[Chorea in hemodialysis: Is chorea just a neurological syndrome or is it related to uremia or dialysis?].##Chronic renal failure and haemodialysis patients are prone to develop encephalopathy. The causes of encephalopathy are often unclear. Clinical signs of encephalopathy in the uraemic patient often overlap with several other affections causing neurological disorders. Whenever basal ganglia are anatomically involved, movement disorders arise, including chorea. Some acute and chronic neurological syndromes associated with chronic uraemia have consistently been reported (uraemic encephalopathy, dialysis disequilibrium syndrome, dialysis dementia, nephroangiosclerosis neuropathy and ageing neuropathy). Other clinical conditions in which neurological involvement exists are not so frequent in both haemodialysis patients and in the general population (Wernicke's encefalopathy, Creutzfeldt-Jacob disease). Because of the non specific symptoms and the very heterogeneous aetiology, a careful physical examination should be performed in haemodialysis patients with clinical signs of encephalopathy and the main metabolic alterations should be sought; moreover, central nervous system imaging examination is often appropriate. In case of basal ganglia anatomical involvement, supported by findings of imaging techniques, it is necessary to evaluate individual causes of encephalopathy by means of more accurate tests including analysis of cerebro-spinal fluid, measurement of plasma levels of vitamin B components and laboratory tests searching for more uncommon diseases such as Huntington's chorea and Wilson's disease.
12420912##2002-11-8##Wilson's disease.##Wilson's disease (WD), an inborn error of copper (Cu) metabolism, is now one of the leading liver diseases in children in India. The clinical presentation can be extremely varied viz.,--all forms of acute and chronic liver disease, minimal to severe neurological disease, psychiatric problems, bony deformities, hemolytic anemia and endocrine manifestations. A high index of suspicion is necessary along with a judicious battery of investigations for diagnosis. Hepatic copper estimation is the most reliable test but is not easily available in India. Liver biopsy may not be possible because of bleeding problems and histological features are often not diagnostic of WD. In the absence of hepatic Cu, a low ceruloplasmin, high 24 hour urinary copper and presence of KF rings aid in making the diagnosis. The mainstay of initial therapy is Cu-chelators like D-Penicillamine, and Trientine for reduction in body copper to sub-toxic levels. Subsequent maintenance therapy is necessarily lifelong with D-Penicillamine, Trientine or Zinc. Children on therapy must be monitored regularly for response, side-effects, compliance and rehabilitation. Response to therapy may be unpredictable, but acute and early presentations like fulminant hepatic failures have a poor outcome. All siblings must be screened for WD as early diagnosis and treatment result in a good outcome. The identification of the WD gene on chromosome 13 has led to the possible use of molecular genetics (haplotype and mutational analyses) in the diagnosis of WD. Parent groups/associations must take active part in holistic management of WD.
12227652##2002-9-14##Not all absent serum ceruloplasmin is Wilson disease: a review of aceruloplasminemia.##
12360563##2002-10-3##Cognitive functioning in neurologically symptomatic and asymptomatic forms of Wilson's disease.##We sought to determine the pattern of cognitive deficits in patients with Wilson's disease (WD) with different type and degree of neurological involvement, and to interpret the findings in relation to the underlying pathology. A total of 67 WD patients were examined with a neuropsychological test battery assessing different aspects of cognitive processing. The patients were subdivided into three groups: neurologically asymptomatic, neurological with pure basal ganglia lesions, and neurological with more extensive pathology. The results were compared with 50 matched healthy controls. Patients with a neurological form of WD showed a mild but definitive impairment in all cognitive functions. In contrast, the neurologically asymptomatic patients showed no deficits when compared with normal controls. Multifocal pathology was associated with more severe cognitive deficits than selective basal ganglia lesions but did not contribute significantly to memory impairment. A range of cognitive functions, including frontal-executive ability, aspects of memory and visuospatial processing, are affected in the neurologically symptomatic WD patients. In contrast, no subliminal deficits were observed in the asymptomatic patients. The lesions of the basal ganglia seem to be of central importance in explaining the symptomatology.
12202071##2002-8-31##Rapid identification of Wilson's disease carriers by denaturing high-performance liquid chromatography.##
12029094##2002-5-25##Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity.##Copper is essential for the growth and development of mammalian cells. The key role in the intracellular distribution of copper belongs to the recently discovered family of metallochaperones and to copper-transporting P-type ATPases. The mutations in the ATPase ATP7B, the Wilson's disease protein (WNDP), lead to intracellular accumulation of copper and severe hepatic and neurological abnormalities. Several of these mutations were shown to disrupt the protein-protein interactions between WNDP and the metallochaperone Atox1, suggesting that these interactions are important for normal copper homeostasis. To understand the functional consequences of the Atox1-WNDP interaction at the molecular level, we produced recombinant Atox1 and characterized its effects on WNDP. We demonstrate that Atox1 transfers copper to the purified amino-terminal domain of WNDP (N-WNDP) in a dose-dependent and saturable manner. A maximum of six copper atoms can be transferred to N-WNDP by the chaperone. Furthermore, the incubation of copper Atox1 with the full-length WNDP leads to the stimulation of the WNDP catalytic activity, providing strong evidence for the direct effect of Atox1 on the function of this transporter. Our data also suggest that Atox1 can regulate the copper occupancy of WNDP. The incubation with apo-Atox1 results in the removal of copper from the metalated N-WNDP and apparent down-regulation of WNDP activity. Interestingly, at least one copper atom remains tightly bound to N-WNDP even in the presence of excess apo-Atox1. We suggest that this incomplete reversibility reflects the functional non-equivalency of the metal-binding sites in WNDP and speculate about the intracellular consequences of the reversible Atox1-mediated copper transfer.
12190204##2002-8-23##Elastosis perforans serpiginosa secondary to D-penicillamine treatment in a Wilson's disease patient.##
12210790##2002-9-5##Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo.##Copper toxicity contributes to neuronal death in Wilson's disease and has been speculatively linked to the pathogenesis of Alzheimer's and prion diseases. We examined copper-induced neuronal death with the goal of developing neuroprotective strategies. Copper catalyzed an increase in hydroxyl radical generation in solution, and the addition of 20 microM copper for 22 hours to murine neocortical cell cultures induced a decrease in ATP levels and neuronal death without glial death. This selective neuronal death was associated with activation of caspase-3 and was reduced by free radical scavengers and Z-Val-Ala-Asp fluoromethylketone, consistent with free radical-mediated injury leading to apoptosis. Pyruvate dehydrogenase is especially vulnerable to inhibition by oxygen free radicals, and the upstream metabolites, pyruvate, phosphoenolpyruvate, and 2-phosphoglycerate were elevated in cortical cells after toxic exposure to copper. One approach to protecting pyruvate dehydrogenase from oxidative attack might be to enhance binding to cofactors. Addition of thiamine, dihydrolipoic acid, or pyruvate reduced copper-induced neuronal death. To test efficacy in vivo, we added 1% thiamine to the drinking water of Long Evans Cinnamon rats, an animal model of Wilson's disease. This thiamine therapy markedly extended life span from 6.0 +/- 1.6 months to greater than 16 months.
12205794##2002-9-11##[Hematologic manifestations of inborn errors of metabolism].##Haematological symptoms can be helpful for the diagnosis of metabolic diseases. A megaloblastic anemia orientates to folate and cobalamine anomalies when associated with homocystinemia and decreased plasma methionine levels, or to congenital oroticuria (hypochromia), Pearson syndrome (sideroblasts and vacuolisation of precursors) and thiamine transporter abnormality (sideroblasts) in the absence of homocystinuria. An hemolytic anemia orientates to anomalies of anaerobic glycolysis, heme synthesis, or iron metabolism, and Wilson disease. A pancytopenia orientates to organic aciduria, lysinuric protein intolerance, mevalonic aciduria and lysosomal storage diseases (Gaucher, Niemann Pick, Wolman) when hepatosplenomegaly is present. Uremic hemolytic syndrome and hemophagocytic lymphohistiocytosis respectively orientate to B12 anomalies, lysinuric protein intolerance, lysosomal storage diseases and organic aciduria.
12196182##2002-8-28##The Wilson's disease protein expressed in Sf9 cells is phosphorylated.##The Wilson's disease protein (WNDP), a copper transporter, is a crucial mediator of copper homoeostasis in mammalian cells. We recently found that changes in copper concentration regulate the phosphorylation level of WNDP. WNDP phosphorylation was observed in several mammalian cell lines, suggesting that a common phosphorylation pathway exists in these cells. Here we demonstrate that WNDP expressed in Sf9 insect cells is also phosphorylated, as evidenced by metabolic labelling of these cells with [(32)P]P(i). Because the baculovirus system allows us to generate large amounts of protein, we are using this expression method to isolate WNDP and map the sites of WNDP phosphorylation. The identification of phosphorylation sites is the first step towards understanding the physiological role of WNDP phosphorylation.
12142063##2002-7-27##Evoked potentials in children with Wilson's disease.##We assessed multimodal evoked potentials (EPs) in 13 children with newly diagnosed neurologically symptomatic Wilson's disease (WD) and in their first degree symptom-free relatives, consisting of seven presymptomatic and 15 asymptomatic siblings and 22 asymptomatic parents. EP abnormalities of at least one modality and one side stimulation were observed in 38.5% of patients, 42.9% of presymptomatic siblings, 21.4% of asymptomatic siblings and 18.2% of parents. Patients tended to have more prolonged central latencies of EPs. However, the left I-V interpeak brainstem auditory EP latency difference was the only one to reach at the statistical significance (P = 0.001). Abnormal VEP P100 latency was detected more frequently in presymptomatic siblings than those in asymptomatic ones (42.9% vs 7.1%, P = 0.049). In all relatives, other diagnostic tests including electroencephalography, electromyography and head magnetic resonance imaging (MRI) for subclinical nervous system involvement and Kayser-Fleischer rings examination yielded normal results. In pre/asymptomatic siblings, genetic and biochemical studies may aid to initiate treatment prior to the development of permanent tissue damage. Our results indicate that abnormal EPs may signal unique pathological finding in some subjects. Importantly, these abnormalities occur earlier than Kayser-Fleischer rings and MRI lesions. In early stages of WD, EP recordings may, therefore, be used to help decide on treatment initiation and treatment efficacy evaluation. Moreover, EP recordings can readily be added to family screening studies.
12192499##2002-8-23##Functional anatomy of thalamus and basal ganglia.##THALAMUS: The human thalamus is a nuclear complex located in the diencephalon and comprising of four parts (the hypothalamus, the epythalamus, the ventral thalamus, and the dorsal thalamus). The thalamus is a relay centre subserving both sensory and motor mechanisms. Thalamic nuclei (50-60 nuclei) project to one or a few well-defined cortical areas. Multiple cortical areas receive afferents from a single thalamic nucleus and send back information to different thalamic nuclei. The corticofugal projection provides positive feedback to the "correct" input, while at the same time suppressing irrelevant information. Topographical organisation of the thalamic afferents and efferents is contralateral, and the lateralisation of the thalamic functions affects both sensory and motoric aspects. Symptoms of lesions located in the thalamus are closely related to the function of the areas involved. An infarction or haemorrhage thalamic lesion can develop somatosensory disturbances and/or central pain in the opposite hemibody, analgesic or purely algesic thalamic syndrome characterised by contralateral anaesthesia (or hypaesthesia), contralateral weakness, ataxia and, often, persistent spontaneous pain. BASAL GANGLIA: Basal ganglia form a major centre in the complex extrapyramidal motor system, as opposed to the pyramidal motor system (corticobulbar and corticospinal pathways). Basal ganglia are involved in many neuronal pathways having emotional, motivational, associative and cognitive functions as well. The striatum (caudate nucleus, putamen and nucleus accumbens) receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas (prefrontal, premotor and supplementary motor areas) which are concerned with motor planning. These circuits: (i) have an important regulatory influence on cortex, providing information for both automatic and voluntary motor responses to the pyramidal system; (ii) play a role in predicting future events, reinforcing wanted behaviour and suppressing unwanted behaviour, and (iii) are involved in shifting attentional sets and in both high-order processes of movement initiation and spatial working memory. Basal ganglia-thalamo-cortical circuits maintain somatotopic organisation of movement-related neurons throughout the circuit. These circuits reveal functional subdivisions of the oculomotor, prefrontal and cingulate circuits, which play an important role in attention, learning and potentiating behaviour-guiding rules. Involvement of the basal ganglia is related to involuntary and stereotyped movements or paucity of movements without involvement of voluntary motor functions, as in Parkinson's disease, Wilson's disease, progressive supranuclear palsy or Huntington's disease. The symptoms differ with the location of the lesion. The commonest disturbances in basal ganglia lesions are abulia (apathy with loss of initiative and of spontaneous thought and emotional responses) and dystonia, which become manifest as behavioural and motor disturbances, respectively.
12436085##2002-11-19##Applications of transcranial magnetic stimulation in movement disorders.##The author reviews the applications of transcranial magnetic stimulation (TMS) in a series of movement disorders--namely, Parkinson's disease, corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, essential tremor, dystonia, Huntington's chorea, myoclonus, the ataxias, Tourette's syndrome, restless legs syndrome, Wilson's disease, Rett syndrome, and stiff-person syndrome. Single- and paired-pulse TMS studies have been done mainly for pathophysiologic purposes. Repetitive TMS has been used largely for therapy. Many TMS abnormalities are seen in the different diseases. They concur to show that motor cortical areas and their projections are the main target of the basal ganglia dysfunction typical of movement disorders. Interpretation has not always been clear, and sometimes there were discrepancies and contradictions. Largely, this may be the result of the extreme heterogeneity of the methods used and of the patients studied. It is premature to give repetitive TMS a role in treatment. Overall, however, TMS gives rise to a new, outstanding enthusiasm in the neurophysiology of movement disorders. There is reason to predict that TMS, with its continuous technical refinement, will prove even more helpful in the near future. Then, research achievements are reasonably expected to spill over into clinical practice.
12227457##2002-9-14##Cardiac involvement in Wilson disease.##
12195459##2002-8-27##Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease.##Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation.
12174008##2002-8-14##Diagnosing Wilson's disease in a 5-year-old child.##
12432829##2002-11-16##Inherited movement disorders.##The inherited movement disorders comprise a rapidly growing category of human disease. Advances in genetics have led to the identification of the gene mutation in Huntington's disease and three different gene mutations, which may lead to Parkinson's disease. In addition, gene mutations have been identified in less common movement disorders including Wilson's disease, Hallervorden-Spatz syndrome, paroxysmal kinesogenic choreoathetosis, neuroacanthocytosis, and some forms of dystonia. This article summarizes what is known about the genetic mutations that cause these movement disorders, as well as the clinical features of each disease and the symptomatic treatments currently available.
12234269##2002-9-18##Long-term survival after liver transplantation in children with metabolic disorders.##
12486857##2002-12-19##[Late presentation of Wilson's disease].##
12187774##2002-8-22##[Appropriate administration schedule of D-penicillamine for pediatric Wilson's disease patients based on urinary copper excretion].##The purpose of this study was to increase the amount of copper excreted resulting from the administration of D-penicillamine(DP) in pediatric Wilson's disease(WD) patients. By measuring the urinary copper excretion after adjusting the administration schedules, the appropriate timing for DP administration was investigated. The subjects were three brothers with pediatric WD. The initial daily dose of DP was 5 mg/kg/day, and gradually increased to the maintenance dose of 20 mg/kg/day. Until the maintenance daily dose was reached, DP was administered 2 h after the morning and evening meal. After reaching the maintenance daily dose of DP, the appropriate timing for taking DP was investigated in both the morning and evening. Three schedules of DP administration were compared: 2 h after meals; 30 min before meals (with fasting); and 1 h before the morning and 1.5 before the evening meal (direction 1). The resulting urinary copper excretion on each dosing schedule was compared. Little difference was found in urinary copper excretion on the first two schedules, i.e., 2 h after meals and 30 min before meals. When DP was administered 30 min before meals, urinary copper excretion [microgram/day] was 1173 in the first brother, 918 in the second, and 875 in the third. When DP was administered according to direction 1, however, urinary copper excretion was increased significantly to 1701 in the first brother, 2701 in the second, and 3808 in the third. It is known that the efficiency of urinary copper excretion with DP administration depends on the maintenance of chelating ability after absorption from the gastrointestinal tract. Our results indicate that the excretion was lower when DP was administered 2 h after or 30 min before meals (with fasting), as recommended in the package insert. Thus to achieve better copper excretion efficiency, direction 1 is recommended for WD patients.
12076686##2002-6-22##Liquid chromatographic determination of triethylenetetramine in human and rabbit sera based on intramolecular excimer-forming fluorescence derivatization.##A highly selective and simple fluorimetric liquid chromatographic method for the determination of triethylenetetramine (TETA), a therapeutic drug for Wilson's disease, in human and rabbit sera is described. This method is based on intramolecular excimer-forming fluorescence derivatization, which allows spectrofluorometric discrimination of polyamino compounds from monoamino species, followed by liquid chromatography. TETA and 1,6-hexanediamine (internal standard) were converted to the corresponding excimer-forming derivatives with a pyrene reagent, 4-(1-pyrene)butyric acid N-hydroxysuccinimide ester. The derivatives were separated within 20 min on a reversed-phase column using isocratic elution and detected spectofluorometrically at 480 nm with excitation at 345 nm. This method was successfully applied to the monitoring of TETA in human and rabbit sera with a simple pretreatment. The detection limit for TETA in serum was 18 ng/ml (0.13 nmol/ml) corresponding to 0.2 pmol on column at a signal-to-noise ratio of 3.
12128158##2002-7-20##Elevated plasma nociceptin level in patients with Wilson disease.##Plasma level of nociceptin, the endogenous agonist of orphanin FQ/ORL1 receptor was found to be significantly elevated in Wilson disease patients (13.98+/-2.44pg/ml, p<0.001, n=20) compared to age-matched healthy controls (9.18+/-1.63pg/ml, n=25). Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutation of the gene ATP7B leading to toxic copper accumulation in the liver and other organs such as brain, kidney and cornea. Measurements were performed by 125I-radioimmunoassay. Neither sex differences nor correlation between plasma nociceptin levels and liver function test results were found. It is suggested that elevated plasma nociceptin level found in Wilson disease patients is due to inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N (APN) and endopeptidase 24.15) by the toxic copper deposits in liver and/or brain.
12044251##2002-6-5##Diagnosis and treatment of Wilson's disease.##Wilson's disease (WD) is an autosomal recessive disease that causes increased copper deposition in the liver and basal ganglia with resultant hepatic and neurologic sequelae. In the past few years, dramatic new discoveries have changed our understanding of the pathophysiology of WD. Although there are potentially life-saving therapies for WD, there is much controversy surrounding the optimal treatments of patients in the various stages of the disease. Specifically, the relative roles of penicillamine, trientene, and tetrathiomolybdate in the initial treatment of the symptomatic patient with WD remain to be defined. Zinc monotherapy for maintenance treatment and in the treatment of asymptomatic patients with WD is still controversial. It is also unclear whether neurologic status alone is an indication for liver transplantation in WD. This paper reviews the pathogenesis, genetics, clinical presentation, and diagnosis, with a special emphasis on the treatment controversies that arise in the care of the WD patient.
12173707##2002-8-14##Gall stones, G-6PD deficiency and Wilson's disease.##
12080239##2002-6-25##Wilson's disease with neuropsychiatric manifestations and liver disease but no Kayser-Fleischer ring.##
12080225##2002-6-25##A rare case of ulcerative colitis complicating Wilson's disease: possible association between the two diseases.##A case of ulcerative colitis complicated by Wilson's disease is described. In this case, ulcerative colitis occurred 12 years after the diagnosis of Wilson's disease, and the colitis was intractable to prednisolone and salazosulfapyridine. Because copper is one of the trace elements necessary for antioxidant defenses during inflammatory process, altered copper metabolism may have contributed to the intractability of the ulcerative colitis in this case.
12140675##2002-7-26##Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal motor brain regions.##In Wilson's disease a disturbed glucose metabolism especially in striatal and cerebellar areas has been reported. This is correlated with the severity of extrapyramidal motor symptoms (EPS). These findings are only based on a small number of patients. Up to now it is unknown whether EPS are caused by various patterns of disturbed basal ganglia glucose metabolism. We investigated 37 patients and 9 normal volunteers to characterize the disturbed glucose metabolism in Wilson's disease more precisely. The glucose metabolism was determined in 5 cerebellar and cerebral areas (putamen, caput nuclei caudati, cerebellum, midbrain and thalamic area) by using (18)F-Fluorodesoxyglucose-Positron-Emission-Tomography ( [(18)F]FDG-PET). The database was evaluated by a cluster analysis. Additionally, the severity extrapyramidal motor symptoms were judged by a clinical score system. Three characteristic patterns of glucose metabolism in basal ganglia were obtained. Two of them may be assigned to patients with neurological symptoms whereas the third cluster corresponds to most patients without EPS or normal volunteers. The clusters can be identified by characteristic consumption rates in this 5 brain areas. The severity of EPS can not clearly be assigned to one of the clusters with disturbed glucose metabolism. However, the most severe cases are characterized by the lowest consumption in the striatal area. When there is marked improvement of EPS impaired glucose consumption reveals a persistent brain lesion. Finally, the neurological symptoms in Wilson's disease are caused by (at least) two different patterns of disturbed glucose metabolism in basal ganglia and cerebellum. The severity of EPS seems to be determined by a disturbed consumption in the striatal area.
12154159##2002-8-3##Psychiatric features and disturbance of circadian rhythm of temperature, pulse, and blood pressure in Wilson's disease.##Wilson's disease (hepatolenticular degeneration), a disease of genetic origin, is due to abnormal copper metabolism affecting many organs and systems, especially the liver and the nervous system. The initial symptoms can be exclusively or predominantly psychiatric, including psychotic features. Three cases are reported in which the clinical picture at the beginning was compatible with a psychiatric diagnosis. During hospitalization, before treatment, there were abnormal and spontaneous changes in the circadian rhythm of temperature, pulse, and blood pressure, recorded every 6 hours, with febrile peaks in the absence of infectious focus. Because the hypothalamus is important in the regulation of these autonomic functions, the hypothesis of a possible hypothalamic dysfunction was made, justifying a wide clinical and laboratory investigation that allowed the diagnosis of Wilson's disease. Alertness to circadian rhythm abnormalities in such cases may help the psychiatrist avoid an erroneous diagnosis.
12036681##2002-5-31##Kayser-Fleischer ring as the presenting sign of Wilson disease.##
12023893##2002-5-25##Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1).##The human copper transporter 1 gene (hCTR1) was previously identified by functional complementation in ctr1-deficient yeast. Overexpression of hCTR1 in wild-type yeast leads to increased sensitivity to copper toxicity, and mice with a homozygous disruption at the Ctr1 locus die early during embryogenesis. It is proposed that hCTR1 is responsible for high-affinity copper uptake into human cells, but the underlying molecular mechanisms are unknown. To begin to investigate the biochemical characteristics of hCTR1, a polyclonal antiserum was raised against recombinant hCTR1-fusion peptides. Biosynthetic studies using this antiserum revealed that hCTR1 was synthesized as a precursor protein of 28 kDa containing N-linked oligosaccharides, and is then converted to a mature protein of approx. 35 kDa, which is ubiquitously expressed. Immunofluorescence studies showed that subcellular hCTR1 localization differed markedly between cell types. In some cell lines, hCTR1 was located predominantly in an intracellular vesicular perinuclear compartment, and in others hCTR1 was located predominantly at the plasma membrane. In contrast with the copper export P-type ATPases mutated in Wilson disease and Menkes disease, the localization of hCTR1 was not influenced by copper concentrations. Inhibition of endocytosis by methyl-beta-cyclodextrin caused a partial redistribution of hCTR1 to the cell surface of HeLa cells. Taken together, the results in this study suggest a cell-specific control of copper uptake, which involves subcellular localization of the hCTR1 protein.
12269552##2002-9-25##Autonomic cardiovascular reflexes in Wilson's disease.##We studied autonomic cardiovascular function in fourteen patients with Wilson's disease. Four had abnormalities on autonomic testing and, of these, three had evidence of severe central nervous system abnormalities. In contrast, of the remaining ten patients with normal cardiovascular reflexes, only two had severe deficits of the central nervous system. We suggest that autonomic impairment in Wilson's disease is due to involvement of central autonomic neurons.
12269551##2002-9-25##Autonomic dysfunction in Wilson's disease --a clinical and electrophysiological study.##Wilson's disease is known for its protean manifestations; however involvement of the autonomic nervous system has not received much attention. Fifty patients with varying duration and severity of illness were evaluated for autonomic dysfunction clinically and electrophysiologically, using sympathetic skin response (SSR) and RR interval variability (RRIV) on deep breathing. The change in heart rate (AHR) was calculated from RRIV. Five patients had at least one autonomic symptom and one asymptomatic patient had significant postural hypotension. Absent SSR and abnormal AHR were noted in seven patients each. Overall, 13 patients had electrophysiological dysautonomia and an additional six had clinical dysautonomia. All had normal peripheral conductions and all but one had normal hepatic functions. Dysautonomia was more common among patients with neurological presentation (12/32) than non-neurological (1/18) (p = .012). Dysautonomia, often subclinical is common in Wilson's disease and is probably of central origin. It is more frequent among those with neurological presentation. Sympathetic and parasympathetic functions are equally affected.
12269542##2002-9-25##Autonomic dysfunction in Wilson's disease.##
12010149##2002-5-16##Hepatic copper concentration in children undergoing living related liver transplantation due to Wilsonian fulminant hepatic failure.##Liver transplantation is indicated for Wilson's disease (WD) patients having the fulminant form and end-stage liver failure. To evaluate whether living related liver transplantation (LRLT) can correct the copper metabolism in WD patients, we studied two children who underwent LRLT because of fulminant hepatic failure. They were 7 and 13 yrs old at the time LRLT was performed. Serum ceruloplasmin levels, serum copper levels, copper urine excretion, and hepatic copper concentrations were measured. Serum ceruloplasmin levels (16.7 +/- 1.2 mg/dL) and serum copper levels (67.0 +/- 1.4 microg/dL) were lower than the normal range after LRLT in case 1. In both patients, urinary copper excretion was reduced markedly after LRLT, but was not normalized (case 1, 191.2 +/- 182.2 microg/d; case 2, 140.0 +/- 156.7 microg/d). Hepatic copper concentrations were slightly elevated (case 1, 158.8 +/- 44.6 microg/g dry weight; case 2, 147.0 microg/g dry weight) after LRLT in both cases, but did not exceed 250 microg/g dry weight. LRLT is a curative procedure in Wilson's disease presenting fulminant hepatic failure or advanced cirrhosis. However, this study indicates that the conditions of copper metabolism in WD patients undergoing LRLT are similar to those in heterozygous genetic carriers. Because the living related donors are the parents who carry the abnormal gene, LRLT cannot completely restore the copper balance in WD patients.
12133157##2002-7-23##Improving the National Board of Medical Examiners internal Medicine Subject Exam for use in clerkship evaluation.##
12181646##2002-8-16##Wilson disease.##Wilson disease is an autosomal recessive inherited disorder of copper metabolism, characterized by the accumulation of copper in the body due to defective biliary copper excretion from hepatocytes. Recently, novel components involved in copper metabolism, including Menkes disease protein (ATP7A), Wilson disease protein (ATP7B), and copper chaperones, have been identified. It has been demonstrated that ATP7B functions in copper secretion into the plasma, coupled with ceruloplasmin synthesis and biliary copper excretion. However, the precise intracellular localization of ATP7B has been disputed. Various mutations of ATP7B have been reported in patients with Wilson disease, and investigations of genotype-phenotype correlations are now being conducted in the patients. These recent findings provide us with information on the molecular pathogenesis of Wilson disease, as well as the biological mechanisms of copper homeostasis. In this review, recent advances in this field are briefly summarized.
12083810##2002-6-27##Pilot study of mass screening for Wilson's disease in Korea.##Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism with copper accumulation in the liver as well as in the central nervous system. Treatment of WD includes oral chelating agents and diet and it is effective. However, once irreversible damage has occurred, the effect of treatment is diminished and the patient's quality of life is compromised. It is estimated that at least half of the patients with WD remain undiagnosed and die of untreated disease. Early detection of patients presymptomatically has been hampered by the lack of effective methods for mass screening. Recently, a sandwich ELISA method for ceruloplasmin measurement in blood spots was developed. We have used this method to analyze blood specimens collected on filter paper from 3667 children aged 3 months-15 years. The mean value of ceruloplasmin was 30.5+/-9.5 mg/dL. Among these children, we identified one WD case, a 32-month-old boy with markedly reduced ceruloplasmin concentration (2.3 mg/dL). Measurement of CP level in dried blood spot sample is proposed as a reliable method for population screening of WD.
12194694##2002-8-27##[Fulminant hepatic failure].##Fulminant hepatic failure (FHF) is an acute and eventually fatal illness, caused by a severe hepatocyte damage with massive necrosis. Its hallmarks are hepatic encephalopathy and a prolonged prothrombin time (< 40%). FHF is currently defined as hyperacute (encephalopathy appearing within 7 days of the onset of jaundice), acute (encephalopathy appearing between 8 and 28 days) or subacute (encephalopathy appearing between 5 and 12 weeks). FHF can be caused by viruses, drugs, toxins, and miscellaneous conditions such as Wilson's disease, Budd-Chiari syndrome, ischemia and others. However, a single most common etiology is still not defined. Factors that are valuable in assessing the likelihood of spontaneous recovery are age, etiology, degree of encephalopathy, prothrombin time and serum bilirubin. The management is based in the early treatment of infections, hemodynamic abnormalities, cerebral edema, and other associated conditions. Liver transplant has emerged as the most important advance in the therapy of FHF, with a survival rate that ranges between 60 and 80%. The use of hepatic support systems, extracorporeal liver support and auxiliary liver transplantation are innovative therapies.
12020274##2002-5-22##White matter changes in Wilson disease.##
12087666##2002-6-29##[The Kayser-Fleischer ring and its diagnostic importance].##This paper described Kayser-Fleischer ring as an early diagnostic sign of the Wilson's disease. This disease is demonstrated in case of 37-years old white man, a member of affected family. We discuss about typical manifestations of the disease in the eye and especially about Kayser-Fleischer ring with the use of the slit lamp biomicroscopy, spectrophotometry and electron-microscopy.
17033300##2006-10-13##Inherited metabolic disease.##The elucidation of metabolic pathways and the genetic basis for diseases of the liver continues to increase our understanding of disease pathogenesis and advance treatment options. This selective review covers a wide range of subjects, from the identification of novel proteins and the importance of specific transport pathways to phenotypic expression of disease and management of acute liver failure. Three selected disorders--Wilson disease, genetic hemochromatosis and other hereditary iron overload disorders, and alpha(1)-antitrypsin disease--are the focus of this review.
12137229##2002-7-26##Primary and secondary defects of the mitochondrial respiratory chain.##Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
12032531##2002-5-29##Mass screening for Wilson's disease by measuring urinary holoceruloplasmin.##We conducted a mass-screening method to detect presymptomatic Wilson's disease in children by measuring urinary holoceruloplasmin. Two cases of Wilson's disease were found by testing urine samples from 48,819 children. The diagnosis was confirmed by clinical laboratory tests and the detection of a mutated ATP 7B gene.
12032512##2002-5-29##Population screening for Wilson's disease.##
12064213##2002-6-18##[Wilson's disease. Clinical presentation, treatment and evolution in 21 cases].##
11823463##2002-2-2##Zinc binding to the NH2-terminal domain of the Wilson disease copper-transporting ATPase: implications for in vivo metal ion-mediated regulation of ATPase activity.##Mutations in the Wilson disease copper transporting, P-type ATPase lead to the accumulation of toxic levels of copper in the liver, brain, and kidney causing extensive tissue damage and eventual death. The NH(2)-terminal domain ( approximately 70 kDa), which contains six copies of the heavy metal-associated repeat GMT/HCXXC, is also able to bind zinc. We have used circular dichroism (CD) and x-ray absorption spectroscopy (XAS) to characterize zinc binding to the NH(2)-terminal metal-binding domain. These studies have revealed that zinc is able to bind to this domain with a stoichiometry of 6:1, and upon binding, induces conformational changes in the NH(2)-terminal domain. These conformational changes are completely different from those previously observed for copper binding to the domain and lead to an overall loss of secondary structure in the domain. The XAS spectra indicate that zinc is ligated primarily by nitrogen atoms and therefore has low affinity for the heavy metal-associated repeats where copper has been shown to bind. The differences between zinc and copper binding may serve as the basis for the metal-ion mediated regulation of the ATPase in vivo.
12080495##2002-6-25##[Wilson's disease: a clinical case is presented with neuropsychiatric dominant form and probable physiopathology interpretation with magnetic resonance of the brain].##
12133509##2002-7-23##[A clinical report of 12 case-times of living related liver transplantation].##
12039002##2002-6-1##Metal transporters and disease.##Iron and copper are essential nutrients that must be meticulously regulated to exploit their usefulness in biological reactions while protecting against their tendency to promote formation of toxic free-radicals. This review summarizes recently described steps in the transport of these metals, and explores how defects in these steps lead to human diseases including hemochromatosis, Menkes disease and Wilson disease.
12042066##2002-6-4##The molecular basis of copper homeostasis copper-related disorders.##Copper is an essential trace element that can be extremely toxic in excess due to the pro-oxidant activity of copper ions. Inherited disorders of copper transport, Menkes disease (copper deficiency), and Wilson disease (copper toxicosis) are caused by mutations of two closely related Cu transporting-ATPases, and demonstrate the essentiality and potential toxicity of copper. Other copper toxicosis conditions in humans and animals have been described, but are not well understood at a molecular level. Copper homeostatic mechanisms are being discovered. One such mechanism is copper-induced trafficking of the Cu-ATPases, which allows cells to provide copper to secreted cupro-proteins but also to efflux excess copper. Oxidative damage induced by copper may be involved in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, familial amyotrophic lateral sclerosis, and prion diseases.
11985593##2002-5-3##Nuclear proteins that bind to metal response element a (MREa) in the Wilson disease gene promoter are Ku autoantigens and the Ku-80 subunit is necessary for basal transcription of the WD gene.##Wilson disease (WD), an inherited disorder affecting copper metabolism, is characterized by hepatic cirrhosis and neuronal degeneration, which result from toxic levels of copper that accumulate in the liver and brain, respectively. We reported previously that the approximately 1.3-kb promoter of the WD gene contains four metal response elements (MREs). Among the four MREs, MREa plays the most important role in the transcriptional activation of the WD promoter. Electrophoretic mobility shift assays (EMSAs) using synthetic MREa and an oligonucleotide containing the binding site for transcription factor Sp1 revealed the presence of nuclear factors that bind specifically to MREa. Two MREa-binding proteins of 70 and 82 kDa were purified using avidin-biotin affinity chromatography. Amino acid sequences of peptides from each protein were found to be highly homologous to the Ku proteins. Immunoblot analysis and EMSAs showed that the MREa-binding proteins are immunologically related to the Ku proteins. To study further the functional significance of these Ku-related proteins in transcriptional regulation of the WD gene, we performed RNA interference (RNAi) assays using a Ku-80 inverted-repeat gene to inhibit expression of the Ku-80 gene in vivo. Results of the RNAi assays showed that expression of the Ku-80 protein was suppressed in transfected cells, which in turn led to the suppression of the WD gene. In addition, a truncated Ku-80 (DeltaKu-80) mutant inhibited WD promoter activity in HepG2 cells in a dominant-negative manner. We also found that WD promoter activity was decreased in Xrs5 cells, which, unlike the CHO-K1 cells, are defective in the Ku-80 protein. When Ku-80 cDNA was transfected into Xrs5 and CHO cells, WD promoter activity was recovered only in Xrs5 cells. Taken together, our findings suggest that the Ku-80 subunit is required for constitutive expression of the WD gene.
11960241##2002-4-18##Similarities and differences of MR findings between Japanese encephalitis and Wilson's disease.##Although Japanese Encephalitis (JE) and Wilson's disease (WD) are different entities, MR findings in both these conditions are quite similar. The purpose of this retrospective study was to find out the similarities and differences between JE and WD on MR imaging. The study group comprised 25 proven cases of JE and 10 cases of WD. Spin echo (SE) TI- and T2-weighted imaging was performed on a 1.5-T MR system. Fourteen of these 35 cases (10 JE, 4 WD) were also examined using T1-weighted magnetization transfer (MT) SE sequence before and after contrast administration. Although both JE and WD showed similar topographical distribution of lesions, predominant involvement of the basal ganglia and thalami, there were some differences. Brain stem lesion was more frequent for WD than for JE, and posteromedial part of the thalami was spared in WD. The lesion characteristics were also different between both; in WD mixed intensity in the basal ganglia and hyperintense linear rim at the peripheral putamen was observed frequently, whereas hyperintense basal ganglia on T2-weighted images, subacute hemorrhage in the thalami and meningeal enhancement were seen only in the patients with JE. These characteristic lesion criteria may help in differentiation of JE from WD on MR imaging.
11897564##2002-3-19##Activation of hepatic stellate cells--a key issue in liver fibrosis.##Hepatic fibrosis describes the presence of excess collagen due to new fiber formation, laid down as part of the tissue repair response to chronic liver injury. The causes of injury include toxins, disorders of the immune system, viral and parasitic infections, as well as rarer liver diseases such as haemochromatosis, Wilson's disease and galactosaemia. Whatever the cause of injury, the cells and soluble factors contributing to this wound healing response are similar. The principal effector of hepatic fibrogenesis is now widely recognized as the hepatic stellate cell. Stellate cells are usually quiescent cells, but in response to liver injury they undergo an activation process in which they become highly proliferative and synthesize a fibrotic matrix rich in type I collagen. Initiation of stellate cell activation is largely due to paracrine stimulation, whereas perpetuation of activation involves autocrine as well as paracrine loops, and is dependent on a number of functional changes. The principal paracrine and autocrine factors currently thought to be involved in these processes are discussed in this review, as are the roles of the extracellular matrix, the nuclear receptor superfamily, non-peptide ligands, and oxidative stress.
12040983##2002-6-4##[Cerebral MRI and evoked potentials in Wilson disease. Comparison of findings in patients with neurological follow-up].##Wilson's disease is caused by toxic copper accumulation, which leads predominantly to hepatic and basal ganglia damage. Characteristic findings in MRI and electrophysiologic examinations are described according to the occurrence of neurological symptoms. In the present study, 28 patients suffering from Wilson's disease (neurological type) were investigated. The results of MRI are compared with abnormalities of evoked potentials (BAEP, MSEP, T-VEP, MEP). All patients show hypodensities in the basal ganglial area (putamen and GI. pallidus) regularly combined with atrophy of the cerebrum and cerebellum in MRI. Signal abnormalities in the mesencephalic region (46% occurrence) and Nc. dentatus (36% occurrence) are combined with the other findings in variable patterns. Only slight changes are found in the pontine region. BAEP are disturbed in 71% of all cases and MSEP in 46%. Combined abnormalities of BAEP and MSEP were found in 39%. Pathological values occurred with a lower frequency in T-VEP (36%) and MEP (39%). The comparison of MRI findings with electrophysiological data done separately for each patient reveals no strong correlation between both methods. Individual MRI findings do not correspond with the patterns of disturbed evoked potentials and vice versa. Therefore we conclude that these methods, MRI and electrophysiological evaluation, supplement each other. Magnetic resonance imaging and electrophysiological evaluation should be performed simultaneously for therapy monitoring.
12013905##2002-5-17##[Wilson disease].##
12185935##2002-8-21##[Wilson's disease and pregnancy].##
11984483##2002-5-2##[The varied etiologies of childhood-onset dystonia].##Dystonia is not uncommon in childhood, and identification of its etiology is an ultimate aim in the clinical evaluation of dystonia. Advances in neuroimaging, recent identification of gene or loci implicated in dystonic syndromes, and characterisation of new pathological entities (creatine deficiency, biotin-responsive basal ganglia disease) enlarge our understanding of childhood dystonia, and expend its diagnosis spectrum. Awareness of the diverse etiologic categories of childhood-onset dystonia is necessary to accurate diagnosis approach. Clinical examination and cerebral magnetic resonance imaging are the keys of this diagnosis approach. Primary dystonia is defined as syndromes in which dystonia is the sole phenotypic manifestation (especially no cognitive deterioration is observed, and brain MRI is normal); DYT1 dystonia, in which the abnormal gene is located on chromosome 9, is the most frequent childhood-onset primary dystonia; progressive generalisation of the abnormal movements occur in 70p.cent of the patients. Dopa - Responsive Dystonia are characterized by marked diurnal fluctuations of the dystonic symptoms and by their marked and sustained response to dopaminergic therapy; associated parkinsonian signs are usually observed later in the course of the disease. Clinical presentation of DRD might be atypical (mimicking cerebral palsy or isolated limb pain without diurnal fluctuation). DRD is rare, but a trial of L-dopa should be performed on all patients with childhood-onset dystonia, lasting at least one month. Secondary dystonias or heredodegenerative diseases are the most frequent etiology of childhood-onset dystonic syndromes. Among a huge range of heredodegenerative disease, those that are amenable to a specific treatment, such as Wilson's disease or creatine deficiency, should be particularly investigated. The main objective of investigation of dystonia is to identify secondary dystonias or heredodegenerative diseases. Further investigations will be performed according to the clinical characteristics of the dystonia, to the presence of associated neurological or extraneurological symptoms, and according to brain imaging; this approach must be discussed for each single patient. The aim of the diagnosis strategy is the rapid identification of the etiology of dystonia which will lead to accurate treatment and pertinent genetic counselling.
12061187##2002-6-14##[Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) leading to the diagnosis of Wilson's disease].##Authors describe the case of a patient suffering from Thrombotic Thrombocytopenic Purpura--Hemolytic-Uremic syndromee. Any cause of the disease was not found, except signs of liver injury. The etiology of indefinite liver disease that had been diagnosed several years before was examined. Wilson's disease was considered as a final eventuality. The finding of 488 micrograms of copper in the dry liver tissue confirmed the diagnosis of Wilson's disease in the end.
11961729##2002-4-19##Chances and shortcomins of adenovirus-mediated ATP7B gene transfer in Wilson disease: proof of principle demonstrated in a pilot study with LEC rats.##
12584791##2003-2-15##[Study on relationship between Arg778Leu/Gln gene mutation spot in ATP7B and TCM syndrome type in Chinese patients with Wilson disease].##
11874474##2002-3-5##Introducing Wilson disease mutations into the zinc-transporting P-type ATPase of Escherichia coli. The mutation P634L in the 'hinge' motif (GDGXNDXP) perturbs the formation of the E2P state.##ZntA, a bacterial zinc-transporting P-type ATPase, is homologous to two human ATPases mutated in Menkes and Wilson diseases. To explore the roles of the bacterial ATPase residues homologous to those involved in the human diseases, we have introduced several point mutations into ZntA. The mutants P401L, D628A and P634L correspond to the Wilson disease mutations P992L, D1267A and P1273L, respectively. The mutations D628A and P634L are located in the C-terminal part of the phosphorylation domain in the so-called hinge motif conserved in all P-type ATPases. P401L resides near the N-terminal portion of the phosphorylation domain whereas the mutations H475Q and P476L affect the heavy metal ATPase-specific HP motif in the nucleotide binding domain. All mutants show reduced ATPase activity corresponding 0-37% of the wild-type activity. The mutants P401L, H475Q and P476L are poorly phosphorylated by both ATP and P(i). Their dephosphorylation rates are slow. The D628A mutant is inactive and cannot be phosphorylated at all. In contrast, the mutant P634L six residues apart in the same domain shows normal phosphorylation by ATP. However, phosphorylation by P(i) is almost absent. In the absence of added ADP the P634L mutant dephosphorylates much more slowly than the wild-type, whereas in the presence of ADP the dephosphorylation rate is faster than that of the wild-type. We conclude that the mutation P634L affects the conversion between the states E1P and E2P so that the mutant favors the E1 or E1P state.
11914925##2002-3-27##Interactions between Zn and Cu in LEC rats, an animal model of Wilson's disease.##The effect of oral Zn treatment was studied in the liver and kidneys of 26 male Long-Evans Cinnamon (LEC) rats (mutant animals, 5 weeks old) in relation to both the interaction between Zn and Cu and the localisation and concentration of metallothionein (MT). Rats receiving 80 mg zinc acetate daily by gavage and control rats receiving no treatment were killed after 1 or 2 weeks. By immunohistochemical and analytical chemical techniques we revealed that treated rats had higher levels of MT in the hepatic and renal cells compared to untreated ones. Tissue Zn concentrations were significantly higher in treated rats compared to untreated whereas Cu concentrations decreased in the liver and kidneys as indicated by analytical chemical analyses. MT levels also decreased with treatment period. A histochemical procedure, obtained using autofluorescence of Cu-metallothioneins, confirms these findings: after 2 weeks, the signal decreased in both the liver and kidney sections. This gives a greater understanding of the mechanism of Cu metabolism in the two tissues considered. These results suggest that Zn acts both to compete for absorption on the luminal side of the intestinal epithelium and to induce the synthesis of MT.
11896571##2002-3-16##Radiotherapy and antiangiogenic TM in lung cancer.##Tetrathiomolybdate (TM) is a potent nontoxic orally delivered copper complexing agent under development for the last several years for the treatment of Wilson's disease. It has been shown to block angiogenesis in primary and metastatic tumors. Therefore, the combination of cytotoxic radiotherapy (RT) and antiangiogenic TM could target both the existing tumor and the tumor microvasculature in a comprehensive strategy. Using a Lewis lung high metastatic (LLHM) carcinoma mouse tumor model, we demonstrate that the combination of TM and RT is more effective than either used as monotherapy. We also show that their therapeutic effects are additive, with no additional toxicity. We show that TM has no significant cytotoxicity in vitro against LLHM tumor cells, further supporting the antiangiogenic mechanism for its action.
12499822##2002-12-25##[A case of fulminant hepatic failure in Wilson's disease combined with systemic lupus erythematosus].##Patients with systemic lupus erythematosus (SLE) have a chance of developing liver involvement in their lifetime. The main cause of liver involvement in SLE patients is previous treatment with hepatotoxic drugs or hepatotropic viral hepatitis. Wilson's disease is a hereditary disorder and is usually diagnosed in patients presenting either neuropsychiatric disorders or manifestations related to chronic liver disease. Fulminant hepatic failure as the initial manifestation of Wilson's disease is rare. The relationship between systemic lupus erythematosus and Wilson's disease has not been established. We report a case of a 12-year-old girl with SLE who presented fulminant hepatic failure as an initial manifestation of Wilson's disease. The diagnosis was established with decreased serum ceruloplasmin level and the presence of Kayser-Fleischer ring. We treated with repeated plasma exchange. Despite repeated plasma exchange she died of multi-organ failure on the 16th hospital day. Considering this case, Wilson's disease should be considered as a cause of fulminant hepatic failure, especially in juvenile age cases.
11857545##2002-2-22##Common mutations of ATP7B in Wilson disease patients from Hungary.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The H1069Q mutation in exon 14 of ATP7B is far the most frequent in Wilson patients of European origin. Mutations in exon 8 and 15 are also common among the over 150 described mutations in the WD gene. The aim was to investigate the frequency of these common WD gene mutations in Hungarian patients. A total of 42 patients with WD from 39 Hungarian families were examined. The H1069Q mutation was assessed by a seminested polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay, while mutations in exons 8, 13, 15, and 18 of WD gene were identified by sequencing. In addition, haplotype analysis was performed using three common microsatellite markers (D13S314, D13S301, D13S316). The H1069Q mutation was found in 27 patients (64.3%). Nine patients were H1069Q homozygous. Eighteen patients were H1069Q compound heterozygous, two of them had H1069Q/P969Q and one patient H1069Q/3400delC genotype. In two of the 15 H1069Q-negative patients a novel mutation in exon 13 (T977M) was detected. One H1069Q-negative patient had a mutation in exon 8 (G710S). None of the studied mutations was detected in 12 WD patients. H1069Q-positive patients from various European countries had the same haplotype pattern. The H1069Q point mutation is frequent in Hungarian patients with WD and appears to have originated from a single founder in Eastern Europe. In contrast, mutations in exons 8, 13, 15, and 18 are uncommon in Hungarian WD patients.
11890207##2002-3-14##Mechanisms of liver injury relevant to pediatric hepatology.##Hepatocyte injury and necrosis from many causes may result in pediatric liver disease. Influenced by other cell types in the liver, by its unique vascular arrangements, by lobular zonation, and by contributory effects of sepsis, reactive oxygen species and disordered hepatic architecture, the hepatocyte is prone to injury from exogenous toxins, from inborn errors of metabolism, from hepatotrophic viruses, and from immune mechanisms. Experimental studies on cultured hepatocytes or animal models must be interpreted with caution. Having discussed general concepts, this review describes immune mechanisms of liver injury, as seen in autoimmune hepatitis, hepatitis B and C infection, the anticonvulsant hypersensitivity syndrome, and autoimmune polyendocrinopathy. Of the monogenic disorders causing significant liver injury in childhood, alpha-1 antitrypsin deficiency and Niemann-Pick C disease demonstrate the effect of endoplasmic or endosomal retention of macromolecules. Tyrosinemia illustrates how understanding the biochemical defect leads to understanding cell injury, extrahepatic porphyric effects, oncogenesis, pharmacological intervention, and possible stem cell therapy. Pathogenesis of cirrhosis in galactosemia remains incompletely understood. In hereditary fructose intolerance, phosphate sequestration causes ATP depletion. Recent information about mitochondrial disease, NASH, disorders of glycosylation, Wilson's disease, and the progressive familial intrahepatic cholestases is discussed.
11954751##2002-4-17##Presymptomatic diagnosis of Wilson disease associated with a novel mutation of the ATP7B gene.##
11842829##2002-2-15##Image of the month. Nodular fatty infiltration of the liver in Wilson's disease.##
11832458##2002-2-8##Early cell transplantation in LEC rats modeling Wilson's disease eliminates hepatic copper with reversal of liver disease.##
14607616##2003-11-11##Bioartificial liver assist devices in support of patients with liver failure.##Bioartificial liver assist devices (BALs) offer an opportunity for critical care physicians and transplant surgeons to stabilize patients prior to orthotopic liver transplantation. Such devices may also act as a bridge to transplant, providing liver support to patients awaiting transplant, or as support for patients post living-related donor transplant. Four BAL devices that rely on hepatocytes cultured in hollow fiber membrane cartridges (Circe Biomedical HepatAssist(r), Vitagen ELADTM, Gerlach BELS, and Excorp Medical BLSS) are currently in various stages of clinical evaluation. Comparison of the four devices shows that several unique approaches based upon the same overall system architecture are possible. Preliminary results of the Excorp Medical BLSS Phase I safety evaluation at the University of Pittsburgh, after treating four patients (F, 41, acetominophen-induced, two support periods; M, 50, Wilson's disease, one support period; F, 53, acute alcoholic hepatitis, two support periods; F, 24, chemotherapy-induced, one support period, are presented. All patients presented with hypoglycemia and transient hypotension at the start of extracorporeal perfusion. Hypoglycemia was treated by IV dextrose and the transient hypotension responded positively to IV fluid bolus. Heparin anticoagulation was used only in the second patient. No serious or adverse events were noted in the four patients. Moderate Biochemical response to support was noted in all patients. More complete characterization of the safety of the BLSS requires completion of the Phase I safety evaluation.
12000597##2002-5-10##Hepatic transport systems.##The identification of the genes responsible for various genetic liver disorders lead to a better understanding of basic physiology of hepatic transport systems. In this review we focus on transport systems involved in the generation of bile and in the maintenance of copper homeostasis. Abnormal function of these transporters results in diseases like Wilson's disease, progressive familial cholestasis syndromes, Dubin-Johnson syndrome and cystic fibrosis. Beyond these well defined diseases, functional impairments of transport proteins may predispose to non-genetic diseases ranging from intrahepatic cholestasis of pregnancy to neurodegenerative disorders including Alzheimer's disease.
11850492##2002-2-19##99mTc-mebrofenin scintigraphy for evaluating liver disease in a rat model of Wilson's disease.##
11906637##2002-3-22##Diagnosis and treatment of Wilson's disease.##Wilson's disease (WD) has moved on from being a recognized syndrome that was uniformly fatal to a curative disease for which the genetic basis has been discovered. Most pediatric patients present with hepatic manifestations, but some may have neurologic or psychiatric features. Clinical and biochemical screening, including liver biopsy for hepatic copper analysis, remain the standard for diagnosis, but haplotype analysis for siblings is now available and should be considered for family screening when possible. Lifelong medical therapy remains the mainstay of treatment, but treatment preferences are changing from penicillamine to alternative agents such as trientine and zinc. OLT remains lifesaving for those with fulminant WD and those in whom initial medical therapy fails. The future will probably see the application of rapid and accurate molecular diagnostic testing for this disorder and new therapeutic modalities such as hepatocyte transplantation, gene replacement therapy, and gene modification.
11795876##2002-2-6##Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species.##Copper is implicated in metabolic disorders, such as Wilson's disease or Alzheimer's disease. Analysis of signaling pathways regulating cellular survival and function in response to a copper stress is crucial for understanding the pathogenesis of such diseases. Exposure of human skin fibroblasts or HeLa cells to Cu(2+) resulted in a dose- and time-dependent activation of the antiapoptotic kinase Akt/protein kinase B, starting at concentrations as low as 3 microM. Only Cu(II), but not Cu(I), had this effect. Activation of Akt was accompanied by phosphorylation of a downstream target of Akt, glycogen synthase kinase-3. Inhibitors of phosphoinositide-3-kinase (PI3K) completely blocked activation of Akt by Cu(2+), indicating a requirement of PI3K for Cu(2+)-induced activation of Akt. Indeed, cellular PI3K activity was strongly enhanced after exposure to Cu(2+). Copper ions may lead to the formation of reactive oxygen species, such as hydrogen peroxide. Activation of Akt by hydrogen peroxide or growth factors is known to proceed via the activation growth factor receptors. In line with this, pretreatment with inhibitors of growth factor receptor tyrosine kinases blocked activation of Akt by hydrogen peroxide and growth factors, as did a src-family tyrosine kinase inhibitor or the broad-spectrum tyrosine kinase inhibitor genistein. Activation of Akt by Cu(2+), however, remained unimpaired, implying (i) that tyrosine kinase activation is not involved in Cu(2+) activation of Akt and (ii) that activation of the PI3K/Akt pathway by Cu(2+) is initiated independently of that induced by reactive oxygen species. Comparison of the time course of the oxidation of 2',7'-dichlorodihydrofluorescein in copper-treated cells with that of Akt activation led to the conclusion that production of hydroperoxides cannot be an upstream event in copper-induced Akt activation. Rather, both activation of Akt and generation of ROS are proposed to occur in parallel, regulating cell survival after a copper stress.
11809725##2002-1-26##Identification of a new copper metabolism gene by positional cloning in a purebred dog population.##Domesticated animal species such as dogs and cats, with their many different characteristics and breed-specific diseases, and their close relationship and shared environment with humans, are a potentially rich source for the identification of the genetic contribution to human biology and disease. Copper toxicosis in Bedlington terriers is a genetic disease occurring with a high prevalence worldwide and is unique to this breed. Copper homeostasis appears to be well regulated in mammals. Two copper carrier proteins have been identified in man and rodents which, when dysfunctional, cause either copper deficiency (Menkes disease) or copper accumulation in various tissues (Wilson disease). However, these proteins are not primarily involved in the biliary excretion of copper. Bedlington terriers have a high prevalence of copper toxicosis and it is well documented that their biliary excretion of copper is impaired. This disease is of direct relevance for the understanding of copper metabolism in mammals. Previously, we mapped the copper toxicosis gene to dog chromosome region 10q26. Based on DNA samples obtained from privately owned dogs, we were able to confine the localization of the copper toxicosis gene to a region of <500 kb by linkage disequilibrium mapping. While screening genes and expressed sequence tags in this region for mutations we found that exon 2 of the MURR1 gene is deleted in both alleles of all affected Bedlington terriers and in single alleles in obligate carriers. Although the function of the MURR1 gene is still unknown, the discovery of a mutated MURR1 gene in Bedlington terriers with copper toxicosis provides a new lead to disentangling the complexities of copper metabolism in mammals.
11803042##2002-1-23##Reduction of copper and metallothionein in toxic milk mice by tetrathiomolybdate, but not deferiprone.##Copper is both essential for life and toxic. Aberrant regulation of copper at the level of intracellular transport has been associated with inherited diseases, including Wilson's disease (WND) in humans. WND results in accumulation of copper and the copper and zinc-binding protein metallothionein (MT) in liver and other tissues, liver degeneration, and neurological dysfunction. The toxic milk (TX) mutation in mice results in a phenotype that mimics human WND, and TX has been proposed to be a model of the disease. We characterized TX mice as a model of altered metal ion and MT levels during development, and after treatment with the metal ion chelators tetrathiomolybdate (TTM) and deferiprone (L1). We report that hepatic, renal and brain copper and MT are elevated in TX mice at 3 and 12 months of age. Zinc was significantly higher in TX mouse liver, but not brain and kidney, at both time points. Nodules appeared spontaneously in TX mouse livers at 8-12 months that maintained high copper levels, but with more normal morphology and decreased MT levels. Treatment of TX mice with TTM significantly reduced elevated hepatic copper and MT. Transient increases in blood and kidney copper accompanied TTM treatment and indicated that renal excretion was a significant route of removal. Treatment with L1, on the other hand, had no effect on liver or kidney copper and MT, but resulted in increased brain copper and MT levels. These data indicate that TTM, but not L1, may be useful in treating diseases of copper overload including WND.
11803037##2002-1-23##Roles of metallothionein in copper homeostasis: responses to Cu-deficient diets in mice.##Metallothionein (MT) protects the body from both harmful non-essential and excessive essential metals. Copper (Cu) is an essential metal, and its concentration in the body is regulated at a constant level between excess and deficient ones. Cu accumulating in the livers of Wilson disease patients and its animal model, Long-Evans rats with a cinnamon-like coat color (LEC) rats, is in the form of Cu,Zn-MT, MT being an antioxidant. Contrary to the efficient production of MT in response to excessive accumulation of Cu in LEC rats, Cu-binding to MT only occurs marginally under normal conditions. However, the present study revealed that Cu binds to MT more with a severe Cu-deficiency. Namely, male C57BL/6J mice were fed a Cu-deficient diet (0.037 mg Cu/g) and deionized water containing trientine, and then the concentration and distribution of Cu were determined. It was suggested that the cessation of biliary excretion and limitation of the Cu supply to ceruloplasmin are the first responses on feeding of a Cu-deficient diet, followed by an increase in Cu-MT with maintenance of the Cu concentration in the liver. These results suggest that MT causes the recruitment of Cu in a Cu-deficient environment by sequestering Cu from degraded Cu-enzymes and delivering it to Cu chaperones.
11677246##2001-10-26##Functional properties of the copper-transporting ATPase ATP7B (the Wilson's disease protein) expressed in insect cells.##Copper-transporting ATPase ATP7B is essential for normal distribution of copper in human cells. Mutations in the ATP7B gene lead to copper accumulation in a number of tissues and to a severe multisystem disorder, known as Wilson's disease. Primary sequence analysis suggests that the copper-transporting ATPase ATP7B or the Wilson's disease protein (WNDP) belongs to the large family of cation-transporting P-type ATPases, however, the detailed characterization of its enzymatic properties has been lacking. Here, we developed a baculovirus-mediated expression system for WNDP, which permits direct and quantitative analysis of catalytic properties of this protein. Using this system, we provide experimental evidence that WNDP has functional properties characteristic of a P-type ATPase. It forms a phosphorylated intermediate, which is sensitive to hydroxylamine, basic pH, and treatments with ATP or ADP. ATP stimulates phosphorylation with an apparent K(m) of 0.95 +/- 0.25 microm; ADP promotes dephosphorylation with an apparent K(m) of 3.2 +/- 0.7 microm. Replacement of Asp(1027) with Ala in a conserved sequence motif DKTG abolishes phosphorylation in agreement with the proposed role of this residue as an acceptor of phosphate during the catalytic cycle. Catalytic phosphorylation of WNDP is inhibited by the copper chelator bathocuproine; copper reactivates the bathocuproine-treated WNDP in a specific and cooperative fashion confirming that copper is required for formation of the acylphosphate intermediate. These studies establish the key catalytic properties of the ATP7B copper-transporting ATPase and provide a foundation for quantitative analysis of its function in normal and diseased cells.
11816376##2002-1-31##[Genetic aspects of liver diseases].##Genetic factors play a privotal role in the pathogenesis of several liver diseases. A review is devoted to discussing the genetics of autoimmune hepatitis, chronic viral hepatitis B and C, cholestatic and alcoholic liver diseases, UDP-glucuronyl transferase deficiency, alpha, antitripsin deficiency, hereditary haemochromatosis, Wilson's disease and hepatocellular carcinoma.
12812047##2003-6-19##[Peripheral nociceptin levels in Wilson disease].##Plasma level of nociceptin, the endogenous agonists of orphaninFQ/OP4 receptor was found to be significantly elevated in Wilson's disease patients (14.87 +/- 2.44 pg/ml +/- SD, p < 0.001, n = 21) compared to age-matched healthy controls (9.18 +/- 1.63 pg/ml +/- SD, n = 25). Wilson's disease is an autosomal recessive disorder caused by mutation of the gene ATP7B leading to toxic copper accumulation mainly in the liver and brain and in other organs such as, kidney and cornea. Measurements were performed by 125I-radioimmunoassay. Neither sex differences nor correlation between plasma nociceptin levels and liver function test results were found in Wilson's disease patients. It is suggested that significantly elevated plasma nociceptin level is due to the inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N, endopeptidase 24.15) by the toxic copper levels, as it is known that changing the central Zn atom to Cu results in an approximately 50% inhibition in the activity of these enzymes. The high plasma nociceptin level in Wilson's disease patients may induce significant impairment in nociceptinerg neurotransmission.
12418177##2002-11-7##Understanding the mechanism and function of copper P-type ATPases.##
12465434##2002-12-6##Application of recombinant activated factor VII for treatment of impaired haemostasis during liver transplantation in recipients with Wilson's disease--a report of two cases.##Recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Denmark) is a treatment used to prevent and arrest intra- and postoperative bleeding in patients with haemophilia A or B complicated by circulating anticoagulants (inhibitors of FVIII and FIX) and in patients without haemophilia who spontaneously develop inhibitors of FVIII, i.e. in acquired haemophilia. Patients who qualify for liver transplantation due to liver dysfunction may have varying degrees of coagulation impairment and thus carry an elevated risk of massive bleeding and have worse prognosis. The authors administered recombinant activated factor VII to two patients with coagulation abnormalities in the course of Wilson's disease during liver transplantation.
11801516##2002-1-22##Dense Kayser-Fleischer ring in asymptomatic Wilson's disease (hepatolenticular degeneration).##
12037456##2002-5-31##Factor VII deficiency and a copper metabolism disorder in a patient with Klippel-Trenaunay syndrome.##We report on a patient with Klippel-Trenaunay (KT) syndrome, a factor VII deficiency and a copper metabolism disorder. The KT syndrome involved the left leg and, histologically, the liver. Dermatological examination, duplex ultrasonography and a skin and liver biopsy verified the KT syndrome. A long prothrombin time prompted clotting studies revealing a factor VII deficiency while the other factors were in the normal range. Further laboratory examinations showed a copper metabolism disorder similar to Wilson's disease with a low serum ceruloplasmin level, elevated copper concentration in the urine and increased copper deposition in the liver. Neither liver cirrhosis nor a Kayser-Fleischer corneal ring was present. Sequencing analysis of the Wilson's disease gene ATB7B showed no mutations. The occurrence of these three uncommon pathologies in a single patient has not been described to date, which may suggest a mutation in a hypothetical common regulatory gene leading to this unusual phenotype.
12186999##2002-8-21##Genotype correlation with fine motor symptoms in patients with Wilson's disease.##Wilson's disease, an autosomal recessive disorder of copper metabolism, is caused by about 200 different mutations of the ATP7B gene. Using a genotype-phenotype correlation, 36 patients were examined to see whether the disorder of the automatic handwriting movement depends on the genotype. The findings of this study indicated that no such link exists. Neither the profile of the impairment of the fine motor parameters nor the severity and frequency of pathological findings were different among the three genotype groups (homozygous for H1069Q, compound homozygous for H1069Q and other mutations). By contrast, fine motor disorders were found to correlate with the clinical symptoms recorded when therapy began. The pathophysiology of the basal ganglia and the cerebellar loop therefore cannot be directly attributed to the genotype of the mutation in the ATP7B gene.
12572918##2003-2-8##Morphological analysis of active microglia--rod and ramified microglia in human brains affected by some neurological diseases (SSPE, Alzheimer's disease and Wilson's disease).##The activation of microglial cells in pathological conditions is manifested primarily by their proliferation, as well as by the occurrence of a new morphological form--rod microglia. In the present study immunohistochemical identification of rod microglial phenotype against ramified microglia was performed on segments of 17 brains derived from 7 cases of encephalitis of viral aetiology (including 5 SSPE cases), 6 cases of Wilson's disease and 4 cases of Alzheimer's disease. Segments from frontal, temporal and occipital lobes, cerebellum and brainstem were subjected to histological, histochemical and immunohistochemical reactions. The presence of activated rod and ramified microglia was observed in sections derived from all structures of the brains under study. Both morphological forms of activated microglia reacted to antibodies: HLA II, CD68, HAM56 and lectin RCA-1. Expression of HLA II molecules was less intensive on the surface of microglial rod cells. A positive reaction to PCNA antibody was mainly observed in rod/elongated/cylinder-shaped nuclei, which is a characteristic feature of rod microglia. In the study material, the localisation of microglial processes seemed to depend rather on the structural topography of the cell in the brain than on the nuclear shape of the activated microglial cell. Our observations revealed a strong similarity between immunohistochemical phenotypes of both morphological forms of microglia with the indication that rod microglia is a first developmental form of activated microglia.
11772982##2002-1-5##Diagnosis of Wilson's disease: an experience over three decades.##
12512340##2003-1-7##Wilson disease.##
12658758##2003-3-28##Wilson's disease and hepatic transplantation.##To investigate the changes in neurological symptoms and signs, as well as serum copper, serum ceruloplasmin after hepatic transplantation in patients with Wilson's disease, neurological symptoms and signs, serum copper, serum ceruloplasmin before and after hepatic transplantation in 18 patients with Wilson's disease were observed, and those changes were followed up in 20 non-operative controls treated with penicillamine. Our results showed that the neurological symptoms and signs, serum copper and serum ceruloplasmin were improved in the operative group but deteriorated in the non-operative control group. Our study showed that hepatic transplantation is better than penicillamine in the treatment of Wilson's disease.
12376745##2002-10-12##Two families with Wilson disease in which siblings showed different phenotypes.##We investigated two families with Wilson disease in which siblings showed different clinical phenotypes and different ages at onset. In Family 1, the second and fourth male children demonstrated onset of the neurological type of Wilson disease at 16 and 28 years of age, respectively, and the first female child developed the hepatic type at 38 years of age. In Family 2, the second male child showed neurological symptoms at 32 years of age and was diagnosed as having the hepatoneurological type of Wilson disease; then the 35-year-old first female child was found to have the hepatic type by familial screening. We performed mutation analysis of the ATP7B gene for these patients, and found that the mutation was a compound heterozygote in both families. Previous reports of siblings with Wilson disease have shown an identical clinical phenotype and similar ages at onset. In addition, hepatic-type cases generally occur at lower ages compared with the neurological type. In the present investigation, however, younger patients showed neurological symptoms earlier than their older siblings, and clinical phenotypes differed among siblings in both families. These cases appear to be rare. Individual differences in copper accumulation in hepatic cells and intolerance to copper toxicity might be the reason for this phenomenon. Furthermore, there might be a difference in the dominance of the allele expressing ATP7B protein among these cases, resulting in different clinical phenotypes, because all patients of both families were found to be compound heterozygotes.
11753166##2001-12-26##Serum biotinidase activity in children with chronic liver disease and its clinical significance.##
11802810##2002-1-23##Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma.##This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the ATP7B gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma.
11973039##2002-4-26##Proton MR spectroscopy of basal ganglia in Wilson's disease: case report and review of literature.##Volume localized proton Magnetic Resonance Spectroscopy was carried out in both the left and right basal ganglia of three patients with clinically proven Wilson's Disease. While the untreated patient died 15 days after the spectroscopy study, the other 2 patients have been under treatment and have shown clinical improvement. The spectral features of the untreated patient were very different from those of the other two patients who were under treatment and responding. Asymmetrical changes in NAA and Cho were also observed for this patient.
12372948##2002-10-10##Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b.##Copper is essential for activity of many enzymes, but is toxic in excess. Several copper proteins are required for copper homeostasis. ATP7A and ATP7B are genes encoding membrane copper transporters. ATP7A, defective in Menkes disease (MNK), is expressed in many tissues involved primarily in copper uptake from dietary sources. ATP7B, defective in Wilson disease (WND), is essential for copper excretion. Although MNK patients have a copper deficiency in most tissues, copper accumulates in proximal tubules in the kidney. WND patients also have copper accumulation in the proximal tubules. In some WND patients this copper accumulation may result in tubular dysfunction, resulting in the increased excretion of low molecular weight substances (e.g. amino acids and calcium). In mouse, we have demonstrated, by in situ hybridization, the expression pattern in the kidney of mouse orthologues, Atp7a and Atp7b, and have confirmed Atp7b expression by immunohistochemistry. Both Atp7a and Atp7b are expressed in glomeruli; however, Atp7b is also seen in the kidney medulla. This suggests that glomeruli are responsible for regulating copper levels in the filtrate. In WND patients, urinary copper levels are extremely high suggesting Atp7b in the loops of Henle may have a role in copper reabsorption.
11868351##2002-3-1##[Stereotyped movements in Wilson's disease: a case report].##A 45-year-old Japanese man was admitted to our hospital because of persistent appearance of repetitive, purposeless stereotyped movements such as clapping the hands behind his back, scrubbing or rubbing movements of the hands. Laboratory examination showed low plasma copper and ceruloplasmin concentration. He was diagnosed as having Wilson's disease. Brain MRI revealed degeneration of the striatum and pallidum as well as atrophy of brainstem. Single photon emission computer tomographic scan (SPECT) showed hypoperfusion in the bilateral frontal lobe as well as basal ganglia. It is rare to see stereotyped movements in patients with Wilson's disease. Stereotyped movements observed in the present patient was not likely to be a simple stereotypy, since appearance of the motor acts was variable and complex. We consider that his stereotyped movement is a type of clonic perseveration induced by dysfunctioning of frontal cortico-basal ganglia-thalamo-cortical loops.
12470321##2002-12-10##Sleep in patients with treated Wilson's disease. A questionnaire study.##
15553068##2004-11-24##[Two cases of Wilson disease diagnosed as autoimmune hepatitis].##Authors present two cases of Wilson disease in which the final diagnosis was very difficult and needed the differentiation with autoimmune hepatitis. Observation of those two patients leads to the conclusion that paediatricians have to deepen they knowledge of autoimmune hepatitis and Wilson disease which are seen more often in children now-a-days. It will help to quicker the diagnosis and treatment which is most essential for better prognosis in those patients.
11961571##2002-4-19##[Wilson'S disease: dominant neuropsychiatric form. Case presentation and its physiopathologic interpretation based upon magnetic resonance of the encephalon].##This is a presentation of a clinical case of Wilson s disease. The patient is a 26 year old woman who began to evidence psychological symptoms, which were later accompanied by neurological manifestations such as asymmetrical hand tremor, parkinsonism, dystonia and later on, dysphagia and mutism. The ophthalmological examination found a Kayser Fleischer ring in Descemet s membrane. There was disturbance of copper metabolism documented with reduction of serum ceruloplasmin and increase of the urinary excretion of copper. Cirrhosis was demonstrated through laparoscopy and liver biopsy. The brain magnetic resonance showed frontotemporal atrophy and a degenerative process at the basal ganglia, cerebellum and brain stem. This information could suggest probable neuropsychiatric physiopathology. The stenosis and intense cervical dysphagia, associated with the crycopharyngeal membrane, has not been mentioned previously.
11852582##2002-2-21##[Zinc and copper in diseases of the digestive tract] ].##The author mentions the basic metabolic functions of zinc and copper in the human organism. She emphasizes the relationship of serious diseases, congenital and acquired, associated with deficiency or excess of these mineral trace elements. As to inborn diseases, we encounter most frequently Wilson's disease in impaired copper metabolism, rarely morbus Danbolt in congenital impairment of zinc absorption. In practice we are faced in particular with secondary causes of impaired zinc or copper levels, e.g. in chronic diarrhoeal conditions, coeliac disease, chronic pancreatitis and others.
12607416##2003-2-28##[Current principles of Wilson's disease--diagnosis and treatment].##Wilson's disease defined also as hepatolenticular degeneration is an important clinical problem of young adults still causing diagnostic difficulties. In the course of the last decade, genetic background of the disease has been definitely established and elucidated, confirming the variety of genetic mutations, responsible for its origin. The current scheme of the disease treatment has been elaborated and established. It aims to eliminate the excess of toxic copper ions from the organism as fast as possible. In the initial phase of the treatment, traditional and recently introduced chelating agents administration usually results in prompt tissue copper deposits excretion and copper metabolism balance maintenance. In the chronic therapy, zinc compounds, inducing intestinal and hepatic metallothionein synthesis, have been gaining more common application. Life-long, constant, pharmacological Wilson's disease therapy, administered after its early diagnosis, allows for long periods of patients survival, frequently comparable to the normal population.
11745476##2001-12-18##The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.##Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.
11736990##2001-12-12##SLC11A1 (formerly NRAMP1) and disease resistance.##
12164042##2002-8-8##Rare presentation of Wilson disease.##
11881839##2002-3-8##Pattern of neuropsychological deficits in patients with treated Wilson's disease.##The study aimed to describe the neuropsychological profiles in patients with treated Wilson's disease (WD). The series included 19 symptomatic and 2 asymptomatic patients with a mean age of 35.3 +/- 9.2 years. They were tested with the Automated Psychological Test system (APT), a comprehensive computerised neuropsychological test battery. APT comprised eleven separate tests and assessed five essential types of neuropsychological functions: motor functions, basic neuropsychological functions, specific cognitive functions, memory, and executive functions. The results were compared to current norms of the test battery. The symptomatic WD patients had significantly lower performance than the norms on all finger tapping tasks, the simple reaction time, the simultaneous capacity background task, the short-term memory test, the index of word decoding speed, the grammatical reasoning test, and the perceptual maze test. They were significantly higher on the index of impulsive errors, and used a significantly more global processing mode in the test of selective attention. The female symptomatic patients displayed more pronounced neuropsychological deficits than the males in the complex tasks. WD patients displayed a specific profile of moderate neuropsychological impairment. The results are theoretically interesting and have practical implications for the management of WD patients, e.g. some patients confronted with the results have had increased compliance.
11883310##2002-3-9##[Menstrual cycle in women with Wilson disease before and after liver transplantation].##Four cases of young women with Wilson's disease who underwent liver transplantation are presented. The menstrual disturbances associated with Wilson's disease are presented and discussed.
11723201##2001-11-28##A new neurological entity manifesting as involuntary movements and dysarthria with possible abnormal copper metabolism.##A few patients with an affected CNS involving abnormalities in copper metabolism have been described that do not fit any known nosological entities such as Wilson's disease or Menkes' disease. Three sporadic patients (two men and one woman) were examined with involuntary movements and dysarthria associated with abnormal concentrations of serum copper, serum ceruloplasmin, and urinary copper excretion. The onset of neurological symptoms occurred at the age of 15 to 17 years. The common clinical symptoms were involuntary movements and dysarthria. The involuntary movements included dystonia in the neck, myoclonus in the shoulder, athetosis in the neck, and rapid orobuccal movements. The dysarthria consisted of unclear, slow, and stuttering speech. Two of the three patients did not have dementia. A cousin of the female patient had been diagnosed as having Wilson's disease and had died of liver cirrhosis. Laboratory findings showed a mild reduction in serum copper and ceruloplasmin concentrations, whereas urinary copper excretion was significantly reduced in all three patients. Two of the three patients showed a high signal intensity in the basal ganglia on T2 weighted brain MRI. In conclusion, the unique findings of involuntary movements, dysarthria, and abnormal serum copper and urinary copper concentrations suggest that the three patients may constitute a new clinical entity that is distinct from either Wilson's or Menkes disease.
11769332##2002-1-5##The effect of copper on (3H)-tryptophan metabolism in organ cultures of rat pineal glands.##Copper toxicity has been implicated in various neurodegenerative disorders such as Wilson's disease and Alzheimer's disease. Free copper in the brain is toxic and leads to neuronal and cellular damage, through free radical generation. Melatonin has been investigated as a possible copper ion chelator. Melatonin could prevent copper-induced neuronal and cellular damage through binding with copper and preventing copper-induced free radical generation. The effect of copper on pineal indolamine synthesis has not been studied extensively. In the present study, copper (2 mg/kg) and melatonin (12 mg/kg) were administered daily to Wistar rats for a 2-week and 6-week period. Pineal organ culture was utilized to monitor pineal indolamine synthesis. The pineals from the 2-week copper/melatonin-treated group showed a statistically significant decrease in 5-methoxytryptophol synthesis (p < 0.01), compared to the pineals from the copper-treated group. Conversly, in the 6-week experiment, 5-methoxytryptophol synthesis was increased in both the copper- and copper/melatonin-treated groups. There was a statistically significant decrease in the N-acetyl serotonin level in the pineals from the 6-week copper-treated animals, as compared to the control- and copper/melatonin-treated group (p < 0.01). These results imply that copper reduces N-acetyltransferase activity, which results in a decrease in N-acetyl serotonin synthesis. Melatonin when coadministered with copper appears to prevent the N-acetyltransferase inhibition by copper. Copper exerts contradictory effects on 5-methoxytryptophol synthesis. Further investigations need to be carried out to examine the effects of copper on the pineal enzymes.
11855743##2002-2-22##Pyridoxal isonicotinoyl hydrazone (PIH) prevents copper-mediated in vitro free radical formation.##Pyridoxal isonicotinoyl hydrazone (PIH) is an iron chelator with antioxidant activity, low toxicity and is useful in the experimental treatment of iron-overload diseases. Previous studies on x-ray diffraction have revealed that PIH also forms a complex with Cu(II). Since the main drug of choice for the treatment of Wilson's disease, d-penicillamine, causes a series of side effects, there is an urgent need for the development of alternative copper chelating agents for clinical use. These chelators must also have antioxidant activity because oxidative stress is associated with brain and liver copper-overload. In this work we tested the ability of PIH to prevent in vitro free radical formation mediated by Cu(II), ascorbate and dissolved O2. Degradation of 2-deoxyribose mediated by 10 microM Cu(II) and 3 mM ascorbate was fully inhibited by 10 microM PIH (I50 = 6 microM) or 20 microM d-penicillamine (I50 = 10 microM). The antioxidant efficiency of PIH remained unchanged with increasing concentrations (from 1 to 15 mM) of the hydroxyl radical detector molecule, 2-deoxyribose, indicating that PIH does not act as a hydroxyl scavenger. On the other hand, the efficiency of PIH (against copper-mediated 2-deoxyribose degradation and ascorbate oxidation) was inversely proportional to the Cu(II) concentration, suggesting a competition between PIH and ascorbate for complexation with Cu(lI). An almost full inhibitory effect by PIH was observed when the ratio PIH:copper was 1:1. A similar result was obtained with the measurement of copper plus ascorbate-mediated O2 uptake. Moreover, spectral studies of the copper and PIH interaction showed a peak at 455 nm and also indicated the formation of a stable Cu(II) complex with PIH with a 1:1 ratio. These data demonstrated that PIH prevents hydroxyl radical formation and oxidative damage to 2-deoxyribose by forming a complex with Cu(II) that is not reactive with ascorbate (first step of the reactions leading to hydroxyl radical formation from Cu(II), ascorbate and O2) and does not participate in Haber-Weiss reactions.
11808252##2002-1-26##[Wilson disease].##
11854914##2002-2-21##Copper transportion of WD protein in hepatocytes from Wilson disease patients in vitro.##
11701150##2001-11-10##Excitatory and inhibitory mechanisms in Wilson's disease: investigation with magnetic motor cortex stimulation.##We have evaluated cortical excitability in nine patients affected by Wilson's disease (WD) using transcranial magnetic (TMS) and electric (TES) cortical stimulation and central silent period (CSP) data. A clinical score was derived from the sum of scores assigned to extrapyramidal, pyramidal and cerebellar signs. All patients underwent TMS. Motor evoked potentials (MEPs) from abductor pollicis brevis (APB) and tibialis anterior (TA) muscles were recorded. MEP threshold and amplitude, central motor conduction time (CMCT), CSP threshold, CSP and peripheral silent period (PSP) duration were measured. Three patients also underwent transcranial bifocal electric cortical stimulation (TES) and MEPs were recorded from the APB muscle, and CMCT, MEP threshold and amplitude were measured. TMS MEPs were absent from relaxed muscles in six patients and from contracted muscles in three. CMCT was prolonged in six patients. APB CMCT correlated with clinical score. In three patients in whom TMS revealed abnormal or no MEP, TES MEPs were of normal threshold and amplitude. The CSP threshold was increased in seven patients, and CSP was absent in one. These results suggest an intracortical presynaptic motor dysfunction in WD.
11696373##2001-11-7##Tetrathiomolybdate inhibition of the Enterococcus hirae CopB copper ATPase.##Tetrathiomolybdate (TTM) avidly interacts with copper and has recently been employed to reduce excess copper in patients with Wilson disease. We found that TTM inhibits the purified Enterococcus hirae CopB copper ATPase with an IC(50) of 34 nM. Dithiomolybdate and trithiomolybdate, which commonly contaminate TTM, inhibited the copper ATPases with similar potency. Inhibition could be reversed by copper or silver, suggesting inhibition by substrate binding. These findings for the first time allowed an estimate of the high affinity of CopB for copper and silver. TTM is a new tool for the study of copper ATPases.
11527979##2001-8-31##Functional analysis of chimeric proteins of the Wilson Cu(I)-ATPase (ATP7B) and ZntA, a Pb(II)/Zn(II)/Cd(II)-ATPase from Escherichia coli.##ATP7B, the Wilson disease-associated Cu(I)-transporter, and ZntA from Escherichia coli are soft metal P1-type ATPases with mutually exclusive metal ion substrates. P1-type ATPases have a distinctive amino-terminal domain containing the conserved metal-binding motif GXXCXXC. ZntA has one copy of this motif while ATP7B has six copies. The effect of interchanging the amino-terminal domains of ATP7B and ZntA was investigated. Chimeric proteins were constructed in which either the entire amino-terminal domain of ATP7B or only its sixth metal-binding motif replaced the amino-terminal domain of ZntA. Both chimeras conferred resistance to lead, zinc, and cadmium salts but not to copper salts. The purified chimeras displayed activity with lead, cadmium, zinc, and mercury, which are substrates of ZntA. There was no activity with copper or silver, which are substrates of ATP7B. The chimeras were 2-3-fold less active than ZntA. Thus, the amino-terminal domain of P1-type ATPases cannot alter the metal specificity determined by the transmembrane segment. Also, these results suggest that this domain interacts with the rest of the transporter in a metal ion-specific manner; the amino-terminal domain of ATP7B cannot replace that of ZntA in restoring full catalytic activity.
11721763##2001-11-28##Iron accumulation in the liver of male patients with Wilson's disease.##
11721750##2001-11-28##The irony of treating Wilson's disease.##
11708998##2001-11-16##Identification of a high frequency of mutation at exon 8 of the ATP7B gene in a Chinese population with Wilson disease by fluorescent PCR.##
11702107##2001-11-10##Differential alteration of the nigrostriatal dopaminergic system in Wilson's disease investigated with [123I]ss-CIT and high-resolution SPET.##Wilson's disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2ss-carbomethoxy-3ss-(4[123I]iodophenyl)tropane ([123I]ss-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [123I]ss-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [123I]ss-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [123I]ss-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4+/-3.0 vs 11.7+/-2.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [123I]ss-CIT binding ratios from pseudo-sclerosis CD (9.4+/-2.3), through pseudo-parkinsonian CD (9.1+/-2.1) to arrhythmic-hyperkinetic CD (8.5+/-1.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30+/-0.19 vs 1.11+/-0.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [123I]ss-CIT binding ratios (r=-0.49 to -0.57). For degree of liver alteration, significant correlations were obtained with the putaminal binding ratio (r=-0.37) and the CA/PU ratio (r=0.44). From these results is concluded that in WD the nigrostriatal dopaminergic function is compromised to varying extents. The degree of this presynaptic alteration of dopaminergic neurotransmission depends on the clinical course and severity of this copper deposition brain disorder and also varies in the different striatal substructures.
11706834##2001-11-15##Mallory bodies, like the mutant of ATP7B seen in Wilson disease, are aggresomes.##
11868871##2002-3-1##Cholelithiasis in a child--an unusual presentation of Wilson's disease.##A nine year old mentally retarded girl with moderate splenomegaly and ascites presented with chronic cholelithiasis. The presence of Kayser-Fleischer rings and low serum ceruloplasmin level confirmed the diagnosis of Wilson's disease. Cirrhosis of liver and recurrent episodes of hemolysis--these two common complications of Wilson's disease make an ideal setting for gall stone formation. Only three such cases have been reported worldwide and ours is the first case report from India. We suggest that cholelithiasis and splenomegaly in a child without evidence of congenital hemolytic disease should be taken as a suspect of Wilson's disease.
11690702##2001-11-3##High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.##
11605050##2001-10-18##Expression and cisplatin sensitivity of copper-transporting P-type adenosine triphosphatase (ATP7B) in human solid carcinoma cell lines.##One of the most important clinical problems in the treatment of human solid carcinoma is the intrinsic/acquired resistance. Cisplatin is a platinum compound that is one of the most effective agents in clinic. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance by the experiment of transfection of full cDNA of ATP7B into KB3-1 lacking ATP7B. We examined the relationship between mRNA expression level of ATP7B and sensitivity to cisplatin in nine human ovarian carcinoma cell lines to extend these findings. mRNA expression level of ATP7B was significantly correlated with cisplatin-sensitivity in nine cell lines, raising the possibility that ATP7B could be a chemoresistance marker in some types of human solid carcinoma.
11766636##2002-1-5##[Diagnosis of seronegative chronic hepatitis in tissue].##The evaluation of a liver biopsy in chronic hepatitis should make a statement on the etiology and report the degree of activity and stage of the disease. The category of so called seronegative chronic hepatitis may include cases of chronic hepatitis C or infection with other viruses such as the Epstein-Barr virus (EBV) and cytomegalovirus (CMV), cases of marker-negative autoimmune hepatitis as well as drug-induced injury and Wilson's disease in younger patients. In order to establish the diagnosis, sensitive techniques of molecular biology should be applied as well as copper staining by histochemistry. Exact and detailed histopathologic analysis can reveal certain features of autoimmune hepatitis or drug injury.
11995370##2002-5-9##Prevalence of coeliac disease in unexplained chronic hypertransaminasemia.##
11778157##2002-1-5##Hepatosplenomegaly and progressive neurological symptoms - Late manifestation of Niemann-Pick disease type C - a case report -.##Niemann-Pick disease type C is an inborn error of metabolism that affects lipid degradation and storage. Hepatosplenomegaly and progressive neurological symptoms are the main clinical features. We present a case of an adult-onset type of Niemann-Pick disease in a 33-year-old woman who initially presented with dysarthria. At first, laboratory findings suggested Wilson's disease. Laparoscopy showed macroscopic signs of liver cirrhosis and histology did not confirm Wilson's disease. After bone marrow biopsy showed characteristic sea-blue histiocytes, Niemann-Pick disease was suspected and confirmed by filipin stain of cultured fibroblasts. Though rarely encountered, lipid storage disease should be suspected especially in younger patients with organomegaly and progressive signs of neurologic disease.
11602847##2001-10-17##Orthotopic liver transplantation for Wilson's disease: a single-center experience.##
11578617##2001-10-2##Histological changes in monoaminergic neurons of Long-Evans Cinnamon rats.##The Long-Evans Cinnamon rat, an animal model of Wilson's disease, is an inbred mutant strain with spontaneous hepatitis isolated from Long-Evans rats. The copper concentration in the brains of Long-Evans Cinnamon rats at 4 weeks of age was lower than that of controls, but higher than that of controls at 20 weeks of age. We investigated the tyrosine hydroxylase and 5-hydroxytryptamine immunoreactive fiber densities in the brains of Long-Evans Cinnamon rats aged 4, 10, and 20 weeks by immunohistochemistry, comparing them with Long-Evans Agouti rats used as controls. Tyrosine hydroxylase immunoreactive fiber densities in the cingulate cortex, hippocampus and cerebellum in Long-Evans Cinnamon rats were significantly lower than those of Long-Evans Agouti rats at 4 and 10 weeks of age. On the other hand, 5-hydroxytryptamine immunoreactive fiber densities in the cingulate cortex, caudate-putamen, hypothalamus, and hippocampus in Long-Evans Cinnamon rats were significantly higher than those of controls at 4, 10 and 20 weeks of age. In the cingulate cortex and caudate-putamen, 5-hydroxytryptamine immunoreactive fiber densities became gradually higher with age. The number of aberrant 5-hydroxytryptamine immunoreactive fibers in the cingulate cortex, caudate-putamen, hypothalamus and hippocampus in LEC rats was significantly higher than that of controls. The number of another type of aberrant 5-hydroxytryptamine immunoreactive fibers, which were detected only at 20 weeks of age in the caudate-putamen in LEC rats was significantly higher than that of controls. These results suggest that age-dependent changes in copper concentrations of Long-Evans Cinnamon rats were related to changes in monoaminergic neuron systems.
11594967##2001-10-23##Wilson disease.##
11758609##2002-1-5##Rapid detection of the Wilson's disease H1069Q mutation by melting curve analysis with the LightCycler.##Wilson's disease is an inherited autosomal recessive disorder of copper transport characterized by progressive copper accumulation in the liver and the central nervous system. The disease is caused by mutations in the ATP7B gene. Although many different mutations in this gene were described, a substitution of a histidine by a glutamine residue at codon 1069 (H1069Q) accounts for approximately 30-60% of all mutations in Caucasian patients. We describe a DNA-based method using fluorescence resonance energy transfer probes on the LightCycler for rapid determination of the common H1069Q mutation in the ATP7B gene. We screened 53 patients with Wilson's disease for the H1069Q mutation by the melting curve analysis. The reliability and discriminating power of this technique were documented by comparing results of the LightCycler assay with direct DNA sequencing. The protocol allows genotyping of 30 samples in less than 1 hour without a need for restriction enzyme digestion or gel electrophoresis.
11748326##2001-12-19##Acute, progressive akinetic-rigid syndrome induced by neuroleptics in a case of Wilson's disease.##
11668395##2001-10-23##The Jackson toxic milk mouse as a model for copper loading.##
11762068##2002-1-5##[Development of hepatocellular carcinoma during chronic hepatitis].##
12905873##2003-8-9##[Analysis of 128 Wilson's disease].##
11470780##2001-7-27##Copper specifically regulates intracellular phosphorylation of the Wilson's disease protein, a human copper-transporting ATPase.##Copper is a trace element essential for normal cell homeostasis. The major physiological role of copper is to serve as a cofactor to a number of key metabolic enzymes. In humans, genetic defects of copper distribution, such as Wilson's disease, lead to severe pathologies, including neurodegeneration, liver lesions, and behavior abnormalities. Here, we demonstrate that, in addition to its role as a cofactor, copper can regulate important post-translational events such as protein phosphorylation. Specifically, in human cells copper modulates phosphorylation of a key copper transporter, the Wilson's disease protein (WNDP). Copper-induced phosphorylation of WNDP is rapid, specific, and reversible and correlates with the intracellular location of this copper transporter. WNDP is found to have at least two phosphorylation sites, a basal phosphorylation site and a site modified in response to increased copper concentration. Comparative analysis of WNDP, the WNDP pineal isoform, and WNDP C-terminal truncation mutants revealed that the basal phosphorylation site is located in the C-terminal Ser(796)-Tyr(1384) region of WNDP. The copper-induced phosphorylation appears to require the presence of the functional N-terminal domain of this protein. The novel physiological role of copper as a modulator of protein phosphorylation could be central to understanding how copper transport is regulated in mammalian cells.
11806854##2002-1-25##Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach.##The frequency of Wilson's disease in many populations is thought to be about one in 40000 persons, based on case and autopsy studies. Although the Wilson's disease gene has been identified, there is such a large number of mutations already known that it is not currently feasible to determine disease gene frequency by mutation analysis of a population. We have used a novel approach to obtain an estimate of the number of cases of Wilson's disease expected at birth in the US Caucasian population. We used data from four studies to determine that approximately one-third of Wilson's disease mutations in US Caucasian Wilson's disease patients are due to His-->Gln at the 1069 position. We then determined the frequency of this mutation in random DNA samples from 2601 US Caucasian newborns to be 0.285%. Multiplying by three gives an expected Wilson's disease heterozygote frequency of 0.855% and an allele frequency of 0.428%, or 0.00428. These data translate into a Wilson's disease frequency of about one in 55000 births. The 95% confidence interval is rather broad, ranging from about one in 18000 to one in 700000 births, but will be reduced as more data are added.
11575820##2001-9-29##Safety observations in phase I clinical evaluation of the Excorp Medical Bioartificial Liver Support System after the first four patients.##A Phase I clinical safety evaluation of the Excorp Medical, Inc, Bioartificial Liver Support System (BLSS) is in progress. Inclusion criteria are patients with acute liver failure of any etiology, presenting with encephalopathy deteriorating beyond Parson's Grade 2. The BLSS consists of a blood pump, heat exchanger to control blood temperature, oxygenator to control oxygenation and pH, bioreactor, and associated pressure and flow alarm systems. Patient liver support is provided by 70-100 g of porcine liver cells housed in the hollow fiber bioreactor. A single support period evaluation consists of 12 hour extracorporeal perfusion with the BLSS sandwiched between 12 hours of pre (baseline) and 12 hours of post support monitoring. Blood chemistries and hematologies are obtained every 6 hours during monitoring periods and every 4 hours during perfusion. Physiologic parameters are monitored continuously. The patient may receive a second treatment at the discretion of the clinical physician. Preliminary evaluation of safety considerations after enrollment of the first four patients (F, 41, acetaminophen induced, two support periods; M, 50, Wilson's disease, one support period; F, 53, acute alcoholic hepatitis, two support periods; F, 24, chemotherapy induced, one support period) is presented. All patients tolerated the extracorporeal perfusion well. All patients presented with hypoglycemia at the start of perfusion, treatable by IV dextrose. Transient hypotension at the start of perfusion responded to an IV fluid bolus. Only the second patient required heparin anticoagulation. No serious or unexpected adverse events were noted. Moderate biochemical response to support was noted in all patients. Completion of the Phase I safety evaluation is required to fully characterize the safety of the BLSS.
11585717##2001-10-5##Personality traits in treated Wilson's disease determined by means of the Karolinska Scales of Personality (KSP).##
11585025##2001-10-5##Zinc acetate for the treatment of Wilson's disease.##Zinc acetate (Galzin, Gate Pharmaceutical Co.) has been developed for the treatment of Wilson's disease, an inherited disease of copper accumulation and copper toxicity in brain and liver. Zinc acetate has been approved by the US FDA for maintenance therapy of adult and paediatric Wilson's disease patients but also has efficacy in the treatment of pregnant patients and presymptomatic patients from the beginning. It also has value as adjunctive therapy for the initial treatment of symptomatic patients. Zinc's mechanism of action involves induction of intestinal cell metallothionein (Mt), which blocks copper absorption from the intestinal track. A negative copper balance is caused by blockade not only of absorption of food copper but the blockade of reabsorption of the considerable amount of endogenously secreted copper in saliva, gastric juice and intestinal secretions. Zinc is completely effective in controlling copper levels and toxicity in Wilson's disease, as are other anticopper agents. Zinc's major advantage over other anticopper agents is its extremely low level of toxicity. The only side effect is some degree of initial gastric irritation in approximately10% of patients, which usually decreases and becomes insignificant over time. As with all long-term therapies, compliance is a problem in some patients and dictates regular monitoring with 24 h urine copper and zinc measurements. As with all anticopper therapies, over a long period of time, overtreatment and induction of copper deficiency can occur. This is to be avoided particularly in children because copper is required for growth.
11677941##2001-10-27##Copper metabolism after living donor liver transplantation for hepatic failure of Wilson's disease from a gene mutated donor.##There is a genetic problem in living donor liver transplantation, involving Wilson's disease, because the majority of donors have a kinship relationship. Recently, it was reported that the serum ceruloplasmin level is insufficient in some persons with one allele mutation. The recipient was a 13-year-old male child, and the donor was a 22-year-old woman, who was his sister by a different father. The gene analysis for Wilson's disease (ATP7B gene) was preoperatively carried out by the amplification refractory mutation system-PCR. Homozygous and heterozygous deletion of 2871 cytosine (C) were detected in the recipient and donor, respectively, in the ATP7B gene. Serum ceruloplasmin level was sufficient in the donor. The right hepatic lobe graft was transplanted to the recipient. Immediately after the liver transplantation, the copper metabolism improved to increase the serum ceruloplasmin levels up to the normal range, and decrease the urinary copper excretion. However, the serum ceruloplasmin levels gradually decreased below the normal base line, although the urine copper levels continued to be low without any clinical symptoms. We should perform gene analyses and confirm the serum ceruloplasmin levels in donors before living donor liver transplantation for Wilson's disease, to screen for their impairment of copper metabolism. After living donor liver transplantation for Wilson's disease, we should carefully follow-up the transition of serum ceruloplasmin levels in the recipient.
11532044##2001-9-5##Massive haemosiderosis in Wilson's disease.##
11837754##2002-2-12##Wilson's disease in Eastern India.##
11548740##2001-9-11##Using zinc to remove copper from pediatric patients with Wilson's disease.##
11500054##2001-8-14##Escherichia coli CopA N-terminal Cys(X)(2)Cys motifs are not required for copper resistance or transport.##Escherichia coli CopA is a Cu(I)-translocating P-type ATPase that is involved in copper export and resistance. It is an orthologue of the human Menkes and Wilson disease-related proteins. Each of those two human copper pumps has six N-terminal Cys(X)(2)Cys sequences, but their function in transport is unclear. CopA has two N-terminal Cys(X)(2)Cys sequences, GLSC(14)GHC(17) and GMSC(110)ASC(113). The requirement of these cysteine motifs was investigated by mutagenesis of the codons for all four cysteine residues, singly and in combination. Cells of a copA deletion strain expressing genes for the mutant genes were nearly as resistant to copper as the wild type. In addition, everted membrane vesicles from cells expressing the mutant copA genes exhibited ATP-coupled accumulation of copper similar to that of the wild type. The results indicate that neither of two N-terminal Cys(X)(2)Cys motifs is required for either resistance or transport.
16602679##2006-4-11##Irving S. Cooper and the early surgical management of movement disorders. Video history.##Irving S. Cooper was a pioneer in the field of functional neurosurgery. During his very productive and controversial career, he proposed the surgical treatment of Parkinson disease (PD) by ligating the anterior choroidal artery to control tremor and rigidity. Subsequently, he developed seminal techniques for chemopallidectomy and cryothalamectomy for PD. He also attempted to use electrical stimulation of the cerebellum or the thalamus to treat spasticity. Cooper continued his work on brain stimulation until his death in 1985. He made video recordings of nearly all of his patients during his tenure (1977-1985) at New York Medical College. Cooper's clinical video recordings were reviewed, and selected footage was compiled into a video history of Cooper's surgical management of various movement disorders. Included are pre-, post-, and some intraoperative recordings that Cooper made to document his treatment of patients with PD, tremor, Wilson disease, cerebral palsy, chorea, dystonia musculorum deformans, and some rarer entities.
11485753##2001-8-4##Physiological and clinical implications of proANP(1-98) circulating levels in the perioperative phase of liver transplantation.##
11509115##2001-8-18##Role of Atp7b gene in spontaneous and N-diethylnitrosamine-induced carcinogenesis in a new congenic strain, WKAH.C-Atp7b rats.##To examine whether Long-Evans Cinnamon (LEC) rats, a mutant rat model of Wilson's disease, have a susceptibility gene(s) to hepatocarcinogenesis in addition to the causative gene, Atp7b, we established a new congenic strain, WKAH.C-Atp7b rats, in which the Atp7b gene of the LEC rats is inserted into the normal Wistar-King Aptekman Hokkaido (WKAH) background. Hepatocellular tumors developed spontaneously in both sexes of WKAH.C-Atp7b rats, their incidence being slightly lower than that in LEC rats. Incidences of spontaneous liver tumors in LEC, WKAH.C-Atp7b and WKAH rats correlated with hepatic copper and iron concentrations. Medium-term liver bioassay showed that LEC rats were more susceptible to the induction of glutathione S-transferase placental form-positive preneoplastic foci than WKAH.C-Atp7b rats, and WKAH.C-Atp7b rats were more susceptible than WKAH rats. In an N-diethylnitrosamine (DEN)-induced long-term carcinogenicity study, 1) LEC rats were similarly or rather less susceptible to hepatocellular tumors than WKAH.C-Atp7b and WKAH rats, indicating that the progression of the preneoplastic foci to liver cancer in LEC rats was worse than that in WKAH.C-Atp7b and WKAH rats, 2) the incidences of kidney tumors in LEC and WKAH.C-Atp7b rats were higher than that in WKAH rats and high copper concentrations in the kidneys were observed in LEC and WKAH.C-Atp7b rats, 3) LEC rats were resistant to lung carcinogenesis. These data indicate that the susceptibility of LEC rats to liver and kidney carcinogenesis could be explained by Atp7b gene mutation and that the susceptibility to lung carcinogenesis is controlled by gene(s) other than Atp7b.
11471056##2001-7-27##ATP6H, a subunit of vacuolar ATPase involved in metal transport: evaluation in canine copper toxicosis.##Copper toxicosis (CT), resulting in liver disease, occurs commonly in Bedlington terriers. Canine CT is of particular interest because identification of the causative gene may lead to the discovery of another important gene in the copper transport pathway possibly related to human copper diseases not yet identified. Homologs of the copper transporting ATPase ATP7B, defective in Wilson disease, and the copper chaperone ATOX1 were potential candidates, but both have been excluded. The CT locus in Bedlington terriers has been mapped to canine chromosome region CFA10q26, which has a syntenic human chromosome region, HAS2p13-21. The gene ATP6H, for human vacuolar proton-ATPase subunit M9.2, is associated with copper and iron transport in yeast and has been mapped to HAS2p21 and suggested as a candidate gene for CT. We cloned canine ATP6H, which encodes a predicted protein with 99% amino acid sequence identity to the orthologous human protein. Canine ATP6H shows a conserved potential metal binding site, CSVCC, and a glycosylation site, NET. The canine ATP6H is organized into four exons, with a 246-bp open reading frame. Sequence analysis of the coding regions showed no mutations in ATP6H from genomic DNA of an affected dog. We have also identified two, apparently non-transcribed canine ATP6H pseudogenes. Mapping of the true ATP6H gene and a marker closely linked to the CT locus on a canine radiation hybrid panel indicted lack of close physical association. We have therefore excluded canine ATP6H as a candidate gene for canine copper toxicosis, indicating that some other unidentified gene is responsible for this copper storage disease.
11472585##2001-7-27##Plasma and liver carnitine status of children with chronic liver disease and cirrhosis.##
11957950##2002-4-18##Wilson's disease: from the liver to the brain.##
11445646##2001-7-11##A 13-year-old boy with cognitive impairment, retinoblastoma, and Wilson disease.##A developmentally delayed child manifested retinoblastoma at age 4 years and Wilson disease at age 11, a previously unreported association. Cytogenetic and molecular analysis showed an interstitial deletion in the long arm of the paternally derived homologue of chromosome 13 (13q14.2-13q22.2), which encompasses the retinoblastoma and Wilson disease loci. The authors postulate that the co-occurrence of retinoblastoma and Wilson disease was the consequence of an acquired somatic mutation at the retinoblastoma locus and an inherited mutation at the Wilson disease locus of the maternally derived chromosome 13, superimposed on the hemizygosity associated with the paternally derived deletion.
11467673##2001-7-27##Wilson disease in two consecutive generations: an exceptional family.##
11415452##2001-6-21##Structure-function analysis of purified Enterococcus hirae CopB copper ATPase: effect of Menkes/Wilson disease mutation homologues.##The Enterococcus hirae CopB ATPase (EC 3.6.1.3) confers copper resistance to the organism by expelling excess copper. Two related human ATPase genes, ATP7A (EC 3.6.1.36) and ATP7B (EC 3.6.1.36), have been cloned as the loci of mutations causing Menkes and Wilson diseases, diseases of copper metabolism. Many mutations in these genes have been identified in patients. Since it has not yet been possible to purify the human copper ATPases, it has proved difficult to test the impact of mutations on ATPase function. Some mutations occur in highly conserved sequence motifs, suggesting that their effect on function can be tested with a homologous enzyme. Here, we used the E. hirae CopB ATPase to investigate the impact of such mutations on enzyme function in vivo and in vitro. The Menkes disease mutation of Cys-1000-->Arg, changing the conserved Cys-Pro-Cys ('CPC') motif, was mimicked in CopB. The corresponding Cys-396-->Ser CopB ATPase was unable to restore copper resistance in a CopB knock-out mutant in vivo. The purified mutant ATPase still formed an acylphosphate intermediate, but possessed no detectable ATP hydrolytic activity. The most frequent Wilson disease mutation, His-1069-->Gln, was introduced into CopB as His-480-->Gln (H480Q). This mutant CopB also failed to confer copper resistance to a CopB knock-out strain. Purified H480Q CopB formed an acylphosphate intermediate and retained a small, but significant, ATPase activity. Our results reveal that Cys-396 and His-480 of CopB are key residues for ATPase function, and similar roles are suggested for Cys-1000 and His-1069 of Menkes and Wilson ATPases respectively.
11472373##2001-7-27##Haemolytic onset of Wilson disease in a patient with homozygous truncation of ATP7B at Arg1319.##We describe a 19-year-old woman with haemolytic anaemia and thrombocytopenia as the initial manifestation of Wilson disease (WD). There are two reasons for reporting such an improbable case. First, it emphasizes the importance of recognizing atypical clinical presentations of potentially lethal recessive traits for which therapy is available. Second, it shows that, even in a monogenic disorder like WD, the phenotype cannot be extrapolated from the mutated genotype in a simple fashion; this patient had a relatively late-onset form of WD despite homozygosity for a genetic lesion leading to an apparent complete loss of function of the WD copper transporter.
11910532##2002-3-23##A quick microwave histochemical stain for copper.##A rapid microwave method is described for staining copper in liver. This procedure was compared with a conventional method for copper. To this end, liver sections obtained from patients affected by several liver diseases associated with copper overload, were stained both with the standard rubeanic acid method for copper and with our modification of the same method, incorporating microwave treatment. Liver sections from a normal human newborn were used as a positive control. In Wilson's disease in the cirrhotic stage, copper was detected by the conventional method solely in periportal cells; following the microwave treatment, we were able to demonstrate copper in the whole lobule. In alcoholic cirrhosis, rubeanic acid stained copper only in a few periportal cells, while, by our modified method, copper was detected in almost all periportal hepatocytes. In chronic biliary tract disease, and in the newborn liver, copper was demonstrated in a few periportal cells by both the two histochemical procedures. In conclusion, although copper was detected by both procedures, a different degree of positivity was sometimes observed by using microwaves. Moreover, the microwave-treated sections showed more contrast and less artifacts. From a practical point of view, for the simplicity of employment and, above all, for its quickness (10 min), we suggest the use of our method in all conditions where copper overload is suspected.
11444102##2001-7-11##Copper control as an antiangiogenic anticancer therapy: lessons from treating Wilson's disease.##The search for new anticopper drugs for Wilson's disease is culminating in two excellent new drugs: zinc for maintenance therapy and tetrathiomolybdate (TM) for initial therapy. Both are effective and nontoxic. TM is a very potent, fast-acting new anticopper drug and its properties may be useful well beyond Wilson's disease. Angiogenesis (new blood vessel growth) is required for tumor growth, and a sufficient level of copper appears to be required for angiogenesis. We hypothesize that there is a "window" to which the copper level can be reduced that inhibits angiogenesis in tumors, but does not interfere with vital cellular functions of copper. Using TM therapy, this approach has worked to slow or stabilize tumor growth in several animal tumor models, and preliminary results are also very encouraging in human patients with a variety of advanced and metastatic malignancies. A hypothesis is advanced that copper availability has played a fundamental role in growth regulation throughout evolution and that is the reason that so many angiogenic promoters appear to be dependent upon copper levels.
12024917##2002-5-25##Immunochemical studies in Wilson's disease.##The present study deals with a total of 28 cases of Wilson's disease, 50 normal individuals alongwith siblings and parents of eight cases. Male predominance (18 out of 28 cases), a median age of 11 years and universal presence of Kayser-Fleischer (K. F.) ring marked the cardinal features. Furthermore, 11 patients had hepatic-neural presentation while two had only the K. F. Ring without clinical abnormality. Single Radial Immunodiffusion (SRID) as the absolute quantitative procedure revealed a profound deficiency of ceruloplasmin with the levels ranging anywhere between 0.5 mg/dI to 23 mg/dI amongst the patients of Wilson's disease. The data from siblings and parents also revealed deficiency in 15 out of 23 serum samples when subjected to disc electrophoresis-benzidine screening procedure.
11481698##2001-8-2##Dystonia in Wilson's disease.##The frequency and type of dystonic movements, as well as brain abnormalities, as depicted with magnetic resonance imaging (MRI), which might correlate with dystonia, were studied in 27 consecutive patients with a neurologic form of Wilson's disease (WD) and optimized treatment. Dystonia was found in 10 patients (37%), being generalized in half of them, while two patients had segmental, two patients multifocal dystonia, and one patient bilateral foot dystonia. Dystonia was a presenting sign in four patients and developed later in the course of the disease in six patients, despite the administered therapy for WD. Putamen was the only structure significantly more frequently lesioned in dystonic (80%) in comparison to WD patients without dystonia (24%), suggesting a relation between abnormalities in this brain region and dystonic movements in WD.
11494578##2001-8-10##[Mesial temporal lobe epilepsy in a patient with Wilson's disease receiving FK506 (tacrolimus) after liver transplantation].##Mesial temporal lobe epilepsy (MTLE) developed in a boy receiving FK506 (tacrolimus) after liver transplantation. He had no history of convulsions. At the age of 7, he underwent liver transplantation 13 days after he developed the abdominal form (fulminant hepatitis) of Wilson's disease. On postoperative day 18, he had a generalized tonic seizure (duration 20 min.) with loss of consciousness. FK506 was discontinued under the suspicion of FK506-induced encephalopathy. His symptoms resolved within a few days. FK506 was readministered at 3 months after transplantation. Ten months later, he developed complex partial seizures characterized by right tonic posturing with oral automatism. EEG revealed sporadic spikes in the anterior temporal region. MRI and SPECT showed bilateral (left side dominant) hippocampal lesion, which suggested the diagnosis of MTLE. Since seizures became refractory to medical treatment with progressive worsening of memory functions, FK506 was discontinued again at 36 months after readministration. Six months later, his memory improved remarkably, but there were no changes in seizure frequency and in MRI and SPECT findings. Our findings indicate that FK506 might damage the hippocampus, thereby causing MTLE. Additional case reports, however, will be required to elucidate this new FK506-related neurological complication.
11591995##2001-10-10##Bladder injury during diagnostic laparoscopy. A case report.##We report the case of a bladder injury that was incurred during diagnostic laparoscopy in a 19-year-old man with hepatomegaly, neuropsychiatric disturbances, and urinary retention whose final diagnosis was Wilson's disease. In order to define the nature of his hepatomegaly, the patient underwent laparoscopy. However, the lack of recognition of urinary retention by the operator and the absence of cooperation by the patient caused bladder injury during the insertion of the Veress needle, resulting in the leakage of a yellow fluid consistent with urine. Since the injury was small, it was managed with antibiotics and bladder drainage, alone and deemed not to require surgical repair. We also discuss potential risk factors and describe some approaches that can help to avoid this laparoscopic complication.
11391005##2001-6-8##Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development.##The trace metal copper (Cu) plays an essential role in biology as a cofactor for many enzymes that include Cu, Zn superoxide dismutase, cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine beta-hydroxylase. Consequently, Cu transport at the cell surface and the delivery of Cu to intracellular compartments are critical events for a wide variety of biological processes. The components that orchestrate intracellular Cu trafficking and their roles in Cu homeostasis have been elucidated by the studies of model microorganisms and by the characterizations of molecular basis of Cu-related genetic diseases, including Menkes disease and Wilson disease. However, little is known about the mechanisms for Cu uptake at the plasma membrane and the consequences of defects in this process in mammals. Here, we show that the mouse Ctr1 gene encodes a component of the Cu transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation. These results demonstrate a crucial role for Cu acquisition through the Ctr1 transporter for mammalian Cu homeostasis and embryonic development.
11405812##2001-6-19##Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease.##
11508632##2001-8-18##Low-dose zinc administration as an effective Wilson's disease treatment.##A case of a 11-yr-long Wilson's disease treatment in a 16-yr-old boy with neurologic presentation was analyzed and monitored. In the face of severe symptoms of chelator intolerance, a comparatively low dose of 100 mg of zinc has been administered for the entire 11-yr-long treatment. Considerable improvement of clinical status was achieved, with accompanying regression of central nervous system lesion. The parameters of copper metabolism were normalized with effective urine elimination. The low-dose oral zinc intake proved to be therapeutically effective, eliminating further copper tissue toxicity.
11384817##2001-6-1##Wilson's disease in pregnancy: five successful consecutive pregnancies of the same woman.##Wilson's disease is an autosomal recessive disorder of copper metabolism characterized mainly by liver cirrhosis and neurological disorders. Appropriate treatment with chelating agents allows normal fertility function. We report five consecutive successful pregnancies of the same woman, treated in the high-risk unit at our medical center. The management dilemmas and treatment options are discussed.
11358907##2001-5-19##Wilson's disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine.##
11422628##2001-6-26##Wilson's disease presenting with rapidly progressive visual loss: another neurologic manifestation of Wilson's disease?##Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism resulting in copper-induced tissue damage that primarily involves the liver and central nervous system. The neurologic manifestations of WD almost universally involve a derangement of basal ganglia function or psychiatric disturbance. We report the case of a 46-year-old man presenting with end-stage liver disease caused by WD who had associated rapidly progressive optic neuropathy. We also discuss the possible association between the two conditions.
11422621##2001-6-26##Autoimmune liver disease in children.##
11431635##2001-6-30##[Bifocal avulsion of the patellar tendon in an adult: a case report].##
11402441##2001-6-13##[A study of Wilson's disease gene encoded products and gene mutations].##
11470318##2001-7-27##The response of neurones and glial cells to elevated copper.##Defective copper excretion in Wilson's disease can result in increased neurological copper concentrations. This is thought to occur following exposure to increased circulating copper released from necrotic hepatocytes in a saturated liver. BU17 human glioma cells and SH-SY5Y human neuroblastoma cells were exposed to media supplemented with copper in the range 0-250 microM for periods up to 48 h to investigate this hypothesis. Copper uptake, cell growth, intracellular radical generation, and oxidative stress were measured in copper exposed cells. No increase in copper uptake or inhibition of cell growth could be measured in either cell type at any time point or copper concentration investigated. However, significant increases in radical generation (p < 0.001) could be measured in both BU17 and SH-SY5Y cells. A decreased ability to cope when the cells were exposed to additional pro-oxidants suggested that the cells were under oxidative stress with significant reductions in cell viability following exposure to both copper and ascorbic acid. These data suggest that copper sequestration does not occur in neuronal cells exposed to elevated extracellular copper concentrations.
11470313##2001-7-27##Copper in disorders with neurological symptoms: Alzheimer's, Menkes, and Wilson diseases.##Copper is an essential element for the activity of a number of physiologically important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-superoxide-dismutase which plays a key role in the cellular response to oxidative stress by scavenging reactive oxygen species. Furthermore, copper is a constituent of dopamine-beta-hydroxylase, a critical enzyme in the catecholamine biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptoms will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper binding proteins play important roles in the establishment and maintenance of metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzheimer's disease). The Menkes and Wilson proteins have been characterized as copper transporters and the amyloid precursor protein (APP) of Alzheimer's disease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Experimental, clinical and epidemiological observations in neurodegenerative disorders like Alzheimer's disease and in the genetically inherited copper-dependent disorders Menkes and Wilson disease are summarized. This could provide a rationale for a link between severely dysregulated metal-ion homeostasis and the selective neuronal pathology.
17031168##2006-10-13##Autoimmune liver disease.##Autoimmune hepatitis in children may be associated with sclerosing cholangitis in the absence of inflammatory bowel disease. Wilson disease can have clinical and laboratory features that resemble autoimmune hepatitis, and it may respond initially to corticosteroids. Soluble HLA-DR antigens reflect clinical activity, and they may be useful markers of treatment response. Polymorphisms of the cytotoxic T lymphocyte antigen-4 gene may synergize with other autoimmune promoters or HLA risk factors to increase susceptibility and alter disease expression. DRB1*1301 distinguishes Argentine children from Argentine adults and identifies a unique subgroup. Antibodies to soluble liver antigen/liver-pancreas do not characterize a separate clinical entity. Their target antigen has been isolated, and it shares homologies with a selenocysteine-specific protecting factor (tRNP((Ser)Sec)). CYP2D6 is expressed on the hepatocyte surface, and it can be targeted by antibodies in autoimmune hepatitis and chronic hepatitis C. Perinuclear antineutrophil cytoplasmic antibodies lack sensitivity and specificity for autoimmune hepatitis, and they have diverse antigen specificities. Activation-induced cell death may be impaired in autoimmune hepatitis, and, in contrast to budesonide, mycophenolate mofetil has been effective in a small study of problematic patients.
17031163##2006-10-13##Metabolic liver disease.##The discovery of novel metabolic pathways and the genetic basis for diseases of the liver continues to yield new insights into the pathogenesis of inherited metabolic diseases of the liver, whereas the application of new technologies to their treatment continues to advance therapeutic options. This review of selected articles covers a wide range of subjects, from the identification of novel proteins and transport pathways to disease diagnosis and treatment of acute liver failure. Four selected topics, Wilson disease, hemochromatosis and iron overload disorders, alpha-1 antitrypsin disease, and exciting new therapeutic options for lysosomal storage diseases are the focus of this review.
11432725##2001-7-4##Functional analysis of the sheep Wilson disease protein (sATP7B) in CHO cells.##In this study we investigated the function of the sheep orthologue of ATP7B (sATP7B), the protein affected in the human copper toxicosis disorder Wilson disease. Two forms of sATP7B are found in the sheep, a 'normal' form and one with an alternate N terminus, both of which were expressed in CHO-K1 cells. Cells expressing either form of sATP7B were more resistant to copper than the parental CHO-K1 cells. Subcellular localisation studies showed that both forms of sATP7B were similarly located in the trans-Golgi network (TGN). When the extracellular copper concentration was increased, each form of sATP7B redistributed to a punctate, vesicular compartment that extended throughout the cytoplasm. Both forms of sATP7B recycled to the perinuclear location within one hour when the cells were subsequently incubated in basal medium. After treatment of cells with bafilomycin A1 sATP7B accumulated in cytoplasmic vesicles, implying that ATP7B continuously recycles via the endocytic pathway. These results suggest that both forms of sATP7B are functional copper-transport proteins and that the intracellular location and trafficking of the sheep protein within the cell also appears normal.
11340094##2001-5-8##Tumor suppressor protein p53 mRNA and subcellular localization are altered by changes in cellular copper in human Hep G2 cells.##Copper toxicity causes hepatic damage that can lead to the development of hepatocarcinoma. Similarly, copper deficiency has been reported to increase hepatocyte tumorigenesis. Thus, the objective of this work was to explore the role of copper toxicity and deficiency in the regulation of the tumor suppressor protein p53. Using Northern analysis, Western analysis, immunocytochemistry and the human hepatoma cell line Hep G2, this work showed that elevations in hepatocyte copper consistent with Wilson's disease (5.7-fold increase) induced p53 mRNA and confirmed that copper toxicity is correlated with apoptotic cell death. However, Western analysis and immunocytochemistry showed that post-transcriptional mechanisms are a significant part of the process, with p53 translocation from the cytosol into the nucleus of copper-treated cells. Treatment of Hep G2 cells with increasing concentrations of the copper chelator tetraethylenepentamine (TEPA, 0-50 micromol/L, 48 h) reduced cellular copper and increased mean p53 mRNA abundance by over fourfold with nuclear translocation of the wild-type protein. However, TEPA treatment did not result in a loss of cell viability or appear to induce apoptosis.
11388783##2001-6-5##Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease?##Zinc has several crucial functions in brain development and maintenance: it binds to p53, preventing it from binding to supercoiled DNA and ensuring that p53 cause the expression of several paramount genes, such as the one that encodes for the type I receptors to pituitary adenine cylase-activator peptide (PACAP), which directs embryonic development of the brain cortex, adrenal glands, etc.; it is required for the production of CuZnSOD and Zn-thionein, which are essential to prevent oxidative damage; it is required for many proteins, some of them with Zn fingers, many of them essential enzymes for growth and homeostasis. For example, the synthesis of serotonin involves Zn enzymes and since serotonin is necessary for melatonin synthesis, a Zn deficiency may result in low levels of both hormones. Unfortunately, Zn levels tend to be low when there is excess Cu and Cd. Moreover, high estrogen levels tend to cause increased absorption of Cu and Cd, and smoking and eating food contaminated with Cd result in high levels of the latter. Furthermore, ethanol ingestion increases the elimination of Zn and Mg (which acts as a cofactor for CuZnSOD). Increased Cu levels may also be found in people with Wilson's disease, which is a rather rare disease. However, the heterozygote form (only one faulty copy of the chromosome) is not so rare. Therefore, the developing fetus of a pregnant women who is low in Zn and high in Cu may experience major difficulties in the early development of the brain, which may later manifest themselves as schizophrenia, autism or epilepsy. Similarly, a person who gradually accumulates Cu, will tend to experience a gradual depletion of Zn, with a corresponding increase in oxidative damage, eventually leading to Parkinson's disease. Also discussed are the crucial roles of histidine, histamine, vitamin D, essential fatty acids, vitamin E, peroxynitrate, etc. in the possible oxidative damage involved in these mental diseases.
12211753##2002-9-6##Acute liver failure due to Wilson's disease.##
12211729##2002-9-6##Acute haemolytic syndrome and liver failure as the first manifestations of Wilson's disease.##Acute liver failure and haemolytic syndrome appeared quite suddenly as the first manifestations of Wilson disease (WD) in five of our patients previously regarded as healthy persons (although an interview showed that 2-4 weeks prior to the illness the patients complained of several non-specific symptoms, such as abdominal pain, headaches, fever, weakness or behavioural changes). All the patients were young women (17-23 years), none of them had any history of liver disease. They were admitted with icterus, nausea, vomiting and symptoms of increasing haemolysis. The diagnosis of WD was given as disturbed copper metabolism. After a short period of observation ascites and anasarca occurred, haemorrhagic diathesis and other symptoms of liver failure increased. Levels of clotting factors decreased rapidly. Despite treatment with D-penicillamine, plasmapheresis, and symptomatic drugs, three of the women died in irreversible liver coma, due to the unavailability of liver transplantation. The fourth woman was carried to the Transplantation Centre, due to aggravation of the symptoms of liver failure, where liver transplantation was performed. Histopathologically micronodular cirrhosis was shown in all these cases. The fifth patient survived having undergone the above treatment without liver transplantation. The main differences between the patient who survived and those who died or underwent transplantation were relatively higher activity of alkaline phosphatase (26 U/l vs. 10-20 U/l), slightly higher levels of clotting factors and prothrombin time, which never fall below 68% of the control (versus 14-44% in other patients). Only in the surviving patient was the Kayser-Fleischer ring present. In four of our patients we found family members who were carriers of WD.
11391761##2001-6-8##Penicillamine-induced lethal status dystonicus in a patient with Wilson's disease.##A 37-year-old man with Wilson's disease is described, in whom the introduction of penicillamine therapy was followed after 3.5 weeks by the development of the status dystonicus with a fatal outcome.
11424353##2001-6-27##[Menkes' disease and brain dysfunction].##
11548410##2001-9-11##[The role of the yolk sac in copper metabolism during rat embryogenesis].##Using the immunoblotting method, the synthesis of two copper-transporting P1-type ATPases, ATP7A (a candidate for the product of the Menkes disease gene) and ATP7B (presumed product of the Wilson disease gene), in the yolk sac cells of rat embryos at days 11 and 20 of embryogenesis was demonstrated. Concomitantly, yolk sac cells produce ceruloplasmin, a soluble copper-transporting glycoprotein, a proportion of which in secreted proteins progressively diminishes, attaining 5.2% at day 11 and 3.1% at day 20 of development. At different stages of embryogenesis, yolk sac cells synthesize two molecular forms of [14]C-ceruloplasmin, one of which is secreted towards the embryo, whereas the other, towards the decidual membrane. Two forms of ceruloplasmin secreted in polar directions differ in the rate of secretion. The role of the yolk sac as a key organ controlling the delivery and secretion of copper in the embryo during the postimplantation period is discussed.
11436572##2001-7-5##Imaging of diffuse liver disease.##Advances in imaging technology and development of liver-specific contrast agents have significantly increased the role of radiology in the detection and characterization of processes diffusely involving the liver. Tailored magnetic resonance imaging (MRI) sequences allow an accurate detection of many storage and metabolic diseases, such as iron overload disorders and steatosis (fatty liver). Faster scanning techniques available with both computed tomography (CT) and MRI provide, by assessing contrast dynamics, sufficient information for the characterization of diffuse neoplastic and vascular disorders. Characteristic changes in attenuation on CT, signal intensity on MRI, and enhancing features can be used to diagnose specific diffuse diseases such as candidiasis, diffuse/multifocal hepatocellular carcinoma, and schistosomiasis. Although an overlap in imaging findings still exists, familiarity with the imaging features of uncommon disorders such as Wilson's disease, amyloidosis, and sarcoidosis may be diagnostic in the proper clinical setting. This review focuses on the current role of imaging in the detection and characterization of diffuse liver disorders. Recent developments that have amplified the role of noninvasive diagnostic evaluation of these conditions are especially highlighted.
11360740##2001-5-22##[Psychiatric disorders treated with clozapine in a patient with Wilson's disease].##
11579422##2001-10-2##Mitochondria and degenerative disorders.##In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.
11315910##2001-4-24##Images in focus laparoscopic findings in Wilson's disease without cirrhosis.##
11338076##2001-5-8##Genotype-phenotype interactions in Wilson's disease: insight from an Icelandic mutation.##Wilson's disease, an autosomal recessive disorder of copper transport, usually presents with symptoms from the liver or central nervous system. Rarely, the initial manifestation is fulminant hepatic failure. The abnormal gene (ATP7B) is located on chromosome 13q and encodes a copper-transporting ATPase. A large number of mutations have been reported. We describe a previously healthy 16-year-old girl who presented with fulminant hepatic failure. The girl died within 24 h of admission to a hospital from refractory shock. Autopsy revealed cirrhosis and widespread necrosis of the liver. The copper content of the liver was markedly increased (975 micrograms/g dry weight), strongly suggesting a diagnosis of Wilson's disease. Genetic studies revealed that the girl was homozygous for the mutation 2007 del7, which is the mutation found in all Wilson's disease patients previously identified in Iceland. This is the first known case of fulminant hepatic failure due to Wilson's disease in Iceland. Despite the same mutation, the clinical picture is vastly different from other Icelandic patients with Wilson's disease, who all presented with relatively late-onset neurological disease. This suggests that factors other than the specific mutation have significant impact on the phenotype of the disease.
11254776##2001-3-20##Wilson's disease presenting in a family with an apparent dominant history of tremor.##A patient with Wilson's disease is described who presented with dystonic tremor in a family with an apparent dominant history of tremor. Subsequent investigation showed that the patient's mother had essential tremor, with molecular analysis of the ATP7B gene excluding the possibility of pseudodominant inheritance. This case highlights the importance of considering the possibility of Wilson's disease in every young patient with a movement disorder, even where the clinical picture does not suggest a recessively inherited disorder.
11350685##2001-5-15##[A study of gene products encoded by Wilson disease gene].##
11237756##2001-3-10##Functional studies on the Wilson copper P-type ATPase and toxic milk mouse mutant.##The Wilson protein (WND; ATP7B) is an essential component of copper homeostasis. Mutations in the ATP7B gene result in Wilson disease, which is characterised by hepatotoxicity and neurological disturbances. In this paper, we provide the first direct biochemical evidence that the WND protein functions as a copper-translocating P-type ATPase in mammalian cells. Importantly, we have shown that the mutation of the conserved Met1386 to Val, in the Atp7B for the mouse model of Wilson disease, toxic milk (tx), caused a loss of Cu-translocating activity. These investigations provide strong evidence that the toxic milk mouse is a valid model for Wilson disease and demonstrate a link between the loss of catalytic function of WND and the Wilson disease phenotype.
11182525##2001-2-22##In vivo evidence for accelerated generation of hydroxyl radicals in liver of Long-Evans Cinnamon (LEC) rats with acute hepatitis.##The Long-Evans Cinnamon (LEC) rats accumulate excess copper (Cu) in the liver in a manner similar to patients with Wilson's disease (WD) and spontaneously develop acute hepatitis with severe jaundice. Although hydroxyl radicals (*OH) have been proposed to be a cause of hepatitis by the accumulation of Cu, it is not clear whether or not *OH can be produced in the liver of hepatitic LEC rats in vivo and also can be involved in the onset of hepatitis. In the present study, *OH production in plasma and liver of hepatitic LEC rats was quantified by trapping *OH with salicylic acid (SA) as 2, 3-dihydroxybenzoic acid (2, 3-DHBA). The ratios of 2, 3-DHBA/SA were significantly higher in plasma and liver of hepatitic LEC rats than those of Wistar rats and LEC rats showing no signs of hepatitis. Furthermore, the ratios of 2, 3-DHBA/SA in plasma and liver of hepatitic LEC rats were almost the same as those of Wistar rats treated orally with CuSO(4) (0.5 mmol/kg) 2 h before acetylsalicylic acid (ASA) injection. We also evaluated the protective effects of D-mannitol (a *OH scavenger) treatment against acute hepatitis in LEC rats. D-mannitol (500 mg/kg) was administered intraperitoneally to 10-week-old LEC rats for 3 weeks. D-mannitol treatment suppressed the increases in serum aspartate aminotransferase activity and total bilirubin concentration. In addition, D-mannitol treatment significantly reduced hepatic mitochondrial lipid peroxidation, which is thought to be important in the pathogenesis of Cu-induced hepatotoxicity. These observations suggest that accelerated generation of *OH catalyzed by free Cu in the liver may, at least in part, play a role in the pathogenesis of acute hepatitis in LEC rats.
11231950##2001-3-7##A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates.##
11293185##2001-4-11##Wilson disease.##
11241029##2001-3-10##Treatment of Wilson's disease with zinc XVI: treatment during the pediatric years.##The objectives were to evaluate appropriate doses of zinc acetate and its efficacy for the maintenance management of Wilson's disease in pediatric cases. Pediatric patients of 1 to 5 years of age were given 25 mg of zinc twice daily; patients of 6 to 15 years of age, if under 125 pounds body weight, were given 25 mg of zinc three times daily; and patients 16 years of age or older were given 50 mg of zinc three times daily. Patients were followed for efficacy (or over-treatment) until their 19th birthday by measuring levels of urine and plasma copper, urine and plasma zinc and through liver function tests and quantitative speech and neurologic scores. Patients were followed for toxicity by measures of blood counts, blood biochemistries, urinalysis, and clinical follow-up. Thirty-four patients, ranging in ages from 3.2 to 17.7 years of age, were included in the study. All doses met efficacy objectives of copper control, zinc levels, neurologic improvement, and maintenance of liver function except for episodes of poor compliance. No instance of over-treatment was encountered. Four patients exhibited mild and transient gastric disturbance from the zinc. Zinc therapy in pediatric patients appears to have a mildly adverse effect on the high-density lipoprotein/total cholesterol ratio, contrary to results of an earlier large study of primarily adults. In conclusion, zinc is effective and safe for the maintenance management of pediatric cases of Wilson's disease. Our data are strongest in children above 10 years of age. More work needs to be done in very young children, and the cholesterol observations need to be studied further.
11479773##2001-8-2##Ultrastructural identification of iron and copper accumulation in the liver of a male patient with Wilson disease.##There is accumulating evidence that ceruloplasmin, a copper-containing protein with ferroxidase activity, plays an important role in iron metabolism. Reduction of ferroxidase activity secondary to ceruloplasmin deficiency may induce iron accumulation in various organs as the result of impaired iron transport. A 37-year-old man presented with intention tremor of the right hand. Liver function tests were almost normal, but parameters of trace elements were abnormal: hypocupremia, hypoceruloplaminemia, and hyperferritinemia. Imaging of the abdomen showed a cirrhotic liver with increased density. A diagnosis of the neurological form of Wilson disease was confirmed by copper deposits in the liver obtained by a blind biopsy, and the patient was diagnosed as compound heterozygous for ATP7B mutations. He was treated with 2500 mg/day trientine hydrochloride per os. The second examination was performed after 20 months of treatment. The treatment further reduced serum ceruloplasmin level from 8.9 to less than 4.0 mg/dl. Serum ferroxidase activity was as low as 70 U/l during treatment. Posttreatment liver histology became negative for copper but remained positive for iron. Copper X-rays from hepatocyte lysosomes were no longer detected, but the iron X-ray was still very high post treatment. Thus, microanalysis confirmed compound overload of copper and iron in this male patient with Wilson disease.
11243728##2001-3-13##Molecular diagnosis of Wilson disease.##Wilson disease (WD) is caused by mutations in the ATP7B gene. The diagnosis is based on clinical and biochemical criteria but these are increasingly recognized to have low sensitivity. Genetic diagnosis is considered impractical due to the large coding region of the ATP7B gene and extreme diversity of mutations. We assessed the feasibility and utility of genetic diagnosis in WD. The coding region of the ATP7B gene was scanned by single-stranded conformation polymorphism (SSCP) analysis in 6 cases in whom the diagnosis of WD was uncertain. In addition, we attempted molecular diagnosis in 26 WD patients of similar ethnicity but variable disease manifestations. In 6 individuals in whom the biochemical/clinical diagnosis was uncertain, DNA analyses were useful for assigning their status with respect to WD. Molecular diagnosis identified presymptomatic individuals in families affected by WD and assigned heterozygote carrier or wild-type status to individuals previously diagnosed as affected. In 26 WD patients, 92% of disease alleles were identified. The most common mutations were H1069Q, L936X, and 2532delA representing 48, 10, and 8% of disease alleles, respectively. Three novel mutations were identified: Q898R, 3061(-1)g --> a, and 3972insC. Genetic diagnosis is feasible for WD. Greater application of molecular diagnosis should enable an appreciation of the full spectrum of WD phenotype that is not possible with currently available diagnostic criteria.
11273771##2001-3-29##Correction of liver disease following transplantation of normal rat hepatocytes into Long-Evans Cinnamon rats modeling Wilson's disease.##To establish the efficacy of cell therapy in Wilson's disease, we used the Long-Evans Cinnamon (LEC) rat model with atp7b gene mutation and copper toxicosis. Several groups of LEC rats were established, including animals pretreated with retrorsine to exacerbate copper toxicosis and inhibit proliferation in native hepatocytes followed by partial hepatectomy to promote liver repopulation. Hepatocytes from normal, syngeneic LEA rats were transplanted intrasplenically. Animal survival, biliary copper excretion, and hepatic copper were determined. The magnitude of liver repopulation was demonstrated by measuring serum ceruloplasmin and hepatic atp7b mRNA. Long-term survival in LEC rats treated with retrorsine, partial hepatectomy, and cell transplantation was up to 90%, whereas fewer than 10% of animals pretreated with retrorsine, without cell therapy, survived, P < 0.001. Liver repopulation occurred gradually after cell transplantation, ranging from <25% at 6 weeks, 26 to 40% at 4 months, and 74 to 100% at 6 months or beyond. Liver repopulation restored biliary copper excretion capacity and lowered liver copper levels. Remarkably, liver histology was completely normal in LEC rats with extensive liver repopulation, compared with widespread megalocytosis, apoptosis, oval cell proliferation, and cholangiofibrosis in untreated animals. These data indicate that liver repopulation with functionally intact cells can reverse pathophysiological perturbations and cure Wilson's disease.
11270271##2001-3-29##[Hemolytic anemia disclosing Wilson's disease. Report of 2 cases].##
11407524##2001-6-16##Electron microscopic detection of copper in the liver of two patients with morbus Wilson by EELS and EDX.##A 20-year-old male patient with morbus Wilson was liver transplanted because of terminal failure of liver function. The explanted liver showed a strong macronodular cirrhosis as typically seen in Wilson disease. There were visible granular accumulations in the hepatocytes after the rubeanic acid or rhodanine method for histochemical detection of copper. The electron microscopic studies on ultrathin sections revealed numerous electron-dense lysosomes and residual bodies. The elemental analysis in transmission electron microscope (TEM) with electron energy loss spectroscopy (EELS) and in scanning electron microscope (SEM) with energy dispersive x-ray analysis (EDX) showed copper-specific signals of electron-dense accumulations inside these dark lysosomes and residual bodies. In a second case, Wilson disease was diagnosed after autopsy of a 31-year-old patient by liver electron microscopy and EELS; strong electron-dense lysosomes and residual bodies with positive copper signals were found inside hepatocytes. For negative control, hepatocytes with iron accumulation after idiopathic hemochromatosis and liver cirrhosis were also analyzed by EELS in TEM, which showed strong iron, but only a few or no copper signals. Atomic absorption spectroscopy (AAS) in 16 liver samples of healthy and cirrhotic liver revealed only in both cases of Wilson disease a strong increased copper concentration higher than 100 microg Cu/g. The electron microscopic detection of copper-containing hepatocytic lysosomes is helpful for the diagnosis of early stages of Wilson disease in addition to the quantification of hepatic copper by AAS.
11444216##2001-7-11##8th International Conference on Wilson Disease and Menkes Disease. Leipzig, Germany, April 16-18, 2001. Abstracts.##
11234295##2001-3-10##[An adolescent with hemolytic anemia and coagulation disorders as manifestation of Wilson's disease, treated with liver transplantation].##A 16-year-old woman presented with anaemia, jaundice, vomiting and nosebleed. She had acute hepatic failure and haemolytic anaemia and developed acute respiratory distress syndrome (ARDS). Wilson's disease was diagnosed. After the ARDS resolved the patient underwent a successful orthotopic liver transplantation. Diagnostic combinations for Wilson's disease are ceruloplasmin < 0.2 g/l with Kayser-Fleischer rings, liver copper > 250 micrograms/g (dry weight) with Kayser-Fleischer rings, or homozygosity for a Wilson mutation on the 13th chromosome. In acute liver failure a copper excretion in 24 h-urine above 1 mg is diagnostic for Wilson's disease, while an elevated serum copper concentration makes this diagnosis very likely. Therapeutic options for Wilson's disease are chelation therapy and liver transplantation; in most cases of acute liver failure due to Wilson's disease orthotopic liver transplantation (preceded by albumin dialysis) is indicated. Nazer's index should be used in addition to the regular King's College criteria for liver transplantation indication.
11157799##2001-2-7##Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase.##Wilson disease is an autosomal recessive copper transport disorder resulting from defective biliary excretion of copper and subsequent hepatic copper accumulation and liver failure if not treated. The disease is caused by mutations in the ATP7B (WND) gene, which is expressed predominantly in the liver and encodes a copper-transporting P-type ATPase that is structurally and functionally similar to the Menkes protein (MNK), which is defective in the X-linked copper transport disorder Menkes disease. The toxic milk (tx) mouse has a clinical phenotype similar to Wilson disease patients and, recently, the tx mutation within the murine WND homologue (WND:) of this mouse was identified, establishing it as an animal model for Wilson disease. In this study, cDNA constructs encoding the wild-type (Wnd-wt) and mutant (Wnd-tx) Wilson proteins (Wnd) were generated and expressed in Chinese hamster ovary (CHO) cells. The tx mutation disrupted the copper-induced relocalization of Wnd in CHO cells and abrogated Wnd-mediated copper resistance of transfected CHO cells. In addition, co-localization experiments demonstrated that while Wnd and MNK are located in the trans-Golgi network in basal copper conditions, with elevated copper, these proteins are sorted to different destinations within the same cell. Ultrastructural studies showed that with elevated copper levels, Wnd accumulated in large multi-vesicular structures resembling late endosomes that may represent a novel compartment for copper transport. The data presented provide further support for a relationship between copper transport activity and the copper-induced relocalization response of mammalian copper ATPases, and an explanation at a molecular level for the observed phenotype of tx mice.
11227135##2001-3-3##Comparison of MRI, EEG, EPs and ECD-SPECT in Wilson's disease.##
11177695##2001-2-15##Treatment of Wilson's disease: what are the relative roles of penicillamine, trientine, and zinc supplementation?##New options are available for the medical treatment of patients with Wilson's disease. Penicillamine is no longer the treatment of choice, as there is a growing experience with safer and more effective alternatives. Trientine may be the best choice for initial therapy in symptomatic patients requiring chelation therapy, and it may be even more effective when used in combination with zinc, which is recommended for maintenance therapy. Further studies are needed to determine the best therapy for pregnant patients with Wilson's disease, and whether combination therapy using trientine and zinc will be the next treatment of choice for all symptomatic patients with liver or neurologic disease.
11180609##2001-2-17##Three novel mutations (P760L, L1305P, Q1351Stop) causing Wilson disease.##
11273000##2001-3-29##Alzheimer-type I astrogliopathy (AIA) and its implications for dynamic plasticity of astroglia: a historical review of the significance of AIA.##Alzheimer-type I astrogliopathy (AIA) is an uncommon neuropathological phenomenon encountered in Wilson's disease and less often in acquired hepatic encephalopathy. Since its first description in 1912 it has received little attention. However, after 1971, when the nature of its morphogenesis began to be recognized and it was shown that it could be reproduced experimentally, its significance has been increasingly appreciated. Two intriguing characteristics of the dynamic plasticity of astroglia were revealed from the studies of the inter-relationships between AIA and Alzheimer-type II astrogliopathy (AIIA); normal astroglia and AIIA; and reactive astrogliosis and AIIA, namely, the compensatory "rebound" phenomenon of Alzheimer astrogliopathy, and a dual cellular origin for reactive astrogliosis taking place in both normal and dystrophic astrocytes. More recently the presence of AIA and AIIA has been reported in a case of anoxic encephalopathy, and also in a case of Marchiafava-Bignami's disease. In this review, dependable criteria for the identification of the pathological features of AIA are discussed and emphasized. Both types of Alzheimer astrogliopathy may be used as pathologic markers with specific morphological and immunocytochemical characteristics to study in detail the disturbances of metabolic interactions between the astrocyte-neuron coupling and the exact mechanisms of the dynamic plasticity of astroglia.
11425282##2001-6-27##Is Parkinson's disease the heterozygote form of Wilson's disease: PD = 1/2 WD?##Wilson's disease (WD) patients often present with Parkinson's disease (PD). Furthermore, most patients with PD have reduced ceruloplasmin, a characteristic of Wilson's disease. WD is an autosomal recessive disease (requires two faulty copies of a gene to produce a homozygote individual) that afflicts 1 in 1000 people. However, the number of people with one faulty copy (heterozygotes) is much larger, probably about 2% of the population. I hypothesize that the large number of heterozygotes for WD are at greatly increased risk for idiopathic PD, because these people accumulate free copper in the basal ganglia at a slower rate than homozygotes, which accounts for the fact that PD usually develops after 40 years of age. In WD, a ceruloplasmin deficiency results in accumulation of free Cu in the liver, brain, kidneys, etc. The excess Cu results in impaired Zn absorption, which would account for the low levels of Zn in the brains of PD patients. Moreover, the high levels of Fe found in the substantia nigra of PD patients may perhaps be explained by free Cu binding to iron binding protein-1 (IBP-1), causing it to malfunction and preventing it from detaching itself from the transferrin receptor (TfR) inhibition gene, resulting in expression of TfR even when the cell has plenty of Fe. The gradual accumulation of Fe and Cu would explain the damage inflicted on the substantia nigra by free radicals catalyzed by these two metals and which is exacerbated by the low levels of CuZnSOD, due to the Zn deficiency mentioned above. Moreover, if this hypothesis is correct, then PD could be used to help discover the gene (or genes) responsible for WD and vice versa. Furthermore, idiopathic PD could be prevented by identifying the heterozygote individuals and providing them with Zn supplementation, Cu chelation therapy and phlebotomy to eliminate Fe.
11267403##2001-3-27##Liver transplantation in neurologic Wilson's disease.##
11286757##2001-4-5##The molecular basis of copper-transport diseases.##Copper (Cu) is a potentially toxic yet essential element. MENKES DISEASE, a copper deficiency disorder, and WILSON DISEASE, a copper toxicosis condition, are two human genetic disorders, caused by mutations of two closely related Cu-transporting ATPases. Both molecules efflux copper from cells. Quite diverse clinical phenotypes are produced by different mutations of these two Cu-transporting proteins. The understanding of copper homeostasis has become increasingly important in clinical medicine as the metal could be involved in the pathogenesis of some important neurological disorders such as Alzheimer's disease, motor neurone diseases and prion diseases.
11172635##2001-2-15##[Using fluorescence PCR analysis for early diagnosis and carriers detection of Chinese Wilson's disease].##
11053407##2000-10-29##The Lys1010-Lys1325 fragment of the Wilson's disease protein binds nucleotides and interacts with the N-terminal domain of this protein in a copper-dependent manner.##Wilson's disease, an autosomal disorder associated with vast accumulation of copper in tissues, is caused by mutations in a gene encoding a copper-transporting ATPase (Wilson's disease protein, WNDP). Numerous mutations have been identified throughout the WNDP sequence, particularly in the Lys(1010)-Lys(1325) segment; however, the biochemical properties and molecular mechanism of WNDP remain poorly characterized. Here, the Lys(1010)-Lys(1325) fragment of WNDP was overexpressed, purified, and shown to form an independently folded ATP-binding domain (ATP-BD). ATP-BD binds the fluorescent ATP analogue trinitrophenyl-ATP with high affinity, and ATP competes with trinitrophenyl-ATP for the binding site; ADP and AMP appear to bind to ATP-BD at the site separate from ATP. Purified ATP-BD hydrolyzes ATP and interacts specifically with the N-terminal copper-binding domain of WNDP (N-WNDP). Strikingly, copper binding to N-WNDP diminishes these interactions, suggesting that the copper-dependent change in domain-domain contact may represent the mechanism of WNDP regulation. In agreement with this hypothesis, N-WNDP induces conformational changes in ATP-BD as evidenced by the altered nucleotide binding properties of ATP-BD in the presence of N-WNDP. Significantly, the effects of copper-free and copper-bound N-WNDP on ATP-BD are not identical. The implications of these results for the WNDP function are discussed.
11512412##2001-8-22##MR imaging of seven presumed cases of central pontine and extrapontine myelinolysis.##MRI was performed in seven patients with presumed central pontine and extrapontine myelinolysis. The underlying diseases were diabetes, lung cancer, Wilson disease, trauma, alcoholism, renal insufficiency and hemodialysis. CPM was found in four cases (in two of them extrapontine lesions were considered as resulting from Wilson disease), CPM and EPM in three patients. The localization of extrapontine changes included cerebellum, cerebral peduncles, caudate and lentiform nuclei, internal capsules, white matter and cortex of the cerebrum.
11799848##2002-1-22##Molecular factors affecting the complex formation between deferiprone (L1) and Cu(II). Possible implications on efficacy and toxicity.##Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, L1, CAS 30652-11-0) is a new chelating drug used worldwide for the treatment of iron overloading conditions. Spectrophotometric and potentiometric measurements were carried out to investigate the interaction of L1 with Cu(II) ions under different conditions. The complexation of Cu(II) ions with L1 in aqueous solution leads predominantly to the formation of the Cu(L1)2 species at a pH range of 4-9. The experimental results indicate that L1 has high affinity for Cu(II) with stability constants log beta 11 = 10.3 +/- 0.9 and log beta 12 = 19.2 +/- 0.6. The effect of Cu(II) ions on the affinity of L1 for Fe(III) ions by competition reactions in vitro indicate displacement of Fe(III) in a concentration dependent manner by Cu(II). Similarly, the presence of different buffers at various pH values resulted in the formation of different stoichiometry L1 complexes with Cu(II) and of mixed complexes with buffer anions. The strong interaction of L1 with Cu(II) may have implications on the therapeutic and toxicological properties of this chelating drug. In particular, L1 may be used in the treatment of copper overloading conditions, such as Wilson's disease or other conditions where copper toxicity is implicated.
11817679##2002-1-31##Quercetin cumulatively enhances copper induction of metallothionein in intestinal cells.##Wilson's disease, a genetic copper-overload condition, is currently treated with zinc because of the ability of zinc to induce metallothionein. We are interested in nonmetal chemicals that may alter intestinal copper metabolism and thus help to alleviate copper toxicity. Previously, we have shown that quercetin, a dietary flavonoid, can chelate copper. This study further examined the interaction of quercetin and copper in intestinal epithelial cells. We found that quercetin enhanced metallothoinein induction by copper and the effect was dose dependent. Quercetin also exerted a cumulative effect after repeated exposure. Repeated low-dose treatment (3-10 microM) of cells with quercetin can lead to the same effect on metallothoinein as one higher concentration treatment (100 microM). This property of quercetin is distinct from its chemical interaction with copper, but both can contribute to a reduction of copper toxicity. Among other flavonoids tested, two other copper chelators, catechin and rutin, did not increase copper induction of metallothionein, whereas genistein, an isoflavone that does not interact with copper chemically, increased copper induction of metallothionein. The effect of quercetin on copper metabolism is unique. Quercetin decreased zinc-stimulated metallothionein expression and had no effect on the cadmium induction of metallothionein. The clinical application of our observation needs to be explored.
11936861##2002-4-9##Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD).##Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.
11358083##2001-5-19##Surviving Wilson's disease.##
11680638##2001-10-30##Neuropathological analysis of pathological forms of astroglia in Wilson's disease.##A neuropathological study of Alzheimer type I (Alz I) and Alzheimer type II (Alz II) as well as Opalski (Opl) cells was performed serially on brain tissue from nine autopsied Wilson's disease (WD) cases. Conventional staining methods (Kluver-Barrera, HE, PAS) and immunocytochemical techniques (anti-GFAP and anti-Metallothionein-MT) were used. On conventional staining, each of the studied abnormal cell types retained common morphological characteristics of astroglia, and concurrently demonstrated its own distinctive features, specific only for a given cell type. Anti-GFAP staining revealed positive immunoreactivity of Alz I and Opl cells, and its absence in Alz II cells. On anti-MT staining both the cytoplasm and nucleus of Alz I and Opl cells showed positivity whereas in Alz II cells the cytoplasm was positive in contrast to the negative nucleus. The results of our study confirm the hypothesis of the astroglial origin of all three types of cells. The lack of immunoreactivity for GFAP and similar immunocytochemical staining patterns for MT in Alz II cells and protoplasmic astrocytes may suggest that Alz II cells originate from the protoplasmic type of astroglia. The fact that Alz I and Opl cells resemble fibrous astrocytes in their immunoreactive positivity for GFAP may lead to a supposition that they originate from the fibrous type of astroglia. MT-positive expression by the three abnormal cell types suggests that they may be involved in the process of copper detoxification in WD.
11234997##2001-3-10##The antioxidant effect of DL-alpha-lipoic acid on copper-induced acute hepatitis in Long-Evans Cinnamon (LEC) rats.##The Long-Evans Cinnamon (LEC) rats, due to a genetic defect, accumulate excess copper (Cu) in the liver in a manner similar to patients with Wilson's disease and spontaneously develop acute hepatitis with severe jaundice. In this study we examined the protective effect of DL-alpha-Lipoic acid (LA) against acute hepatitis in LEC rats. LA was administered to LEC rats by gavage in doses of 10, 30 and 100 mg/kg five times per week, starting at 8-weeks-old and continuing till 12-weeks-old. Although LA had little effect against the increases in serum transaminase activities, it suppressed the loss of body weight and prevented severe jaundice in a dose-dependent manner. Antioxidant system analyses in liver showed that LA treatment significantly suppressed the inactivations of catalase and glutathione peroxidase, and the induction of heme oxygenase-1, an enzyme which is inducible under oxidative stress. Furthermore, LA showed dose-dependent suppressive effect against increase in nonheme iron contents of both cytosolic and crude mitochondrial fractions in a dose-dependent manner. Although at the highest dose, LA slightly suppressed the accumulation of Cu in crude mitochondrial fraction, it had no effect on the accumulation of Cu in cytosolic fraction. While LA completely suppressed the increase in lipid peroxidation (LPO) in the microsomal fraction at the highest dose, the suppressive effect against LPO in crude mitochondrial fractions was slight. From these results, it is concluded that LA has antioxidant effects at the molecular level against the development of Cu-induced hepatitis in LEC rats. Moreover, mitochondrial oxidative damage might be involved in the development of acute hepatitis in LEC rats.
11291964##2001-4-9##New method for quantitative mapping of metallic elements in tissue sections by electron probe microanalyser with wavelength dispersive spectrometers.##In this paper, we have proposed a new method that gives quantitative distributions of metallic elements in a tissue section by electron probe microanalyser equipped with wavelength dispersive spectrometers. Its principal merit is the clear expression of element distribution with micrometer resolution in typically prepared section samples for routine histopathological diagnosis. By analysing thin standard films containing metallic atoms of interest, it was confirmed that the detection limit is about 1 x 10(6) atoms microm-2. This value corresponds to 100 microg g(-1) (dry weight) in case of tissue section of 2 microm thickness. Furthermore, for copper, iron and aluminium, the exact linear relationship between the amount of metallic atoms and the characteristic X-ray intensity was established in the range up to 15 x 10(6) atoms microm(-2). The element maps of tissue sections from patients with Wilson's disease proved that the copper levels in analysed areas were not homogeneous and indicated abnormal accumulation in some portions. These results confirmed the usefulness of this method for histopathological diagnosis.
11211896##2001-2-24##The Wilson's disease gene and phenotypic diversity.##
11787982##2002-1-15##Brain copper, iron, magnesium, zinc, calcium, sulfur and phosphorus storage in Wilson's disease.##
11464628##2001-7-24##[Wilson disease. Report of a case of autopsy with copper tissue quantification and electronic microscopy].##
11240557##2001-3-10##[Wilson's disease].##
11529038##2001-9-1##[Wilson disease].##
11217487##2001-2-24##[Eye diseases in mitochondrial encephalomyopathies].##Mitochondria are the principal site of generation of energy in form of adenosine triphosphate (ATP). They contain the enzymes of the Krebs and fatty acid cycles and the respiratory pathway. Ocular tissues with high energy consumption and dependence on oxidative energy production like the optic nerve, the retina, and the pigment epithelium are often involved in mitochondrial diseases. This article reviews the genetic mitochondrial diseases involving the visual system. Their most important ocular findings include: acute or slowly progressive bilateral visual loss and visual field loss due to an optic neuropathy or retinal degeneration, bilateral progressive decreased ocular motility, and bilateral upper lid ptosis. The following diseases are discussed: Leber's Hereditary Optic Neuropathy (LHON); Kearns-Sayre Syndrom (KSS); Chronic Progressive External Ophthalmoplegia (CPEO); Autosomal Recessive Cardiomyopathy, Ophthalmoplegia (ARCO); Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-Like Episodes (MELAS); Neuropathy, Ataxia, Retinitis Pigmentosa (NARP); Mitochondrial Neuropathy, Gastro-Intestinal Encephalomyopathy (MNGIE); Myoclonus Epilepsy, Ragged-Red-Fibers (MERRF); Wilson's disease; Friedreich's ataxia. Diagnosis of mitochondrial encephalomyopathies is established by screening for mutations in blood or muscle biopsy samples. No specific therapies which influence the course of mitochondrial encephalomyopathies are known. Drugs interacting with the mitochondria function, alcohol consumption and smoking should be avoided.
11085952##2000-11-22##Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation.##Toxic milk (tx) is a copper disorder of mice that causes a hepatic accumulation of copper similar to that seen in patients with Wilson disease. Both disorders are caused by a defect in the ATP7B copper-transporting ATPase. A feature of the tx phenotype is the production of copper-deficient milk by lactating dams homozygous for the tx mutation; the milk is lethal to the pups. It has not been determined whether the production of copper-deficient milk is a direct consequence of impaired expression of ATP7B protein in the mammary gland. With the use of immunohistochemistry, our study demonstrated that the ATP7B protein was mislocalized in the lactating tx mouse mammary gland, which would explain the inability of the tx mouse to secrete normal amounts of copper in milk. Confocal microscopy analysis showed that, in the lactating tx mammary gland, ATP7B was predominantly perinuclear in comparison with the diffuse, cytoplasmic localization of ATP7B in the lactating normal mammary gland. Lactating tx mice showed impaired delivery of copper from the mammary gland to the milk and this was not ameliorated by dietary copper supplementation. In contrast, the normal mouse mammary gland responded to increased dietary copper by increasing the amount of copper in milk. A change in the distribution of the ATP7B protein from perinuclear in the non-lactating gland to a diffuse, cytoplasmic localization in the lactating gland of the normal (DL) mouse suggests that the relocalization of APT7B is a physiological process that accompanies lactation. We conclude that the impaired copper transport from the mammary gland into milk in lactating tx mice is related to the mislocalization of ATP7B.
11113937##2000-12-13##High performance liquid chromatography analysis of D-penicillamine by derivatization with N-(1-pyrenyl)maleimide (NPM).##D-Penicillamine (2-amino-3-mercapto-3-methylbutanoic acid), a well-known heavy metal chelator, is the drug of choice in the treatment of Wilson's disease and is also effective for the treatment of several disorders including rheumatoid arthritis, primary biliary cirrhosis, scleroderma, fibrotic lung diseases and progressive systemic sclerosis. The method proposed incorporates a technique, previously developed in our laboratory, that utilizes the derivatizing agent N-(1-pyrenyl)maleimide (NPM) and reversed-phase high-performance liquid chromatography (HPLC). The coefficients of variation for within-run precision and between-run precision for 500 nM standard D-penicillamine (D-pen) were 2.27% and 2.23%, respectively. Female Sprague-Dawley rats were given 1 g/kg D-pen i.p. and the amounts of D-pen in liver, kidney, brain and plasma were subsequently analyzed. This assay is rapid, sensitive and reproducible for determining D-pen in biological samples.
11175281##2001-2-15##Determination of the frequencies of ten allelic variants of the Wilson disease gene (ATP7B), in pooled DNA samples.##Wilson disease is an autosomal recessive disorder characterised by toxic accumulation of copper in liver, brain and other organs. The disorder is caused by mutations in the ATP7B gene, encoding a copper transporting P-type ATPase. Based on the number of known patients with this diagnosis in Sweden, the prevalence can be estimated to 1 in 250,000 to 300,000, whereas the prevalence of Wilson disease has been estimated to be 1 in 30,000 in other populations. We estimated the prevalence of Wilson disease by determining the Swedish population frequencies of two mutant alleles, making up approximately half the mutations in Swedish Wilson patients, in a large number of DNA samples. In addition we determined the allele frequencies of eight common single-nucleotide polymorphisms (SNPs) in the ATP7B gene. For the analyses we devised two strategies for analysing pooled DNA samples using the quantitative minisequencing method. The two procedures allowed sensitive identification of rare mutant alleles present as a mixture with an excess of the normal allele, as well as accurate estimation of the frequencies of the common SNPs in a large pooled DNA sample.
11093740##2000-11-28##High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study.##The molecular basis of Wilson disease (WD), an autosomal recessive disorder, is the presence of mutations in the ATP7B gene, a copper transporting ATPase. Hospital records indicated a higher prevalence of WD (1 in 2,600) in some counties in the northeastern region of the island of Gran Canaria (Canary Islands, Spain) that was around 10-fold higher than that described for European populations (1 in 30,000). The ATP7B gene was analyzed for mutations in 24 affected subjects, revealing a high prevalence of the rare Leu708Pro mutation present in 12 homozygous and 7 heterozygous individuals. In these patients, who constitute one of the largest described cohorts of WD homozygotes, we found a variable clinical presentation of the disease, although the biochemical picture was homogenous and characteristic, thereby confirming that the Leu708Pro change is indeed a mutation associated with WD. Haplotype analysis of subjects homozygous for the Leu708Pro mutation showed a conserved shared region smaller than 1 centimorgan (cM), and the region of linkage disequilibrium between the Leu708Pro mutation and neighboring microsatellite markers extended approximately 4.6 cM. When comparing the amount of linkage disequilibrium versus genetic distance from the disease mutation, it was estimated that a common ancestral Leu708Pro chromosome may have been introduced in Gran Canaria over 56 generations ago, dating it back to pre-Hispanic times. The prevalence, and the tight geographical distribution of the Leu708Pro chromosome suggests that the Canary Islands can be considered a genetic isolate for linkage disequilibrium studies.
11262988##2001-3-27##Burden of genetic disorders in India.##India, like other developing countries, is facing an accelerating demographic switch to non-communicable diseases. In the cities congenital malformations and genetic disorders are important causes of morbidity and mortality. Due to the high birth rate in India a very large number of infants with genetic disorders are born every year almost half a million with malformations and 21,000 with Down syndrome. In a multi-centric study on the causes of referral for genetic counselling the top four disorders were repeated abortions (12.4%), identifiable syndromes (12.1%), chromosomal disorders (11.3%) and mental retardation (11%). In a more recent study in a private hospital the top reasons for referral were reproductive genetics (38.9%)--comprising prenatal diagnosis, recurrent abortions, infertility and Torch infections--mental retardation +/- multiple congenital anomalies (16.1%), Down syndrome (9.1%), thalassemia/haemophilia (8.8%), and muscle dystrophy/spinal muscular atrophy (8.4%). The disorders for which prenatal has been done over an 18-month-period are given. A recent study carried out in three centers (Mumbai, Delhi and Baroda) on 94,610 newborns by using a uniform proforma showed a malformation frequency of 2.03%, the commonest malformations are neural tube defects and musculo-skeletal disorders. The frequency of Down syndrome among 94,610 births was 0.87 per 1000, or 1 per 1150. Screening of 112,269 newborns for aminoacid disorders showed four disorders to be the commonest--tyrosinemia, maple syrup urine disease and phenylketonuria. Screening of cases of mental retardation for aminoacid disorders revealed four to be the commonest--hyperglycinemia, homocystinuria, alkaptonuria, and maple syrup urine disease. Metabolic studies of cases of mental retardation in AIIMS, Delhi and KEM Hospital, Mumbai, demonstrated that common disorders were those of mucopolysaccharides, lysosomes, Wilson disease, glycogen storage disease and galactosemia. It is estimated that beta- thalassemia has a frequency at birth of 1:2700, which means that about 9,000 cases of thalassemia major are born every year. Almost 5200 infants with sickle cell disease are born every year. Disorders, which deserve to be screened in the newborn period, are hypothyroidism and G-6-PD deficiency, while screening for aminoacid and other metabolic disorders could presently be restricted to symptomatic infants.
11139993##2001-1-5##[Clinical and fine motor therapy assessment in Wilson disease].##At the time of diagnosis and after therapy, we examined 33 patients suffering from Wilson's disease. We applied a standardized diagnostic score system on the basis of clinical signs. Without observing any differences between pseudoparkinsonian and pseudosclerosis subtypes, patients with neurological symptoms significantly improved by 2.33 points. Patients with initially more severe symptoms showed the same improvement as less affected patients. Fine motor disturbances were evaluated using the V-scope system. Finger tapping and drawing a spiral were compared to values of a healthy control group (n = 52). Patients with neurological symptoms showed significantly decreased frequencies in both tests. The clinical score was related to frequencies in finger tapping but not in drawing a spiral. Therefore finger tapping can be used as an objective diagnostic tool to evaluate the severity of Wilson's disease, while spiral testing appears to be a sensitive screening tool.
11146611##2001-1-9##'Face of the giant panda' sign in Wilson's disease: revisited.##We report a patient, with Wilson's disease, who showed the characteristic radiological sign known as 'Face of the giant panda sign' on magnetic resonance imaging (MRI) of the brain.
11134754##2001-1-3##Wilson's disease: challenging diagnosis, management, and liver transplantation timing.##
11090950##2000-11-25##Ultrasensitive and specific detection methods for exocylic DNA adducts: markers for lipid peroxidation and oxidative stress.##Among exocyclic DNA adducts, etheno (epsilon) bases (epsilond A, epsilond C, N(2),3-epsilond G) are generated by reactions of DNA bases with lipid peroxidation (LPO) products derived from endogenous sources and from the carcinogens vinyl chloride or urethane. The recent development of ultrasensitive methods has made it possible to detect these epsilon-adducts in vivo and to study their formation and role in experimental and human carcinogenesis. The promutagenic epsilon-DNA modifications can be detected by immunoaffinity/32P-postlabelling or by immunohistochemistry. When epsilon-adducts are excised from tissue DNA, the modified nucleosides can be quantified in urine by an immunoaffinity-HPLC-fluorescence method. Highly variable background levels of epsilon-adducts were detected in tissues from unexposed humans and rodents, suggesting an endogenous pathway of formation from reaction of trans-4-hydroxy-2-nonenal (via its 2,3-epoxide) with DNA bases. Several known cancer risk factors increased the level of these DNA lesions: Elevated epsilon-adducts were found in hepatic DNA from patients with excess metal storage (haemochromatosis, Wilson's disease), resulting in oxidative stress and high risk of liver cancer. Reactive O/N-intermediates generated during inflammatory processes, for example in patients with inflammatory bowel disease (IBD) and familial adenomatous polyposis (FAP) led to the formation of epsilon-adducts likely through peroxynitrite-mediated LPO and/or increased oxidative arachidonic acid metabolism. A high omega-6-polyunsaturated fatty acid (PUFA) diet increased epsilon-DNA adducts in white blood cells (WBC), particularly in female subjects (about 40-fold), while the level of adducted malondialdehyde in deoxyguanosine of WBC-DNA was only moderately elevated. In conclusion, there is now growing evidence that epsilon-adducts were elevated in cancer-prone patients and in rodents (liver, pancreas, colon, skin), suggesting that promutagenic epsilon-adducts, when formed as a consequence of persistent oxidative stress, can drive cells to malignancy. Therefore, biomonitoring of exocyclic DNA adducts offers useful tools: (i) to evaluate the etiological contributions of dietary fats, oxidative stress, and chronic inflammatory/infectious processes; (ii) to verify the efficacy of chemopreventive agents on endogenous DNA damage and cancer risk; and (iii) to gain mechanistic insights into the role of oxidative stress/LPO-derived lesions in the initiation and progression of human cancer.
11050162##2000-10-26##Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases.##Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.
11310382##2001-4-20##Role of autoimmunity in nonviral chronic liver disease.##
11127261##2000-12-29##ACP Best Practice No 163. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring.##Wilson's disease, the most common inherited disorder of copper metabolism, is a recessive genetic condition. The clinical presentation of Wilson's disease is very variable. It is characterised by low serum copper and caeruloplasmin concentrations coupled with the pathological accumulation of copper in the tissues. However, there are diagnostic difficulties and these are discussed. The current value of DNA diagnosis, both in gene tracking in families or as applied to de novo cases, is examined. Wilson's disease can be treated successfully but treatment must be life long. Patients are best treated by specialist centres with experience and expertise in the condition.
11032641##2000-10-14##Early detection of non-compliance in Wilson's disease by consecutive copper determination in cerebrospinal fluid.##
11060541##2000-11-4##Severe hepatic Wilson's disease in preschool-aged children.##A 3-year-old girl presented with hemolytic anemia, hepatosplenomegaly, ascites, and evidence of decompensated chronic liver disease. Genotypic DNA analysis revealed that the patient was homozygous for a splice site mutation now designated IVS4-1:G>C, expected to destroy completely the functional gene product of ATP7B, the gene responsible for Wilson's disease. We suggest that this severe mutation caused very early liver disease. Wilson's disease should be considered in the differential diagnosis of established liver disease in the preschool-aged child.
11209485##2001-2-24##Clinical manifestations and survival pattern of Wilson's disease.##
11037385##2000-10-19##Cyproterone for hypersexuality in a psychotic patient with Wilson's disease.##
11124346##2000-12-22##A single determination of liver copper concentration may misdiagnose Wilson's disease.##
11041690##2000-10-21##Acute hepatitis after starting zinc therapy in a patient with presymptomatic Wilson's disease.##
11327325##2001-5-1##Copper-dependent oxidative stress and neurodegeneration.##Copper is an essential trace element, but its redox reactivity leads to risks of damage to cell and tissues. These are well exemplified by several forms of neurodegenerative diseases, either arising as inherited disorders of copper metabolism, such as Menkes' and Wilson's disease, or as conformational diseases such as Alzheimer's disease and prion diseases. This review will cover some aspects of the involvement of copper-mediated oxidative stress in degenerative processes in the central nervous system, with special focus on the familial form of amyotrophic lateral sclerosis (FALS). Furthermore, a possible role of copper reactivity in inducing critical steps in the apoptotic pathways leading to neurodegeneration is envisaged.
11054498##2000-10-31##A novel deletion mutation within the carboxyl terminus of the copper-transporting ATPase gene causes Wilson disease.##In patients with Wilson disease (WD), an autosomal recessive disorder, toxic accumulation of copper results in fatal liver disease and irreversible neuronal degeneration. ATP7B, the gene mutated in WD, contains 21 exons and encodes a copper-transporting ATPase. In this study, all exons of the ATP7B gene of nine WD patients were screened for alterations by conventional mutation detection enhancement (MDE) heteroduplex analysis, followed by direct sequencing of the regions that showed heteroduplex formation. For the first time, a novel deletion mutation (4193delC) in exon 21, causing a frameshift leading to premature truncation of the protein was detected in four of nine patients. The 4193delC removes several signals within the carboxyl terminal domain that may disrupt trafficking of ATP7B protein through trans-Golgi network at the cellular level.
11372428##2001-5-25##[Copper transport and associated genetic disorders].##
11082702##2000-11-18##[Biological regulation of copper and selective removal of copper: therapy for Wilson disease and its molecular mechanism].##Copper (Cu) is an essential trace element and constitutes the active center of the redox Cu enzymes such as Cu, Zn-superoxide dismutase (Cu, Zn-SOD), ceruloplasmin and cytochrome c oxidase. Among hereditary diseases due to a defect in the metabolism of Cu, Menkes disease (caused by a Cu deficiency) and Wilson disease (caused by the excessive accumulation of Cu) have been shown to be caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu, ATP7A and ATP7B, respectively. Following the identification of these causative genes, intracellular Cu transporters (Cu chaperones) specific for the Golgi apparatus, mitochondria and Cu, Zn-SOD were discovered, and these findings have facilitated the study of the underlying mechanisms of the biological regulation of Cu. Apart from these physiological and biochemical studies, toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. In these toxicological studies, two biological aspects of metallothionein (MT), i.e., antioxidant and prooxidant depending on the Cu/Zn ratio in Cu-containing MT have been proposed. The present article overviews the recent findings on the biological regulation of Cu and on the toxicological aspect of Cu. It is known that Cu forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. On the basis of this observation, tetrathiomolybdate (TTM) has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC) rats. Precise mechanisms underlying the complex formation between Cu bound to MT and TTM were presented, and an appropriate protocol for the chelation therapy was also proposed together with the mechanisms underlying the occurrence of side-effects.
11016632##2000-10-4##Increased mutant frequency and altered mutation spectrum of the lacI transgene in Wilson disease rats with hepatitis.##The mutant strain Long-Evans Cinnamon (LEC) rat, which accumulates copper in the liver because of a mutation in the Atp7b gene, encoding a copper-ATPase, is a model of Wilson disease. It spontaneously develops hepatitis, and subsequently hepatocellular carcinoma and cholangiofibrosis. Excess intracellular copper has been thought to induce DNA damage through reactive oxygen species produced by Cu (II)/Cu (I) redox cycling, and also by direct interaction with DNA. We have developed lacI transgenic Wilson disease (WND-B) rats by mating LEC with Big Blue F344 rats carrying a lambda shuttle vector harboring the lacI gene. lacI mutations of the livers of C-B heterozygous (Atp7b w/m, lacI) and WND-B homozygous (Atp7b m/m, lacI) rats at 6, 24, and 40 weeks of ages were analyzed. Mutant frequencies in the WND-B rats were 2.0 +/- 0.7 x 10(-5), 5.3 +/- 0.9 x 10(-5), and 5.3 +/- 1.0 x 10(-5), respectively, significantly higher than those of C-B rats. Nucleotide sequence analysis revealed that the frequency of deletion mutations of more than two nucleotides were much higher, 15% in WND-B rats, but only 2% in C-B rats. In addition, the average size of deletion was larger in the former. Loss of oligonucleotide-repeat units was specific and relatively frequent in WND-B rats. This type of mutation might be implicated in the induction of DNA strand scissions by reactive oxygen species. These findings suggest that the increase in mutant frequencies and/or the specific type of mutation according to copper accumulation play a crucial role in hepatocarcinogenesis in LEC rats.
10973814##2000-9-7##Copper does not alter the intracellular distribution of ATP7B, a copper-transporting ATPase.##Wilson's disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion. However, the mechanism of biliary copper excretion has not been fully clarified. We examined the effect of copper on the intracellular localization of the Wilson disease gene product (ATP7B) and green fluorescent protein (GFP)-tagged ATP7B in a human hepatoma cell line (Huh7). The intracellular organelles were visualized by fluorescence microscopy. GFP-ATP7B colocalized with late endosome markers, but not with endoplasmic reticulum, Golgi, or lysosome markers in both the steady and copper-loaded states. ATP7B mainly localized at the perinuclear regions in both states. These results suggest that the main localization of ATP7B is in the late endosomes in both the steady and copper-loaded states. ATP7B seems to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes.
11071101##2000-11-9##DNA haplotype analysis for the diagnosis of Wilson disease in siblings.##
11054133##2000-10-29##Frequency of His1069Gln and Gly1267Lys mutations in Polish Wilson's disease population.##Wilson's disease is an autosomal recessive disorder. More than 60 mutations of the Wilson's disease gene have been described so far. We have analysed 148 Polish Wilson's disease patients from 95 families for His1069Gln and Gly1267Lys mutations and correlated this finding with age and clinical form of the disease at presentation. To identify these mutations, single strand conformation polymorphism analysis was performed. In our group there were 94 patients with neurological presentation, 28 with hepatic presentation, whilst 26 were in a pre-clinical stage of the disease. His1069Gln mutation was present on 171 (57%) of the 296 studied chromosomes, and Gly1267Lys mutation was present on 27 chromosomes (9.1%). Most of our patients were homozygous or heterozygous for His1069Gln mutation (39.9% and 30.4%, respectively); 4% of the patients were homozygous for Gly1267Lys mutation and 5.4% had both of these described mutations on their chromosomes. His1069Gln and Gly1267Lys mutations occurred often in our Wilson's disease patient population but we did not find any relationship between investigated mutations and the clinical form of Wilson's disease or age of first symptoms.
11054132##2000-10-29##The level of serum lipids, vitamin E and low density lipoprotein oxidation in Wilson's disease patients.##
11054129##2000-10-29##Juvenile parkinsonism: a heterogeneous entity.##We studied the clinical features, laboratory investigation, management and natural history of a cohort of patients with Juvenile Parkinsonism (JP), seen at a tertiary referral centre. JP was defined as Parkinsonism with onset at age 20 years or less. Six patients (five male, one female) entered the study. The mean age at onset of Parkinsonism was 12.5 years (range 7-19) and the mean follow-up time was 49.3 months (range 40-57). Bradykinesia, rigidity, and postural instability were observed in all patients and five subjects had tremor. Dystonia was present in four subjects. Other clinical features were dementia (five subjects), supranuclear ophthalmoparesis (five subjects), seizures (three subjects), multifocal myoclonus (one subject), decreased deep reflexes (one subject), pyramidal signs (one subject). Family history of Parkinson's disease (PD) was positive in one subject. Work-up for Wilson's disease was negative in all patients. Neuroimaging studies showed cortical atrophy in two subjects and mild brainstem atrophy in two others. Sea-blue histiocytes were found in one subject. L-dopa improved the Parkinsonism in all subjects but four rapidly developed fluctuations and dyskinesias, requiring, in one, stereotaxic surgery. After a mean disease duration of 6.5 years, five subjects require assistance for performance of all daily activities. JP is a heterogeneous clinical entity. In the majority of patients, no underlying cause is identified. The unusual clinical features suggest most subjects have a CNS degenerative disease distinct from PD. There is, however, evidence suggesting that PD may rarely cause JP. Gangliosidosis is another cause of L-dopa-responsive JP. Regardless of the cause, in the present study JP displays an aggressive and rapidly progressive course in most patients.
10982773##2000-9-13##Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion.##
10980554##2000-9-12##Three novel mutations, c314C>A, C778insC, and c1285+2T>A, in exon 2 of the Wilson disease gene.##
10940034##2000-8-12##Role of a Candida albicans P1-type ATPase in resistance to copper and silver ion toxicity.##Copper ion homeostasis is complicated in that copper is an essential element needed for a variety of cellular processes but is toxic at excess levels. To identify Candida albicans genes that are involved in resistance to copper ion toxicity, a library containing inserts of C. albicans genomic DNA was used to complement the copper sensitivity phenotype of a Saccharomyces cerevisiae cup1Delta strain that is unable to produce Cup1p, a metallothionein (MT) responsible for high-level copper ion resistance. A P1-type ATPase (CPx type) that is closely related to the human Menkes and Wilson disease proteins was cloned. The gene encoding this pump was termed CRD1 (for copper resistance determinant). A gene encoding a 76-amino-acid MT similar to higher eukaryotic MTs in structure was also cloned, and the gene was termed CRD2. Transcription of the CRD1 gene was found to increase upon growth with increasing copper levels, while the CRD2 mRNA was expressed at a constant level. Strains with the CRD1 gene disrupted were extremely sensitive to exogenous copper and failed to grow in medium containing 100 microM CuSO(4). These crd1 strains also exhibited increased sensitivity to silver and cadmium, indicating that Crd1p is somewhat promiscuous with respect to metal ion transport. Although strains with the CRD2 gene disrupted showed reduced growth rate with increasing copper concentration, the crd2 mutants eventually attained wild-type levels of growth, demonstrating that CRD2 is less important for resistance to copper ion toxicity. Crd1p is the first example of a eukaryotic copper pump that provides the primary source of cellular copper resistance, and its ability to confer silver resistance may enhance the prevalence of C. albicans as a nosocomial pathogen.
11045386##2000-10-25##Penicillamine induced lupus-like syndrome: a case report.##Several drugs have been suggested to cause lupus-like syndrome. However, penicillamine-induced lupus-like syndrome has only rarely been reported in patients with Wilson's disease. We describe a 6- year-old Taiwanese girl, with a diagnosis of Wilson's disease in November, 1997, who developed lupus-like syndrome 17 months after penicillamine treatment. After treatment with prednisolone and decrease in the dose of penicillamine, her symptoms subsided gradually. This is the first such case reported in a Taiwanese patient. Because the symptoms of drug-induced lupus (DIL) are nonspecific, subjective and variable, the diagnosis of DIL requires awareness of DIL-inducing potential of chronic medication.
10945806##2000-8-17##Repetitive speech phenomena in Parkinson's disease.##
11041671##2000-10-21##Transplant livers in Wilson's disease for hepatic, not neurologic, indications.##
10966647##2000-8-31##Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins.##The Hah1 metallochaperone protein is implicated in copper delivery to the Menkes and Wilson disease proteins. Hah1 and the N-termini of its target proteins belong to a family of metal binding domains characterized by a conserved MT/HCXXC sequence motif. The crystal structure of Hah1 has been determined in the presence of Cu(I), Hg(II), and Cd(II). The 1.8 A resolution structure of CuHah1 reveals a copper ion coordinated by Cys residues from two adjacent Hah1 molecules. The CuHah1 crystal structure is the first of a copper chaperone bound to copper and provides structural support for direct metal ion exchange between conserved MT/HCXXC motifs in two domains. The structures of HgHah1 and CdHah1, determined to 1.75 A resolution, also reveal metal ion coordination by two MT/HCXXC motifs. An extended hydrogen bonding network, unique to the complex of two Hah1 molecules, stabilizes the metal binding sites and suggests specific roles for several conserved residues. Taken together, the structures provide models for intermediates in metal ion transfer and suggest a detailed molecular mechanism for protein recognition and metal ion exchange between MT/HCXXC containing domains.
11376358##2001-5-29##Catalase evaluation in different human diseases associated with oxidative stress.##
10942420##2000-8-15##Copper-dependent trafficking of Wilson disease mutant ATP7B proteins.##We have previously developed a functional assay in yeast for the copper transporter, ATP7B, defective in Wilson disease (WND). Analysis of WND variant ATP7B proteins revealed that several were able to completely, or nearly completely, complement a mutant yeast strain in which the ATP7B ortholog CCC2 was disrupted, indicating that these ATP7B proteins retained copper transport activity. We analyzed the intracellular localization of these active WND ATP7B variant proteins using transient transfection of Chinese hamster ovary cells and triple-label immunofluorescence microscopy, as a second possible aspect of defective function. Two ATP7B variants, Asp765Asn and Leu776Val, which have normal copper transport activity in yeast, retained partial normal Golgi network localization, but were predominantly mislocalized throughout the cell. Asp765Asn and Leu776Val proteins were capable of only partial copper-dependent redistribution. WND variant protein Arg778Leu, which has defective function in yeast, was extensively mislocalized, presumably to the endoplasmic reticulum. ATP7B variant proteins Gly943Ser, which has nearly normal function in yeast, and CysProCys/Ser (mutation of the conserved CysProCys motif to SerProSer), inactive in yeast, were localized normally but were unable to redistribute in response to copper. Localization data from this study, combined with functional data from our yeast studies, provide a biochemical mechanism that can explain in part the variable biochemical features of WND, in particular the normal holo-ceruloplasmin levels observed in some patients. Our data have direct implications for WND diagnosis, indicating that decreased serum ceruloplasmin concentration is not likely to be observed with certain genetic variants of WND.
10981891##2000-9-12##Oxidative-phosphorylation defects in liver of patients with Wilson's disease.##
10949533##2000-8-19##Correlation of neurological manifestations and MR images in a patient with Wilson's disease after liver transplantation.##Orthotopic liver transplantation (OLT) has been applied to patients with Wilson's disease (WD) for correction of irreversible liver cirrhosis. However, the neurological outcome and the correlation between clinical manifestations and neuroimage findings after OLT remain uncertain. We present a WD patient who showed an improvement in both liver functions and neurological manifestations after OLT. Serum levels of ceruloplasmin and copper returned to normal rapidly after the operation. His ataxic gait was improved 5 months later and dysmetria and tremor disappeared 11 months later. The high signal intensities on T2-weighted brain magnetic resonance images regressed at bilateral thalami 5 months later and disappeared in bilateral thalami and red nuclei 16 months after OLT. We conclude that the neurological improvement could be expected in WD patients after OLT. The improvement was correlated with the MRI changes in red nuclei and bilateral thalami.
11177225##2001-2-15##Biological functions of ceruloplasmin and their deficiency caused by mutation in genes regulating copper and iron metabolism.##Ceruloplasmin, a multicopper ferroxidase, is involved in iron and copper homeostasis and integrates these metabolic pathways. Impaired biosynthesis of ceruloplasmin caused by gene mutations disturbs iron metabolism with iron deposition in different organs, especially in the basal ganglia, and severe neuronal damage. Dysfunction of ATP7B, a copper-transporting ATPase leads to the development of Wilson's disease, i.e., multiple abnormalities in copper metabolism associated with reduced synthesis of holoceruloplasmin and biliary copper excretion controlled by both proteins. The lowest content of serum ceruloplasmin is observed in the most grave early neurological form of Wilson's disease (according to N. V. Konovalov's classification), which confirms the important role of ceruloplasmin in the striatal metabolism of catecholamines.
11004765##2000-9-27##[Living donor liver transplantation in Kyushu University].##We performed living donor liver transplantation (LDLT) for 40 patients at Kyushu University Hospital, Fukuoka Japan during the period from October 1996 to April 2000. The patients consisted of 32 adults and 8 children with a mean age of 35.8 years (range: 1 year and 10 months to 65 years old). The underlying liver diseases of the 40 patients included the fulminant hepatic failure (n = 14), biliary atresia (n = 7), liver cirrhosis (HCV) (n = 6), primary biliary cirrhosis (n = 5), primary sclerosing cholangitis (n = 2), familiar amyloidotic polyneuropathy (n = 2), Alagille syndrome (n = 1), glycogen storage disease (n = 1), huge hepatic hemangiomas (n = 1), and Wilson's disease (n = 1). All liver grafts were obtained from each patient's family members except for one domino transplant donor's case, comprised of 13 parents, 13 sons and daughters, 11 brothers and sisters, and 3 wives. The donors are presently all doing well. The patient survival rate is presently 92.5%.
10931244##2000-8-10##Massive hepatic haemosiderosis in Wilson's disease.##
10944815##2000-8-17##Distribution of patients with Wilson disease carrying the H1069Q mutation in Austria.##
10994503##2000-9-20##[Analysis of mutations and haplotypes of polymorphic markers in patients with Wilson-Konovalov disease from Bashkir].##Mutations of the Wilson disease (WD) gene were studied in patients from Bashkortostan. Four mutations were identified: His1069Gln, 3402delC, Glu1064Lys, and 3559 + 1G-->T. The latter mutation was described for the first time. Mutation His1069Gln was found to be the most prevalent in Bashkortostan; its frequency was 43.5%. The associations of the mutations found with the haplotypes for polymorphic loci D13S316, D13S133, and D13S228 were studied. The mutations were found to be linked with specific haplotypes, and the study of polymorphic haplotypes can therefore facilitate the search for mutations in the gene for WD. The results of the molecular genetic study of WD can be used for direct and indirect DNA diagnostics of this disease in Bashkortostan.
21407963##2011-3-17##Wilson'S disease presenting with obsessive-compulsive disorder.##Wilson's disease, a disorder of copper metabolism, is known to be associated with psychiatric symptoms. Psychiatrists see about 20% of these cases before they are labeled as Wilson's disease. Reports of these patients treated mistakenly as primary psychiatric illnesses exist in literature. This report thus emphasizes a thorough underpinning in this disease on the part of psychiatrists in order to arrive at the correct diagnosis at first contact. Besides this, the emergence of obsessive-compulsive symptoms in a case of Wilson's disease is described, which is a rare association. Finally, the authors discuss the role of basal ganglia in obsessive-compulsive disorder.
10979329##2000-9-9##Hereditary juvenile-onset craniocervical predominant generalized dystonia with parkinsonism.##
10864623##2000-6-23##Sunflower cataract in Wilson's disease.##
10896082##2000-7-15##Wilson disease: diagnostic dilemmas?##
10856972##2000-6-17##Absence of linkage between radiosensitivity and the predisposing atp7b gene mutation for heritable hepatitis in the LEC rat.##The LEC rat is known to be a mutant strain that spontaneously develops heritable hepatitis due to copper accumulation, caused by mutation of the copper-transporting ATPase gene (Atp7b). Immunodeficiency and radiosensitivity have also been observed. Hayashi et al. extensively examined the radiosensitivity of the LEC rat and concluded that its hypersensitivity is controlled by a single autosomal gene. Furthermore, they suggested the possibility that it correlates to copper accumulation due to the Atp7b gene mutation, because ionizing radiation-induced hydroxyl radicals might act in concert with copper-induced hydroxyl radicals. In the present experiment, we analyzed linkage between radiosensitivity and the mutation responsible for hepatitis in F(1) animals of a cross with the F344 rat. Our results clearly demonstrated an absence of any significant association. In addition, partial dominance for radiosensitivity was observed, and radiosensitive (F(1) x LEC) backcross rats were twice as numerous as their radioresistant counterparts, suggesting the possibility of control by two or more recessive genes.
10856939##2000-6-17##Energetics in the pathogenesis of neurodegenerative diseases.##Mitochondria have been linked to both necrotic and apoptotic cell death, which are thought to have a major role in the pathogenesis of neurodegenerative diseases. Recent evidence shows that nuclear gene defects affecting mitochondrial function have a role in the pathogenesis of Friedreich's ataxia, Wilson's disease and hereditary spastic paraplegia. There is also accumulating evidence that mitochondrial dysfunction might have a role in the pathogenesis of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease. If this is so, a number of therapeutic targets are implicated that might result in novel treatments for neurodegenerative diseases.
11105631##2000-12-6##Acute lymphoblastic leukemia in a child with Wilson disease.##Wilson disease is an autosomal recessively inherited disease of copper metabolism and is characterized by liver and central nervous system dysfunction. The heterozygote carrier state rate is about one in 90 persons and the incidence of the disease is about 30 in 1,000,000. Although leukemia is the most common form of childhood malignancies, the probability of the presence of Wilson disease and acute lymphoblastic leukemia in the same patient is very low. We report an unusual case of a child with Wilson disease who developed acute lymphoblastic leukemia in three months.
10858308##2000-6-20##Inhibition of carboxypeptidase A by D-penicillamine: mechanism and implications for drug design.##Zinc metalloprotease inhibitors are usually designed to inactivate the enzyme by forming a stable ternary complex with the enzyme and active-site zinc. D-Cysteine inhibits carboxypeptidase, ZnCPD, by forming such a complex, with a K(i) of 2.3 microM. In contrast, the antiarthritis drug D-penicillamine, D-PEN, which differs from D-Cys only by the presence of two methyl groups on the beta-carbon, inhibits ZnCPD by promoting the release of the active-site zinc. We have given the name catalytic chelator to such inhibitors. Inhibition is a two-step process characterized by formation of a complex with the enzyme (K(i(initial)) = 1.2 mM) followed by release of the active-site zinc at rates up to 420-fold faster than the spontaneous release. The initial rate of substrate hydrolysis at completion of the second step also depends on D-PEN concentration, reflecting formation of a thermodynamic equilibrium governed by the stability constants of chelator and apocarboxypeptidase for zinc (K(i(final)) = 0.25 mM). The interaction of D-PEN and D-Cys with the active-site metal has been examined by replacing the active-site zinc by a chromophoric cobalt atom. Both inhibitors perturb the d-d transitions of CoCPD in the 500-600 nm region within milliseconds of mixing but only the CoCPD.D-Cys complex displays a strong S --> Co(II) charge-transfer band at 340 nm indicative of a metal-sulfur bond. While the D-Cys complex is stable, the CoCPD.D-PEN complex breaks down to apoenzyme and Co(D-PEN)(2) with a half-life of 0.5 s. D-PEN is the first drug found to inhibit a metalloprotease by increasing the dissociation rate constant of the active-site metal. The ability of D-PEN to catalyze metal removal from carboxypeptidase A and other zinc proteases suggests a possible mechanism of action in arthritis and Wilson's disease and may also underlie complications associated with its clinical use.
10871381##2000-6-28##PCR-generated padlock probes detect single nucleotide variation in genomic DNA.##Circularizing oligonucleotide probes, so-called padlock probes, have properties that should prove valuable in a wide range of genetic investigations, including in situ analyses, genotyping and measurement of gene expression. However, padlock probes can be difficult to obtain by standard oligonucleotide synthesis because they are relatively long and require intact 5'- and 3'-end sequences to function. We describe a PCR-based protocol for flexible small-scale enzymatic synthesis of such probes. The protocol also offers the advantage over chemical synthesis that longer probes can be made that are densely labeled with detectable functions, resulting in an increased detection signal. The utility of probes synthesized according to this protocol is demonstrated for the analysis of single nucleotide variations in human genomic DNA both in situ and in solution.
10877157##2000-7-6##Procreation ability in Wilson's disease.##
10852553##2000-6-14##Changes of copper-transporting proteins and ceruloplasmin in the lentiform nuclei in primary adult-onset dystonia.##A recent study reported an increase of brain tissue copper content in the lentiform nuclei of patients with primary adult-onset dystonia. In this study we analyze copper-metabolizing proteins (Menkes protein, Wilson protein, ceruloplasmin) by Western blot analysis in frozen brain tissue (lentiform nuclei) of 3 patients with primary dystonia. Menkes protein was reduced in all patients, while Wilson protein and ceruloplasmin were increased in the 2 patients with focal dystonia and reduced in the patient with generalized dystonia. Our data provides further evidence for a disturbance of copper metabolism in primary dystonia.
10925743##2000-8-5##Hereditary disorders mimicking and/or causing premature osteoarthritis.##Osteoarthritis is the most common joint disease, causing considerable disability and impairment of quality of life. Hereditary osteochondrodysplasias and some inborn errors of metabolism may mimic or cause premature osteoarthritis. Osteochondrodysplasias usually cause joint deformities, such as coxa vara or genu varum, which can cause abnormal biomechanics. In most of these disorders, the articular cartilage is originally defective as a result of genetically determined collagen or matrix protein abnormalities, or the deposition of mucopolysaccharides. In the case of inborn errors of metabolism, the pathological process affects healthy articular structures, causing secondary osteoarthritis. In alkaptonuria, the pathological deposition of polymerized homogenistic acid causes defective changes in cartilage, articular capsule and tendons. In Wilson's disease, the premature osteoarthritis might be caused by the copper deposition. It is worth paying attention to these rare disorders, even when they are mild or incomplete, because early diagnosis can lead to prevention and effective treatment. In addition, research is discovering the specific gene defects and molecular abnormalities that are responsible for disease expression. This may in turn lead to opportunities for prenatal diagnosis; thus, genetic counselling and gene replacement therapy may be a realistic possibility in the near future.
10962511##2000-8-30##Copper toxicity affects proliferation and viability of human hepatoma cells (HepG2 line).##In Wilson's disease and Indian childhood cirrhosis (ICC) copper accumulates in the liver resulting in poor hepatocyte regeneration and fibrosis. An inhibition of hepatocyte proliferation and an increase in cell death could account for these outcomes. To establish how the toxicity of this metal ion impacts upon the proliferation and viability of the HepG2 cells they were cultured in 4-32 microM copper(II) sulphate (CuSO4)). These levels were comparable to the circulatory and tissue concentrations of copper recorded for these two diseases. Specific uptake comparable to levels of copper recorded in the livers of patients with Wilson's disease and ICC was measured in the HepG2 cells. After 48 h acid vesicle function increased from 4 to 32 microM Cu2+ but significantly declined at 64 microM compared to the controls. Lysosomal acid phosphatase showed a concentration dependent decline in activity at 72 h. Cellls exposed to 64 microM Cu2+ had a potential doubling time (Tpot) 21 h longer than the control cells due to a prolonged DNA synthesis phase. At 64 microM Cu2+, increases of necrosis up to 18% were seen whereas comparable levels of apoptotic and necrotic cells (<5%) were seen below this concentration. Chronic exposure over 8 weeks impaired colony-forming efficiency at concentrations of 16 microM Cu2+ and above. This study suggests that when liver cells sequester large amounts of copper, the toxic effects include delayed cell-cycle progression, a gradual loss of replicative capacity, and an increased incidence of cell death.
10869138##2000-6-27##Wilson's disease--early onset and lessons from a pediatric cohort in India.##
10879086##2000-7-6##[Two recovery cases of Wilson's disease initiated with severe hemolysis and acute hepatic failure].##
11086396##2000-11-22##[A young adult female case of Wilson's disease presenting with mental disorder and frontal lobe signs].##We report a young adult female case of Wilson's disease presenting with mental disorder and frontal lobe signs. The patient was admitted to our neurological unit on October 4, 1999 because of schizophrenia-like symptom, dysphagia, dysarthria and gait disturbance. She showed slowly progressive rigidity and dystonia. Her parents were the second cousins. Neurological examination revealed bilateral pyramidal and extrapyramidal signs, frontal lobe signs (include the imitation behavior). Tendon reflexes were slightly exaggerated in all extremities. Bilateral Babinski, Chaddock and Hoffmann signs were positive. Her verbal IQ on the Wechsler Adult Intelligence Scale-revised was 49. Biochemical examination revealed low plasma copper and ceruloplasmin concentration. Cerebrospinal fluid was normal. Cranial MRI demonstrated diffuse brain atrophy and enlargement of the lateral ventricles. T2-weighted images of the MRI demonstrated hyperintense signal in both thalamus and basal ganglia. SPECT showed hypoperfusion in the left frontal lobe, both thalamus and basal ganglia. EEG revealed diffuse theta wave. The diagnosis of Wilson's disease was made and the treatment of D-penicillamine 900 mg per day was started. This hypoperfusion of SPECT and EEG findings improved after 2 months under D-penicillamine therapy. Neurological findings showed slight improvement. A few Wilson's disease patients presenting with mental disorder have been reported. Wilson's disease should always be considered in differential diagnosis of mental disorders. We emphasize the importance of early diagnosis and treatment of Wilson's disease.
11051587##2000-10-29##Comparative efficacy of several potential treatments for copper mobilization in copper-overloaded rats.##D-Penicillamine (DPA) is effective in the treatment of Wilson's disease, whereas zinc salts are also used as a therapy for this disorder of copper transport. Recently, it has been shown that the copper chelators 1,4,7,11-tetraazaundecane tetrahydrochloride (TAUD) and tetraethylenepentamine pentahydrochloride (TETREN) could be useful for copper mobilization in rats. Because these agents could be potential clinical alternatives to DPA for patients with Wilson's disease who are intolerant to this drug, we examined whether oral administration of TAUD and TETREN could be effective in mobilizing copper in experimental copper-overloaded rats. The efficacy of a combined administration of zinc and DPA, TAUD, or TETREN was also assessed. Rats were copper loaded with 0.125% copper acetate in water for 12 wk. After this period, DPA, TAUD, and TETREN were administered by gavage at 0.67 mmol/kg/d for 5 d, and zinc was given at 2.5 mg Zn/kg/d. Twelve weeks of copper loading resulted in a 32-fold increase in total hepatic copper. TETREN was the most effective chelator in increasing the urinary excretion of copper. However, it did not reduce significantly the hepatic copper levels. In turn, combined administration of zinc and chelating agents significantly reduced the amount of copper found in the feces. Although TAUD and TETREN showed a similar or higher efficacy to DPA in mobilizing copper, concurrent treatment of chelating agents and zinc salts should be discarded according to the current results.
17023879##2006-10-7##Inherited metabolic disease.##This review focuses on two genetic disorders of metal metabolism, genetic hemochromatosis and Wilson disease, and on the most common lysosomal storage disorder, Gaucher disease, for which recombinant enzyme replacement therapy is available. The discovery of the genes for these disorders has led to an explosion of new information about the function of these gene products and the identification of other proteins involved in their metabolism. These discoveries have altered our current diagnostic and therapeutic approaches to these disorders and have furthered our understanding of disease pathophysiology. New modalities being developed for future use include cell transplant and genetic replacement therapies.
11096754##2000-11-30##Dystonia.##Therapy for most people with dystonia is symptomatic, directed at lessening the intensity of the dystonic contractions. For a small minority of patients (eg, those with dopa-responsive dystonia, Wilson's disease, or psychogenic dystonia), specific therapy directed at one of the many causes of dystonia is available. Before initiating treatment, clinicians need to decide if a patient has a form of dystonia amenable to such therapy. The most sensitive and least costly method to diagnose DRD is a therapeutic trial of levodopa. It is, therefore, recommended to treat all those with dystonia beginning in childhood or adolescence with low-dose levodopa. For patients with generalized or segmental signs who do not respond to levodopa, other oral medications, including anticholinergics, baclofen, and benzodiazepines, may provide mild to moderate relief; these medications are often given in combinations. For those with focal dystonia, most having adult-onset disease, botulinum toxin A injections often effectively control contractions. The injections produce transient weakness and need to be repeated, generally every 3 to 5 months. There is growing renewed interest in surgical treatment. Peripheral denervating procedures may be helpful for patients with torticollis who do not obtain adequate benefit with botulinum toxin A. The central procedures of pallidotomy and pallidal stimulation are under study; their place in the treatment of the many dystonia subtypes (eg, limb vs axial, generalized vs focal, primary vs secondary) still needs to be established. There are very few studies evaluating physical and psychological therapies or the impact of diet or lifestyle in dystonia. Most clinicians consider physical therapy, including massage, a potential adjunct to medical therapy, and psychological support and stress reduction may help individuals cope with this chronic and frequently disabling condition.
11096747##2000-11-30##Wilson's Disease.##Appropriate anticopper therapy for Wilson's disease is the critical element in halting progression of the disease and allowing patient recovery. Selection of the drug or drugs to use for a particular patient depends on the stage of the disease (ie, initial acutely ill patient versus chronic maintenance patient) and the type of presentation (ie, neurologic/psychiatric versus hepatic). I treat patients initially presenting with hepatic disease with a combination of zinc and trientine, those presenting with neurologic/psychiatric disease with tetrathiomolybdate, and those in the maintenance phase with zinc.
10784591##2000-4-28##Role of ATP7B in biliary copper excretion in a human hepatoma cell line and normal rat hepatocytes.##
10847448##2000-6-10##Wilson's disease with superimposed autoimmune features: report of two cases and review.##We describe two females, 15 and 23 years old, respectively, who presented with classical features of Wilson's disease (WD) and several features of autoimmune hepatitis (AIH). The first patient was initially diagnosed as AIH and treated with prednisolone which caused clinical improvement, with an increase of serum albumin from 22 to 30 g/L, and a decrease of aspartate aminotransferase from 103 to 47 U/L. Subsequent diagnosis of WD and introduction of penicillamine gave excellent improvement and complete normalization of liver function tests. The second patient, at first also diagnosed as having AIH, was treated with steroids and azathioprine with initial improvement, but subsequent deterioration. The diagnosis of WD was made 2 years after initial diagnosis of AIH, as the patient reached end-stage liver disease and required a transplant. Therefore, d-penicillamine treatment was not attempted. We conclude that, in patients with AIH, a thorough screening for WD is necessary, particularly when the response to steroid therapy is poor. Conversely, in patients suffering from WD with superimposed features of AIH, a combination of steroids and penicillamine may be of benefit.
10865087##2000-6-24##Visual pathway abnormalities Wilson's disease: an electrophysiological study using electroretinography and visual evoked potentials.##The pathogenesis of the pattern reversal visual evoked potential (PRVEP) abnormalities in patients with Wilson's disease (WD) has not been investigated earlier. Since electroretinography (ERG) assesses the functional integrity of the retina, it was used along with PRVEP to localize the abnormalities in PRVEP in Wilson's patients. Ten newly diagnosed Wilson's disease patients underwent PRVEP and flash ERG soon after the diagnosis was established. The PRVEP latencies were prolonged in comparison with the controls (P<0.001). Photopic and scotopic A waves and oscillatory potentials were prolonged (P<0. 02) with reduction in amplitudes of photopic A and B waves (P<0.001). Six of these patients were subjected to repeat PRVEP and flash ERG after the clinical improvement with specific therapy. Comparison of the pre and post-treatment visual electrophysiological studies revealed significant reduction in latencies of PRVEP and flash ERG A wave (P<0.05) with increase in amplitudes of P100 of PRVEP (P<0.05), A and B waves of flash ERG (P<0.01). These findings confirm the reported PRVEP changes in WD and in addition demonstrate the reversibility of the retinal dysfunction which partially contributes to the PRVEP abnormalities. To the best of our knowledge this is the first study of ERG in patients with Wilson's disease in the literature. Further, there have been no earlier reports in the literature evaluating the effect of specific treatment on the PRVEP and ERG in Wilson's disease.
10809192##2000-5-16##Increased cerebral iron uptake in Wilson's disease: a 52Fe-citrate PET study.##
10767723##2000-4-18##Transplanted hepatocytes engraft, survive, and proliferate in the liver of rats with carbon tetrachloride-induced cirrhosis.##Repopulation of the cirrhotic liver with disease-resistant hepatocytes could offer novel therapies, as well as systems for biological studies. Establishing whether transplanted hepatocytes can engraft, survive, and proliferate in the cirrhotic liver is a critical demonstration. Dipeptidyl peptidase IV-deficient F344 rats were used to localize transplanted hepatocytes isolated from the liver of syngeneic normal F344 rats. Cirrhosis was induced by administration of carbon tetrachloride with phenobarbitone and these drugs were withdrawn prior to cell transplantation. Cirrhotic rats showed characteristic hepatic histology, as well as significant portosystemic shunting. When hepatocytes were transplanted via the spleen, cells were distributed immediately in periportal areas, fibrous septa, and regenerative nodules of the cirrhotic liver. Although some transplanted cells translocated into pulmonary capillaries, this was not deleterious. At 1 week, transplanted cells were fully integrated in the liver parenchyma, along with expression of glucose-6-phosphatase and glycogen as reporters of hepatic function. Transplanted cells proliferated in the liver of cirrhotic animals and survived indefinitely. At 1 year, transplanted hepatocytes formed large clusters containing several-fold more cells than normal control animals, which was in agreement with increased cell turnover in the cirrhotic rat liver. The findings indicate that the cirrhotic liver can be repopulated with functionally intact hepatocytes that are capable of proliferating. Liver repopulation using disease-resistant hepatocytes will be applicable in chronic conditions, such as viral hepatitis or Wilson's disease.
10879022##2000-7-6##["Parkinson symptoms" with hepatopathy. Wilson disease].##
10760584##2000-4-13##Cloning, mapping and expression analysis of the sheep Wilson disease gene homologue.##Copper homeostasis in mammals is maintained by the balance of dietary intake and copper excretion via the bile. Sheep have a variant copper phenotype and do not efficiently excrete copper by this mechanism, often resulting in excessive copper accumulation in the liver. The Wilson disease protein (ATP7B) is a copper transporting P-type ATPase that is responsible for the efflux of hepatic copper into the bile. To investigate the role of ATP7B in the sheep copper accumulation phenotype, the cDNA encoding the ovine homologue of ATP7B was isolated and sequenced and the gene was localised by fluorescence in situ hybridisation to chromosome 10. The 6.3 kb cDNA encoded a predicted protein of 1444 amino acids which included all of the functional domains characteristic of copper transporting P-type ATPases. ATP7B mRNA was expressed primarily in the liver with lower levels present in the intestine, hypothalamus and ovary. A splice variant of ATP7B mRNA, which was expressed in the liver and comprised approximately 10% of the total ATP7B mRNA pool, also was isolated. The results suggest that ATP7B is produced in the sheep and that the tendency to accumulate copper in the liver is not due to a gross alteration in the structure or expression of ATP7B.
10770529##2000-4-19##Hypersomnia in Wilson's disease: an unusual symptom in an unusual case.##Wilson's disease (WD) shows a wide heterogeneity in symptoms. In this case report we present hypersomnia as a symptom of WD. The male patient's complaints as fatigue, decreased level of concentration, and highly increased demand of sleeping started at his age of 21 years. No abnormality was found at physical examination. A moderate elevation in liver function tests was found, but all the other laboratory findings were within the normal range. The marked hypersomnia was verified by 24-h cassette EEG polisomnographic monitoring. No abnormality was found at physical examination. EEG, brain CT and MRI were normal. Neither toxic nor infectious disease was detectable. The diagnosis of WD was based on decreased coeruloplasmin level, increased baseline and forced urinary excretion of copper, and decreased level of serum copper. Kayser-Fleischer ring was not detectable. D-penicillamine (DPA) was introduced. At 8-10 months after the initiation of the therapy the patient's complaints gradually resolved. The control sleep record 14 months after the initiation of the DPA therapy was normal. Five years later the patient is currently on penicillamine treatment and he is free of any symptom.
10759239##2000-4-12##Wilson's disease presented with fulminating hepatic failure in children.##
10782921##2000-4-27##Undetectable serum caeruloplasmin in a woman with chronic hepatitis C infection.##There are many causes of a low serum caeruloplasmin. Not only may this be a feature of Wilson's disease, but a low level may be found in association with chronic liver disease of any cause. We report here a case where undetectable serum caeruloplasmin was found during routine investigation of a woman with hepatitis C viral infection.
10830865##2000-6-1##Copper transport and its defect in Wilson disease: characterization of the copper-binding domain of Wilson disease ATPase.##Copper is an essential trace element which forms an integral component of many enzymes. While trace amounts of copper are needed to sustain life, excess copper is extremely toxic. An attempt is made here to present the current understanding of the normal transport of copper in relation to the absorption, intracellular transport and toxicity. Wilson disease is a genetic disorder of copper transport resulting in the accumulation of copper in organs such as liver and brain which leads to progressive hepatic and neurological damage. The gene responsible for Wilson disease (ATP7B) is predicted to encode a putative copper-transporting P-type ATPase. An important feature of this ATPase is the presence of a large N-terminal domain that contains six repeats of a copper-binding motif which is thought to be responsible for binding this metal prior to its transport across the membrane. We have cloned, expressed and purified the N-terminal domain (approximately 70 kD) of Wilson disease ATPase. Metal-binding properties of the domain showed the protein to bind several metals besides copper; however, copper has a higher affinity for the domain. The copper is bound to the domain in Cu(I) form with a copper: protein ratio of 6.5:1. X-ray absorption studies strongly suggest Cu(I) atoms are ligated to cysteine residues. Circular dichroism spectral analyses suggest both secondary and tertiary structural changes upon copper binding to the domain. Copper-binding studies suggest some degree of cooperativity in binding of copper. These studies as well as detailed structural information of the copper-binding domain will be crucial in determining the specific role played by the copper-transporting ATPase in the homeostatic control of copper in the body and how the transport of copper is interrupted by mutations in the ATPase gene.
10881624##2000-7-6##Aetiological spectrum of chronic liver disease in eastern India.##
10700380##2000-3-4##Spontaneous porphyria of the Long-evans cinnamon rat: an animal model of Wilson's disease.##To confirm and extend our previous microspectrophotometric observations of 30-week-old male Long-Evans Cinnamon (LEC) rats, an animal model of human Wilson's disease, we analyzed the porphyrin patterns of the organs, urine, and plasma of LEC rats. Abnormal accumulation of porphyrins, especially highly carboxylated porphyrins (uro- and heptaporphyrin), in the kidneys and liver was seen in male and female LEC rats aged 30 weeks and also in 10-week-old rats, before the onset of spontaneous hepatic dysfunction. Accumulation of copper and iron in the kidneys was not observed in the 10-week-old rats. Massive accumulation of porphyrins was observed only in the kidneys of the 30-week-old male LEC rat, indicating that this symptom is related to sex and age. Renal accumulation of porphyrins was reflected in the rate of urinary porphyrin excretion. Hepatic accumulation of porphyrins appeared to be independent of sex and age. These results indicate that neither renal nor hepatic porphyrin accumulation is the result of renal deposition of metals or of spontaneous hepatic dysfunction and that porphyrinuria in the LEC rat is closely related to the renal accumulation of porphyrins. In contrast to these organs, a reduction in the porphyrin levels was observed in the brain of the LEC rat. This was independent of sex and age. The present work stresses the existence of an abnormal heme metabolism in the LEC rat, and thus, the necessity to study the heme metabolism in human Wilson's disease is strongly suggested.
10714666##2000-3-14##Effect of liver transplantation on neurological manifestations in Wilson disease.##
10777259##2000-4-25##Pencillamine-induced elastosis perforans serpiginosa and cutis laxa in Wilson's disease.##
10686180##2000-2-25##The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease.##Wilson's disease is a disorder of biliary copper excretion that may result in severe neurological symptoms and advanced liver disease. The wide variation of phenotypic disease expression cannot be fully explained by the different mutations of the Wilson disease gene. In neurological disorders, such as Alzheimer's disease, temporal lobe epilepsy and cerebral trauma, the presence of the apolipoprotein E (ApoE) allele epsilon4 is associated with an increased vulnerability of the brain to the effects of the disease, whereas the presence of the ApoE genotype epsilon3/3 appears to provide moderate neuroprotection. We examined whether this hypothesis holds true for the development of neurological symptoms in patients with Wilson's disease. The ApoE genotype and the H1069Q mutation (the most common in Wilson's disease) status were determined by polymerase chain reaction-based mutation assays in 121 well-characterized, symptomatic index patients with Wilson's disease. An investigation profile was established in which the patients were grouped according to the clinical symptoms at presentation, the ApoE genotypes and the status of the H1069Q mutation. Fifty-nine per cent of the 121 patients had the allele combination ApoE epsilon3/3 (21% ApoE epsilon3/4, 19% ApoE epsilon3/2, 1% ApoE epsilon4/2). The distribution of ApoE genotypes did not deviate from known distributions in healthy European subjects. Within the group of 40 H1069Q-homozygous patients, the onset of symptoms was significantly delayed in patients with the ApoE epsilon3/3 genotype (25 +/- 6 years at presentation) compared with patients with the ApoE epsilon3/4 genotype (20 +/- 3 years at presentation). In this study, the ApoE genotype was established as an important factor delaying the onset of neurological and hepatic symptoms, but not modifying phenotypic disease expression in a homogeneous group of patients with Wilson's disease (all H1069Q-homozygotes, similar genetic background). The presence of ApoE epsilon3/3 attenuates clinical manifestations in Wilson's disease by mechanisms which might involve the antioxidant and membrane-stabilizing properties of the ApoE 3 protein.
10728692##2000-3-23##Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance.##The accumulation of cisplatin is decreased in many cisplatin-resistant cell lines, and an active efflux pump for cisplatin exists in some of them, but it has not yet been identified. In this study, we transfected the copper-transporting P-type ATPase cDNA (ATP7B) into human epidermoid carcinoma KB-3-1 cells. The transfectant, KB/WD cell line, which overexpressed the P-type ATPase, ATP7B, was resistant to both cisplatin (8.9-fold) and copper (2.0-fold). The accumulation of cisplatin in KB/WD cells was lower than in mock-transfected KB/CV cells, and the efflux of cisplatin from KB/WD cells was enhanced compared with KB/CV cells. KB/WD cells were sensitive to other heavy metals, such as antimony, arsenate, arsenite, cadmium, and cobalt. ATP7B was overexpressed in cisplatin-resistant prostate carcinoma PC-5 cells but not in the parental PC-3 cells and the revertant PC-5R cells. ATP7B may be involved in cisplatin resistance in some tumors.
10749290##2000-4-5##An autopsy case with clinically and molecular genetically diagnosed Huntington's disease with only minimal non-specific neuropathological findings.##An autopsy case with clinically and molecular genetically diagnosed Huntington's disease (HD) accompanied with minimal non-specific neuropathological features was reported. When the patient was 45 years old, he had faulty memory, mood swing, personality change and agitation. Neurological and psychiatric examinations revealed choreoathetoid movements in limbs and trunk, generalized hyperreflexia and mental deterioration. However, cerebellar ataxia and muscle rigidity were not disclosed. Neuroimaging study did not show a definite atrophy of heads of caudate nuclei. Neuroacanthocytosis and Wilson's disease were ruled out by the peripheral blood examination and serum Cu and ceruloplasmin examination. At the age of 55 he died of pneumonia. Post-mortem examination revealed minimal non-specific neuropathological features for HD (Vonsattel's grade 0), that is, no visible fibrillary gliosis in the striatum, and few neuronal loss and only proliferation of astrocytes (astrocytosis) in the striatum. Molecular-genetic study the patient's brain tissues and his youngest son's blood was performed. These studies revealed 40 CAG repeats in the patient, 56 CAG repeats in his youngest son. These results suggest they may be HD. Vonsattel et al. [ 1998] insist that grade 0 comprises 1% of all HD brains, and grade 1 comprises 4% of all HD brains. But we could not find any reports in which the clinical and neuropathological features were described in detail on the cases with clinically and molecular genetically diagnosed HD without specific pathological findings. Therefore, we present in detail the clinical and neuropathological features of such case.
10975796##2000-9-7##Wilson's disease with late onset.##
10664223##2000-2-9##Serum liver enzymes in Turner syndrome.##
10673307##2000-2-15##Diagnosis of Wilson's disease: an experience over three decades.##
10857907##2000-6-17##Histochemical characterization of silver-induced metallothionein in rat kidney.##Histochemical characterizations of Ag-induced metallothionein (MT) in the kidney of the rat have been reported. Ag, Cu and Zn contents increased in kidney and liver after Ag injection. In particular, the Cu content in kidneys increased dramatically after three injections of Ag. Sephadex G-75 elution profiles of the renal cytosol of rats injected with Ag revealed that the accumulated Cu in the kidney was bound to MT as were Ag and Zn. In addition, localization of Cu- and Ag-MT in the kidney was studied using autofluorescent signals, which are dependent on Cu- or Ag-thiol clusters, and immunohistochemistry. Although the MT induced by Ag was predominantly observed in the cortex of the kidney, some MT signals were also detected in the outer stripe of the outer medulla, as well as in the kidneys of LEC rats, an animal model of Wilson disease (a hereditary disorder of Cu metabolism). In these LEC rats, the Cu-MT also accumulated in the outer stripe of the outer medulla of the kidney. From these results, one possibility could explain that the Cu-MT detected in the outer stripe of the outer medulla in the kidney of Ag-injected rat was associated with the Cu transporter affected by Ag.
10740076##2000-3-31##[Quid? Wilson's disease].##
10932536##2000-8-10##[Wilson's disease revisited].##
10932534##2000-8-10##[The role of zinc in the initial treatment of Wilson's disease in children].##Wilson's disease (WD) is an inherited disease of copper accumulation, caused by a failure of biliary excretion of excess copper. Accumulated copper causes tissue damage. The chelating drugs penicillamine and trientine have been the mainstay of therapy and most patients with WD were treated with the potentially toxic cupriuretic agents. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool, and long term administration induces a negative copper balance. Until recently, most patients have been treated initially with cupriuretic agents to remove excess of copper, and then maintained with oral zinc. Recently, zinc has been used for initial treatment as well and for treatment of the presymptomatic patients. So far, zinc therapy has demonstrated exceptional efficacy and lack of toxicity. In this article we present our data on the long-term follow-up of three children with WD, whose initial as well as consecutive treatment was zinc sulphate. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient and in initial treatment of symptomatic children with WD. Our data also indicate low toxicity. However, pediatric patients must be closely monitored due to tendency to stop the treatment when becoming asymptomatic.
10705077##2000-3-8##Iron and copper in human milk.##The reported concentrations of iron and copper in breast milk show a wide variation. Research published over the past 50 y has reported median values of 0.47 and 0.32 mg/L for iron and copper, respectively. The levels of both metals decrease with the progress of lactation. The calculated iron-to-copper ratio of reported means differs from 0.25 to 6.29 (median = 1.18). Maternal constitutional variables such as undernutrition, iron and copper body reserves, stage of lactation, adolescent motherhood, gestation length, and infection and environmental variables such as iron and copper dietary intake, in addition to supplementation, smoking, vegetarianism, and prolonged use of hormonal contraceptives before and during lactation did not consistently affect the concentrations of iron and copper in breast milk. Extreme cases of either low or high levels of body metal availability or altered metabolism due to chelating therapy or illnesses such as Wilson's disease and infections did not affect metal transfer from blood serum to breast milk. There is no clinical or scientific support for the need of extra iron or copper, besides the quantities provided by milk in the full-term breast-fed infant, at least during the first 6 mo.
10671678##2000-2-15##Genomic DNA analyses of spontaneous hepatocellular carcinomas in LEC rat liver using a new technique.##An inbred rat strain, LEC (long evans cinnamon) has been used as a model of human Wilson's disease. This animal suffers from a severe type of hepatitis, the clinical manifestations of which are similar to human fulminant hepatitis for 4-5 months which is caused by accumulation of copper in the liver. The surviving rats develop chronic hepatitis, followed by the development of spontaneous hepatoma. In contrast to studies with hepatocellular carcinomas (HCCs), the studies have great advantages in that the animals have identical genetic background, can be raised under a fixed condition, and the development of HCC is reproducible. We took two HCC samples and analysed their genomic DNA using RLGS (restriction landmark genomic scanning), which involves two-dimensional electrophoresis of genomic DNA allowing the survey of some 1,000 NotI sites throughout the genome. Using this technique, we discovered landmark spots that were either decreased or increased in intensity in HCC and compared them with the RLGS profile obtained from the DNA of control normal LEC rat liver. Approximately 1,300 spots were compared, and the intensity of two spots was found to be decreased about half and one was increased 1.3-1.7 folds. Although the mechanism of these changes and the properties of the changed DNA are yet to be studied, recurrent genomic changes in the LEC rat HCC could prove to be a good model system for elucidating the essential genetic events in association with hepatocarcinogenesis.
10677240##2000-2-26##Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase.##The Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death. The ATPase has a novel amino-terminal domain ( approximately 70 kDa) which contains six repeats of the copper binding motif GMTCXXC. We have expressed and characterized this domain with respect to the copper binding sites and the conformational consequences of copper binding. A detailed analysis of this domain by X-ray absorption spectroscopy (XAS) has revealed that each binding site ligates copper in the +1 oxidation state using two cysteine side chains with distorted linear geometry. Analysis of copper-induced conformational changes in the amino-terminal domain indicates that both secondary and tertiary structure changes take place upon copper binding. These copper-induced conformational changes could play an important role in the function and regulation of the ATPase in vivo. In addition to providing important insights on copper binding to the protein, these results suggest a possible mechanism of copper trafficking by the Wilson disease ATPase.
10706009##2000-3-8##Psychopathology in treated Wilson's disease determined by means of CPRS expert and self-ratings.##
10681092##2000-2-19##Wilson's disease.##
10728780##2000-3-23##Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats.##Copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, was removed with ammonium tetrathiomolybdate (TTM), and the fate of the Cu complexed with TTM and mobilized from the liver was determined. TTM was injected intravenously as a single dose of 2, 10 or 50 mg TTM/kg body weight into LEC and Wistar (normal Cu metabolism) rats, and then the concentrations of Cu and molybdenum (Mo) in the bile and plasma were monitored with time after the injection. In Wistar rats, most of the Mo was excreted into the urine, only a small quantity being excreted into the bile, while Cu excreted into the urine decreased. However, in LEC rats, Cu and Mo were excreted into the bile and blood, and the bile is recognized for the first time as the major route of excretion. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo. The relative ratio of the amounts of Cu excreted into the bile and plasma was 40/60 for the low and high dose groups, and 70/30 for the medium dose group. The systemic dispositions of the Cu mobilized from the liver and the Mo complexed with the Cu were also determined for the kidneys, spleen and brain together with their urinal excretion. Although Mo in the three organs and Cu in the kidneys and spleen were increased or showed a tendency to increase, Cu in the brain was not increased at all doses of TTM.
11775546##2002-1-5##Identification of a mutation hotspot in exon 8 of Wilson disease gene by cycle sequencing.##
11232186##2001-3-10##Wilson's disease.##During the last 90 years, Wilson's hepatolenticular degeneration has evolved from a disease presenting insurmountable challenges to the clinician's diagnostic acumen to a metabolic disorder which is diagnosable woth certainty, treatable successfully, and even preventable. It may be long before the genetic defect becomes amenable to correction and a cure of the disease becomes possible.
10726383##2000-3-22##[Steatosis and nonalcoholic steatohepatitis. A comparative analysis].##Liver biopsies with a main histological diagnosis of steatosis were selected from 3,422 liver biopsies carried out in our department between January 1995 and December 1998. Patients with known risk factors for steatosis, such as excessive alcohol consumption, hepatitis C infection, treatment with amiodarone, perhexiline maleate, tamoxifen, antiviral drugs (didanosine, zidovudine) methotrexate, sodium valproate or total parenteral nutrition, Wilson's disease and organ transplant were subsequently excluded. Of the 43 liver biopsies finally included in the study, 23 showed simple steatosis and 20 steatohepatitis. Eighty-one per cent of the patients were male (mean age of 44 years) and the majority were asymptomatic. The most frequent indication for liver biopsy was hypertransaminasemia. No differences were observed between the two groups in terms of frequency and severity of classical risk factors for steatosis (diabetes mellitus, dyslipemia and obesity). Thirty-five percent of patients with steatohepatitis and 26% of those with simple steatosis had none of these risk factors. Patients with steatohepatitis were older than those with simple steatosis. They presented more severe symptomatology, the degree of steatosis was more intense and laboratory investigations showed greater alterations. These results suggest that simple steatosis and nonalcoholic steatohepatitis are two different phases of the same disease. The difficulty in clinical differentiation justifies carrying out liver biopsy, especially in patients with more severe symptomatology whose laboratory results show greater alterations, since these patients present more marked histological lesions, are at risk of developing liver cirrhosis and require therapy.
10655282##2000-2-3##Wilson's disease and pregnancy.##
10655259##2000-2-3##Treatment of Wilson's disease with zinc. XVII: treatment during pregnancy.##Therapy of Wilson's disease continues to evolve. In 1997, zinc acetate was added to the list of drugs approved by the Food and Drug Administration, which includes penicillamine and trientine. The mechanism of zinc's anticopper action is unique. It induces intestinal cell metallothionein, which binds copper and prevents its transfer into blood. As intestinal cells die and slough, the contained copper is eliminated in the stool. Thus, zinc prevents the intestinal absorption of copper. It is universally agreed that pregnant Wilson's disease patients should remain on anticopper therapy during pregnancy. There are numerous reports of such patients stopping penicillamine therapy to protect their fetus from teratogenicity, only to undergo serious deterioration and even death from renewed copper toxicity. Penicillamine and trientine have teratogenic effects in animals, and penicillamine has known teratogenic effects in humans. In this report we discuss the results of 26 pregnancies in 19 women who were on zinc therapy throughout their pregnancy. The evidence is good that zinc protects the health of the mother during pregnancy. Fetal outcomes were generally quite good, although one baby had a surgically correctable heart defect and one had microcephaly.
10707858##2000-3-9##Dissolution of copper-rich granules in hepatic lysosomes by D-penicillamine prevents the development of fulminant hepatitis in Long-Evans cinnamon rats.##
10682302##2000-2-22##Psychiatric symptoms of inherited metabolic disease.##Inborn errors of metabolism often present with a variety of psychiatric symptoms. With improved diagnosis and treatment options, many patients have increased lifespans; consequently, issues of long-term quality of life are coming to the forefront. Mental health concerns are among these issues. To demonstrate the connection between the course of metabolic disease and its psychiatric manifestations, four different inborn errors of metabolism are reviewed: phenylketonuria, Wilson disease, acute intermittent porphyria, and metachromatic leukodystrophy.
10722974##2000-3-21##Peliosis hepatis and neoplastic/dysplastic lesions in aged male Long-Evans Cinnamon rats: MR imaging with pathologic correlation.##The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, abnormally accumulates copper in the liver. There have been a lot of reports on preneoplastic and neoplastic hepatic tumors in LEC rats, but few studies have been focused on other lesions. The aim of this study was to describe the MR findings of the liver of LEC rats with pathologic correlation to characterize the hepatic lesions developed in them. We measured MR images of the liver of six aged (over the age of 70 weeks old) male LEC rats. Measurements of T(1), T(2)-weighted images, and the dynamic and delayed studies after i.v. gadolinium injection were performed. The rats were sacrificed immediately after the measurements, and the diagnosis was histologically made. We identified seven lesions of peliosis hepatis, three neoplastic/dysplastic lesions, three cysts and one cholangiofibrosis. Peliosis hepatis was characterized as showing a significantly long T(2) relaxation time of 57.9 +/- 13.3 ms (mean +/- standard deviation) compared with 41.3 +/- 1.7 ms in normal liver, and prolonged enhancement after a gadolinium injection. Neoplastic/dysplastic lesions tended to show prolonged T(2), and they showed isointensity on T(1)-weighted images. They were best characterized by early enhancement followed by a rapid wash-out after a gadolinium injection. In conclusions, the frequent occurrence of peliosis hepatis observed in the present study suggests this can be a characteristic lesion in aged LEC rats. The characteristic MR findings enable us to distinguish between peliosis hepatis and neoplastic/dysplastic lesions.
10689414##2000-2-26##Genetic liver disease in adults. Early recognition of the three most common causes.##The most common clinically important genetic diseases leading to liver dysfunction in adults are Wilson's disease, HHC, and alpha 1AT deficiency. Advances in molecular biology have led to the identification and characterization of the genetic defects in these conditions. Consequently, genetic testing for disease-causing mutations is now available for most of these disorders. However, it is important to understand the strengths and limitations of such testing. Genetic testing is probably most helpful in HHC because of the high frequency of the homozygous C282Y mutation among patients of northern European descent and the relatively high penetrance of the mutation with regard to clinical expression. Genetic testing is much less helpful in the other genetic liver diseases because of the high number of possible mutations and variable clinical expression. However, noninvasive phenotype-based screening tests and specific treatments are available for most genetic liver diseases. Appropriate use of screening tests in routine clinical practice can assist in early identification of genetic liver diseases and prevent development of end-organ damage.
10786613##2000-4-29##Identification of the copper chaperone SAH in Ovis aries: expression analysis and in vitro interaction of SAH with ATP7B.##A clone encoding the putative copper chaperone protein Sheep Atx1 Homologue (SAH) was isolated from a sheep liver cDNA library. The 466-bp cDNA encoded a predicted protein of 68 amino acids, with 44 and 81% amino acid identity to the yeast Atx1 and human Atox1 copper chaperone proteins, respectively. The characteristic MTCxxC and KTGK motifs were conserved in SAH. Northern blot analysis revealed an abundant 0.5-kb mRNA in all tissues examined. Elevated hepatic copper content did not affect the level of SAH mRNA in the liver. Analysis of SAH mRNA in the developing liver revealed low levels of expression in the foetal period, with a steady increase to adult levels occurring during development. In vitro two-hybrid analysis demonstrated SAH interacted with the amino terminal portion of the sheep Wilson's disease protein (ATP7B). The extent of this interaction was significantly reduced by the addition of the copper chelator bathocuproine disulfonic acid to the media. These results suggest SAH is a functional copper chaperone that is able to interact with ATP7B in a copper-dependent manner to facilitate copper transport into the secretory pathway.
10766335##2000-4-15##Metabolic fate of the insoluble copper/tetrathiomolybdate complex formed in the liver of LEC rats with excess tetrathiomolybdate.##Copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, can be removed from the MT with tetrathiomolybdate (TTM). However, the insoluble Cu/TTM complex formed with excess TTM is known to be deposited in the liver. The metabolic fate of the insoluble Cu/TTM complex was investigated in the present study. LEC rats were injected with TTM at the dose of 10 mg/kg body weight for 8 consecutive days and were fed with a standard or low Cu diet for 14 days after the last injection. About 95% of the Cu in the liver became insoluble together with Mo. The concentration of Cu in the liver supernatants of rats fed with the standard diet increased significantly compared with that in rats dissected 24 h after the last injection (control rats), while the concentration in rats fed with the low Cu diet remained at a comparable level to that in the controls. The rate of Cu accumulation in the livers of rats fed with the standard diet did not differ before and after the treatment, suggesting that there was no rebound effect by treatment with TTM. These results suggest that the insoluble Cu/TTM complex is resolubilized in the liver, and that the solubilized complex is excreted into the bile and blood, i.e., the insoluble Cu/TTM complex is not the source of Cu re-accumulation in the form bound to MT in the liver after TTM treatment. It was concluded that, once Cu is complexed with TTM, the metal is excreted either immediately in the soluble form or slowly in the insoluble form into the bile and blood.
10850100##2000-6-13##[Student with homesickness. Wilson disease].##
10639134##2000-1-19##CopA: An Escherichia coli Cu(I)-translocating P-type ATPase.##The copA gene product, a putative copper-translocating P-type ATPase, has been shown to be involved in copper resistance in Escherichia coli. The copA gene was disrupted by insertion of a kanamycin gene through homologous recombination. The mutant strain was more sensitive to copper salts but not to salts of other metals, suggesting a role in copper homeostasis. The copper-sensitive phenotype could be rescued by complementation by a plasmid carrying copA from E. coli or copB from Enterococcus hirae. Expression of copA was induced by salts of copper or silver but not zinc or cobalt. Everted membrane vesicles from cells expressing copA exhibited ATP-coupled accumulation of copper, presumably as Cu(I). The results indicate that CopA is a Cu(I)-translocating efflux pump that is similar to the copper pumps related to Menkes and Wilson diseases and provides a useful prokaryotic model for these human diseases.
10632312##2000-1-13##Hepatic decompensation in patients with cirrhosis during infection with influenza A.##
10940336##2000-8-15##Cellular copper transport and metabolism.##The transport and cellular metabolism of Cu depends on a series of membrane proteins and smaller soluble peptides that comprise a functionally integrated system for maintaining cellular Cu homeostasis. Inward transport across the plasma membrane appears to be a function of integral membrane proteins that form the channels that select Cu ions for passage. Two membrane-bound Cu-transporting ATPase enzymes, ATP7A and ATP7B, the products of the Menkes and Wilson disease genes, respectively, catalyze an ATP-dependent transfer of Cu to intracellular compartments or expel Cu from the cell. ATP7A and ATP7B work in concert with a series of smaller peptides, the copper chaperones, that exchange Cu at the ATPase sites or incorporate the Cu directly into the structure of Cu-dependent enzymes such as cytochrome c oxidase and Cu, Zn superoxide dismutase. These mechanisms come into play in response to a high influx of Cu or during the course of normal Cu metabolism.
11775208##2002-1-5##Identification and analysis of mutations of the Wilson disease gene in Chinese population.##
10656425##2000-2-3##Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study.##Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15-20% of baseline. The level III dose of TM (120 mg/ day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.
11217283##2001-2-24##Acute hemolytic anemia as an initial clinical manifestation of Wilson's disease.##Wilson's disease is an inherited disorder of copper transport in the organism, transmitted in autosomal recessive fashion. It is caused by dysfunction in homologous copper-transporting adenosine triphosphatases. The main clinical symptoms are usually due to hepatic (42%) or/and neurologic (34%) involvement, which is the reason for the name hepatolenticular degeneration. Described in this report are four cases--the first three demonstrate an unusual form of manifestation of Wilson's disease in clinical practice--glucose-6-phosphate dehydrogenase deficiency hemolytic anemia. The fourth case concerns acute intravascular hemolysis that was provoked by the disease and presented without erythrocyte enzyme disturbances. Hemolytic anemia is a recognized but rare (10-15%) complication of the disease. Most often Coombs' negative acute intravascular hemolysis occurs as a consequence of oxidative damage to the erythrocytes by the higher copper concentration. A literature review with discussion of the possible mechanisms for the development of this phenomenon is done.
11216666##2001-2-24##Delineation of the spectrum of Wilson disease mutations in the Greek population and the identification of six novel mutations.##In this study, we report the further results of an ongoing project on the delineation of the spectrum of mutations on the ATP7B gene in Wilson disease (WD) patients of Greek origin. We have analyzed 24 additional families and detected 16 mutations (five frameshifts, two splice site, two nonsense, and seven missense), of which six are novel. On adding these results to the ones already published by us, we conclude that WD shows a marked allelic heterogeneity in the Greek population. Of the total number of mutations so far detected, the most common eight account for the molecular defect in 72.8% of the WD chromosomes. The most frequent mutation is the His0169Gln, which has a frequency of 28.5%, similar to those reported in North European populations. Using these data, an efficient strategy of mutation screening for WD is possible in this population, thus improving the possibility of preclinical diagnosis.
10790207##2000-5-2##Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson's disease.##The gene ATP7B responsible for Wilson's disease (WD) produces a protein which is predicted to be a copper-binding P-type ATPase, homologous to the Menkes disease gene (ATP7A). Various mutations of ATP7B have been identified. This study aimed to detect disease-causing mutations, to clarify their frequency and distribution, to determine whether genotype correlates with phenotype, and to determine the rate of abnormal findings in heterozygotes for the WD gene. We analyzed 41 unrelated Japanese WD families, including 47 patients. Twenty-one mutations, including nine novel ones, were identified. 2871delC (15.9%), 1708-5T-->G (11. 0%), and Arg778Leu (13.4%) were the most common mutations. 2871delC was detected mainly in eastern Japan and 1708-5T-->G in western Japan. The homozygotes for the 1708-5T-->G, 2871delC, or Arg778Leu mutations did not show a correlation with their phenotypes. Ceruloplasmin and copper levels were abnormally low in 28.6% and 35. 0% of heterozygotes, respectively. When patients and their families are screened for WD, a high rate of abnormal laboratory data in heterozygotes must be taken into account.
10745386##2000-4-4##Wilson's disease with hepatic presentation in childhood.##
10789499##2000-5-2##Biliary copper excretion capacity in intact animals: correlation between ATP7B function, hepatic mass, and biliary copper excretion.##Copper toxicosis can occur in the absence of biliary copper excretion. To demonstrate whether biliary copper excretion capacity is correlated with hepatic mass and ATP7B function, we undertook studies in intact animals. Copper-histidine was injected intrasplenically after baseline bile collection, followed by measurement of copper excretion in Long-Evans Cinnamon (LEC) rats lacking atp7b function and in normal, syngeneic Long-Evans Agouti (LEA) rats. The basal biliary copper excretion was very low in LEC rats compared with LEA rats, 8+/-4 and 37+/-18 ng copper/min, respectively; p<0.05. After addition of copper, copper excretion increased significantly (by two- to five-fold) in LEA rats during the 30 minute study period, whereas LEC rats showed only a slight and transient increase in copper excretion. After one-third and two-thirds partial hepatectomy immediately before copper loading, copper excretion decreased progressively. The studies indicate that biliary copper excretion depends on hepatocyte mass and ATP7B gene function. Analysis of copper excretion with our non-radioactive method will facilitate testing of novel therapies and pathophysiological mechanisms in copper toxicity.
10777157##2000-4-25##A new variant deletion of a copper-transporting P-type ATPase gene found in patients with Wilson's disease presenting with fulminant hepatic failure.##A candidate gene (ATP7B) for Wilson's disease, an autosomal recessive disorder of copper transport, has recently been identified. We examined the ATP7B gene in two Japanese sisters with Wilson's disease presenting with fulminant hepatic failure but who did not exhibit Kayser-Fleischer rings or abnormal neurological findings. Genomic DNA was isolated from the whole blood of the patients and their family. Entire exons of ATP7B, and their associated splice junctions, were amplified by polymerase chain reaction. The sequencing of all exons was performed by a non-radioactive sequencing method. The sequencing of exon 12 of ATP7B revealed a 9-bp deletion. The mutation deleted 922Gly, 923Tyr, and 924Phe, and three residues conserved in the Menkes gene, ATP7A, located in the fifth transmembrane region. Of the 14 family members tested, 7 were normal and 7 were heterozygous for the deletion. Mean serum copper and cerulopasmin levels were significantly lower in the family members who were heterozygous for the deletion than in the normal family members, and two heterozygous family members showed abnormally low ceruloplasmin levels; however, there were no differences in mean aspartate aminotransferase or alanine aminotransferase levels between the two groups.
11043508##2000-10-24##Molecular analysis of Wilson disease in Taiwan: identification of one novel mutation and evidence of haplotype-mutation association.##Wilson disease (WND) is caused by a deficiency of the copper-transporting enzyme, P-type ATPase (ATP7B). Twelve different mutations have previously been identified in Taiwan Chinese with Wilson disease. We, herein, report another 4 missense mutations, 1 of which is novel. We did haplotype analysis of Taiwanese WND chromosomes, using three well characterized short tandem repeat markers (haplotype was assigned in the order of D13S314-D13S301-D13S316). Association correlation was found between the mutations and their respective haplotypes. Haplotype-deduced pedigree analysis was shown to be helpful in the mutation analysis of WND chromosomes and in the molecular assessment of both pre-symptomatic WND patients and carriers. Given the complexity and heterogeneity of the mutation spectrum of ATP7B, we suggest that haplotype analysis should be performed before full-scale mutation analysis.
10721669##2000-3-18##Novel mutations of the ATP7B gene in Japanese patients with Wilson disease.##Wilson disease (WD) is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, kidneys, and corneas, and culminating in copper toxication in these organs. In this study, we analyzed mutations of the responsible gene, ATP7B, in four Japanese patients with WD. By direct sequencing, we identified five mutations, of which two were novel, and 16 polymorphisms, of which 6 were novel. The mutations 2871delC and 2513delA shift the reading frame so that truncated abnormal protein is expected. In contrast to these mutations found in patients with hepatic-type of early onset, the mutations A874V, R778L, and 3892delGTC were either missense mutations or in frame 1-amino acid deletion, and occurred in the patients with hepato-neurologic type of late onset. The mutations 2871delC and R778L have been previously reported in a relatively large number of Japanese patients. In particular, R778L is known to be more prevalent in Asian countries than in other countries of the world. Our data are compatible with the hypothesis that the mutations tend to occur in a population-specific manner. Therefore, the accumulation of the types of mutations in Japanese patients with WD will facilitate the fast and effective genetic diagnosis of WD in Japanese patients.
10821440##2000-5-23##CSF copper concentrations, blood-brain barrier function, and coeruloplasmin synthesis during the treatment of Wilson's disease.##During the treatment of four patients with cerebral manifestation of Wilson's disease, we measured the copper concentration in the cerebrospinal fluid (CSF) and serum, the serum coeruloplasmin concentration, the free copper concentration in the serum, and the albumin ratio CSF/serum (AR). These measurements were treated as indicators of the copper-related toxic effects on the brain and the blood-brain barrier (BBB). The half-life of the decrease in the CSF copper concentration during therapy was 23.5 +/- 5.78 months (mean +/- S.E.M.). The therapeutic-target-copper concentration in the CSF (mean normal concentration) is below 20 microg/l. The average length of therapy needed to normalize CSF-copper values in our patients with an average initial value of 76.25 microg/L was 47 month. During the first 10 month of treatment there was an increase in all cases of the measured disturbance in the blood-brain barrier (measured as the ratio of albumin in CSF to albumin in serum, AR). All patients showed an initial worsening of the neurological condition, on average after 1.75 +/- 0.25 months. The maximal rise in AR, from the initial values, was on average 18.4 +/- 5.08%; this maximum was reached after an average of 6.9 +/- 1.5 months. The AR normalized during therapy, indicating a reduction in toxicity in the blood-brain barrier region. The extent of the AR increases in individual patients did not correlate significantly with CSF copper half-life, serum copper half-life, the initial half-life of the reduction in the ratio (copper in serum)/(coeruloplasmin in serum), the initial copper concentration in CSF or serum, the initial free copper concentration in serum, or the initial dose of penicillamine (within the first 2 months). We conclude that the normalization of the CSF copper concentration in patients with the cerebral manifestation of Wilson's disease is a slow process, even if therapy is sufficient. The initial worsening of the neurological condition which has often been reported may be reflected in the disturbance of blood-brain barrier function, which we have measured here for the first time (using the parameter of the albumin ratio CSF/serum). Based on repeated measurements of the AR during the course of treatment it seems that the brain toxicity of mobilized copper can be assessed and the therapy adjusted.
10630439##2000-1-12##Nonalcoholic steatohepatitis in children.##
10632959##2000-1-13##Recognition, diagnosis, and management of Wilson's disease.##Wilson's disease is a relatively rare inherited disorder of copper accumulation and toxicity, caused by a defect in an enzyme that is part of the pathway of biliary excretion of excess copper. Clinically, patients usually present as older children or young adults with hepatic, neurologic, or psychiatric manifestations, or some combination of these. Wilson's disease is unusual among genetic diseases in that it can be very effectively treated. The prevention of severe permanent damage depends upon early recognition and diagnosis by the physician, followed by appropriate anticopper treatment. Anticopper treatments have evolved considerably since the days when the only drug available was penicillamine. Zinc is now the recommended therapy for long-term management of the disease.
11107875##2000-12-7##[Liver transplantation in a patient with hemolytic syndrome in the course of fulminant Wilson's disease].##The case report of a 20 year old woman with fulminant liver failure and hemolytic syndrome was described. Huge amounts of copper excreted in the urine (3555 mg/12 h without, and 5180 mg/12 h after d-penicillamine provocation, respectively) confirmed the diagnosis of fulminant Wilson's disease. Because the patient's general condition worsened rapidly (hemolysis, diathesis hemorrhagic, ascites, encephalopathy increased during 3 days of clinical observation) orthotopic liver transplantation was performed. After the transplantation, ischemic type biliary lesion (ITBL) II stage was diagnosed. The woman is still being treated with Prograf and Urso-Falk. The patient returned to her normal life, continues to work and was married. Two years after OLT she gave birth to a healthy boy. The liver function tests are normal with the exception of GGTP and FALK activities elevation. Copper and ceruloplasmin level, as well as copper excretion in the urine are within the normal values.
10665265##2000-2-9##Neuropsychiatry of Huntington's disease and other basal ganglia disorders.##Degenerative diseases of the basal ganglia, such as Huntington's disease (HD), Parkinson's disease, and Wilson's disease, are characterized by motor, cognitive, and psychiatric manifestations. HD, in particular, can be considered a paradigmatic neuropsychiatric disorder that has all three components of the "Triadic Syndromes": dyskinesia, dementia, and depression. The authors examine the phenomenology, prevalence, and management of psychiatric disturbances occurring in diseases of the basal ganglia. They address psychiatric conditions such as depression, mania, psychosis, obsessive-compulsive disorders, aggression, irritability, apathy, sexual disorders, and delirium, discussing subtleties of diagnosis, and making reference to more unusual disorders of the basal ganglia, such as postencephalitic parkinsonism and Fahr's disease.
11076401##2000-11-15##Wilson's disease.##Wilson's disease is an autosomal recessive disorder of copper metabolism resulting from the absence or dysfunction of a copper transporting P-type ATPase encoded on chromosome 13. This ATPase is expressed in hepatocytes where it is localized to the trans-Golgi network and transports copper into the secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Under physiologic circumstances, biliary excretion represents the sole mechanism for copper excretion, and thus affected individuals have progressive copper accumulation in the liver. When the capacity for hepatic storage is exceeded, cell death ensues with copper release into the plasma, hemolysis, and tissue deposition. Presentation in childhood may include chronic hepatitis, asymptomatic cirrhosis, or acute liver failure. In young adults, neuropsychiatric symptoms predominate and include dystonia, tremor, personality changes, and cognitive impairments secondary to copper accumulation in the central nervous system. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 100 unique mutations have been identified and most individuals are compound heterozygotes. Copper chelation with penicillamine is an effective therapy in most patients and hepatic transplantation is curative in individuals presenting with irreversible liver failure. Elucidation of the molecular genetic basis of Wilson's disease has permitted new insights into the mechanisms of cellular copper homeostasis.
11076393##2000-11-15##Foreword: from classic bile physiology to cloned transporters.##Uptake of drugs and metabolites from the circulation into the liver is facilitated by transporter proteins in the basolateral membrane of the hepatocyte. Among these proteins are the sodium taurocholate cotransporting protein, various multispecific transporters for organic anions and cations, transporters for glucose, amino acids, and prostaglandins. The canalicular membrane contains a number of ATP-dependent transporters belonging to the families of P-glycoproteins and multidrug resistance-associated proteins. Transport across the canalicular membrane represents the rate-determining step in the secretion of compounds from blood to bile. Mutations of genes encoding these canalicular transporters are associated with liver diseases such as progressive familial intrahepatic cholestasis and Dubin-Johnson syndrome. Wilson's disease appears to be due to a defect of a copper-transporting P-type ATPase. Also, bile ductuli contribute to bile formation. Mutations in the CFTR gene, encoding a chloride channel in bile duct epithelial cells, leads to the hepatic component of cystic fibrosis.
10953660##2000-8-23##[The hepatic form of Wilson's disease in young patients].##
10812676##2000-5-17##[A case of delayed diagnosis of Wilson's disease].##
10709288##2000-3-10##[Acoustic brain stem and cognitive evoked potentials (P300) in patients with hepatolenticular degeneration].##18 patients with hepatolenticular degeneration (Wilson's disease, WD) aged 15-38 years were subjected to an overall clinical and neurophysiologic examinations. As a result, the data obtained enable to evaluate functional reserves of CNS of the WD patients in correlation with the illness duration and severity of neurologic symptoms. Correlation between an increase of interpeak I-V and the degree of neurological deficit and, also, level of ceruloplasmin was established (r = -0.45; p < 0.05). Correlation between an increase of latency P300 and the degree of manifestation of neurologic symptoms was identified as well (r = 0.63; p < 0.05). Positive dynamics of evoked potentials was followed in 4 WD patients during copper-eliminative drugs treatment.
10610638##1999-12-28##Plasma exchange for hemolytic crisis in Wilson disease.##
10588844##1999-12-10##Clinical expression of Menkes disease in a girl with X;13 translocation.##Menkes disease is a rare X-linked recessive disorder of copper metabolism, characterised by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We report on a girl with classic Menkes disease, carrying a de novo balanced translocation 46,X,t(X;13)(q13.3; q14.3). The translocation breakpoints at Xq13.3 and 13q14.3 coincide with the Menkes disease and Wilson disease loci, respectively.
10574978##1999-11-27##Circadian rhythm of patched1 transcription in the pineal regulated by adrenergic stimulation and cAMP.##The tumor suppressor patched1 (PTC1), a product of the mammalian homologue of the Drosophila segment polarity gene patched, is a receptor for hedgehog (HH) and is crucial for embryonic development. Although little is known about the signal transduction pathways leading to the activation of ptc1, increased ptc1 transcription has always been associated with elevated HH activity and decreased activity of cAMP-dependent protein kinase A. Here, we demonstrate that in the mammalian pineal gland, ptc1 expression exhibits a dramatic diurnal rhythm with peak expression at midnight. ptc1 mRNA expression in the pineal is regulated by a clock mechanism mediated by the superior cervical ganglion. Most importantly, ptc1 transcription can be induced by agents activating the cAMP signal transduction pathway both in vivo and in vitro and appears to be independent of HH signaling.
10579979##1999-12-2##Localization of the Wilson's disease protein in human liver.##
10715915##2000-3-15##[Problems of contraception in women with Wilson disease].##Because of the constant progress in medical therapy, the fertility status of patients with Wilson's disease may be preserved. Contraceptive counselling is, therefore, essential to these women. Some contraceptive methods can have a negative influence on hepatic function or hepatic insufficiency may reduce the efficacy of other contraceptives. Different contraceptive options for patients with Wilson's disease are described. Second generation intrauterine devices with copper and estrogen-containing oral contraceptives are contraindicated. Spermatocide and barrier contraceptives and progesterone-only preparations can be safely used.
10715914##2000-3-15##[Pregnancy and delivery after liver transplantation: case report].##We report a case of successful pregnancy in a 22-year-old primigravida who became pregnant 19 months after orthotopic liver transplantation for end-stage liver dysfunction caused by Wilson disease. The mother continued immunosuppressive therapy (tacrolimus) during the pregnancy. No complications were observed. Labour started spontaneously at 40th week's gestation. As a result the healthy male infant weighing 3900 g was born. Patient and the baby were discharged from hospital, both in good condition, on the fifth day after delivery.
10604583##1999-12-22##Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins.##
10585777##1999-12-10##The copper chaperone Atox1 in canine copper toxicosis in Bedlington terriers.##Copper toxicosis, resulting in liver disease, commonly occurs in Bedlington terriers. This recessively inherited disorder, similar in many respects to Wilson disease, is of particular interest because the canine Atp7b gene, homologous to ATP7B defective in Wilson disease, is not responsible for canine copper toxicosis as has been expected. Atox1, a copper chaperone delivering copper to Atp7b, therefore became a potential candidate. We cloned canine Atox1, which shows conserved motifs of the copper-binding domain (MTCXXC) and of the lysine-rich region (KTGK), and showed 88, 80, and 41% amino acid sequence identity with the orthologous mouse, human, and yeast proteins. No gross deletions of Atox1 could be identified in the affected Bedlington terriers by Southern blot analysis of genomic DNA. The canine Atox1 gene spans about 4 kb, with a 204-bp open reading frame cDNA contained within two exons. Sequence analysis of the coding regions, including intron/exon boundaries, showed no mutations in Atox1 from genomic DNA of an affected dog. We have also identified an apparently nontranscribed canine Atox1 pseudogene, with 12 sequence changes and no intron. Mapping of Atox1 and a marker closely linked to the canine copper toxicosis locus indicated lack of synteny. Atox1 is therefore excluded as a candidate gene for canine copper toxicosis, indicating that some other unidentified gene must be responsible for this copper storage disease in dogs and also suggesting the possibility of a similar gene responsible for a copper storage disease in humans.
10557326##1999-11-11##Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis.##The delivery of copper to specific sites within the cell is mediated by distinct intracellular carrier proteins termed copper chaperones. Previous studies in Saccharomyces cerevisiae suggested that the human copper chaperone HAH1 may play a role in copper trafficking to the secretory pathway of the cell. In this current study, HAH1 was detected in lysates from multiple human cell lines and tissues as a single-chain protein distributed throughout the cytoplasm and nucleus. Studies with a glutathione S-transferase-HAH1 fusion protein demonstrated direct protein-protein interaction between HAH1 and the Wilson disease protein, which required the cysteine copper ligands in the amino terminus of HAH1. Consistent with these in vitro observations, coimmunoprecipitation experiments revealed that HAH1 interacts with both the Wilson and Menkes proteins in vivo and that this interaction depends on available copper. When these studies were repeated utilizing three disease-associated mutations in the amino terminus of the Wilson protein, a marked diminution in HAH1 interaction was observed, suggesting that impaired copper delivery by HAH1 constitutes the molecular basis of Wilson disease in patients harboring these mutations. Taken together, these data provide a mechanism for the function of HAH1 as a copper chaperone in mammalian cells and demonstrate that this protein is essential for copper homeostasis.
10927964##2000-8-6##Steroids used to desensitize penicillamine allergy in Wilson disease.##Patients with Wilson disease require life-long treatment and penicillamine is the drug of choice. We present a 14-year-old boy with Wilson disease who developed hypersensitivity reaction 2 days after starting penicillamine therapy. His symptoms included fever, maculopapular rash and lip edema. The allergic reaction disappeared when penicillamine was discontinued, but relapsed after reinstituting penicillamine at a lower dose. Desensitization was attempted by introducing steroid therapy, the dose of 0.7 mg per kilogram per day of prednisolone for 2 days, then penicillamine was successfully tolerated. Subsequent tapering of the daily prednisolone dose was performed till it was discontinued one month after treatment began. We suggest that concomitant use of steroid and penicillamine should be used for the treatment of patients who develop penicillamine intolerance.
10650917##2000-1-29##Mechanism of enhanced lipid peroxidation in the liver of Long-Evans cinnamon (LEC) rats.##The Long-Evans Cinnamon (LEC) rat is a mutant strain of rats that accumulate copper (Cu) in the liver in much the same way as individuals who suffer from Wilson's disease (WD) and has been suggested as a model for this disease. Lipid peroxidation (LPO) is considered to be involved in the toxic action of Cu in the livers of LEC rats. We investigated the mechanism of LPO in the livers of LEC rats showing apparent signs of hepatitis. Several-fold higher LPO levels were observed in post-mitochondrial supernatant (S-9) fraction of livers from hepatitic LEC rats than in those from Wistar rats. To mimic living cells, we introduced NADPH-generating system (NADPH-gs) into the S-9 incubation system. Thus was ensured a constant supply of NADPH to vital enzymes that may be directly or indirectly involved in the generation and/or elimination of reactive oxygen species (ROSs), such as glutathione reductase (GSSG-R), which require NADPH for their reactions. The levels of LPO in liver S-9 from hepatitic LEC rats were further increased by incubating liver S-9 at 37 degrees C in the presence of NADPH-gs. This increase was inhibited by EDTA, butylated hydroxytoluene (BHT), and catalase (CAT), suggesting that some metal, most likely the accumulated Cu, and ROSs derived from hydrogen peroxide (H2O2) are involved in the increased levels of LPO in the livers of hepatitic LEC rats. The requirement of NADPH-gs for enhanced LPO in the livers of hepatitic LEC rats indicates the consumption of NADPH during reactions leading to LPO. It is known that H2O2, and consequently hydroxyl radical are generated during Cu-catalyzed glutathione (GSH) oxidation. The cyclic regeneration of GSH from GSSG by NADPH-dependent GSSG-R in the presence of NADPH-gs may cause sustained generation of hydroxyl radical in the presence of excess free Cu. The generation of H2O2 in S-9 fraction of livers from hepatitic LEC rats was observed to be significantly higher than that in S-9 fraction of livers from non-hepatitic LEC rats and Wistar rats. Moreover, in addition to the reported decrease in glutathione peroxidase (GPX) activity, we found that CAT activity was markedly decreased in LEC rats with hepatitis. The increased generation of H2O2 with reduced activities of GPX and CAT may result in cellular accumulation of H2O2 in the liver of hepatitic LEC rats. Taken altogether, it is suggested that the accumulated H2O2 undergoes the Fenton-type reaction with also accumulated free Cu, thus generating hydroxyl radical in the livers of hepatitic LEC rats and increasing LPO levels in these animals.
10682938##2000-2-22##Identification of the zinc-binding protein specifically present in male rat liver as carbonic anhydrase III.##A zinc (Zn)-binding protein that is present specifically in the livers of male adult rats was detected by HPLC with in-line detection by mass spectrometry (ICP MS). The Zn-binding protein was purified on Sephadex G-75 and G3000SW HPLC columns. and was identified as carbonic anhydrase III (CAIII) based on the amino acid sequence of a peptide obtained on lysyl endopeptidase digestion. CAIII is expressed as one of the major Zn-binding proteins in the livers of male rats in an age-dependent manner, a comparable amount of Zn to that of copper, Zn-superoxide dismutase (Cu,Zn-SOD) being bound to CAIII at 8 weeks of age. Castration at 4 or 8 weeks of age was shown to reduce Zn bound to CAIII to 47.5% of the sham-operated control level, suggesting that the sex-dependent expression of CAIII is partly regulated by a sex hormone, androgen. The concentration of CAIII in the livers of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, was also estimated as Zn bound to CAIII and shown to be lower than that in Wistar rats before the onset of hepatitis. The concentration of CAIII was decreased specifically by repeated injections of cupric ions without the Cu,Zn-SOD concentration being affected.
10745331##2000-4-4##Fulminant hepatic failure: etiology, viral markers and outcome.##
10544227##1999-11-2##Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.##In this study, we report further results of mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Mediterranean origin. A total of 136 WD chromosomes, 73 of which were of Italian, 43 of Turkish, 18 of Sardinian, and two of Spanish origin, were analysed and the mutation characterised in 84.5% of them. We found 50 different mutations of which 19 are novel, including three nonsense, one frameshift, and 15 missense mutations. The mutations detected were rare and mostly found in the compound heterozygous state together with other mutations and only rarely in homozygosity. Most of these mutations lie in the transmembrane and ATP binding loop regions. These data expand our knowledge of both the structure-function relationships of the WD protein and the molecular pathology of WD, thus improving our capability of prevention and genetic counselling.
10554138##1999-11-30##Potential hepatotoxicity of penicillamine treatment in three patients with Wilson's disease.##
10545532##1999-11-5##Liver transplantation for Wilson's disease: a single-center experience.##Wilson's disease is a hereditary defect in copper excretion leading to the accumulation of copper in the tissues, with subsequent tissue damage. The most serious sequela is that of progressive central nervous system involvement. The use of orthotopic liver transplantation (OLT) has been controversial for those patients with neurological symptoms attributed to Wilson's disease. The aim of this study is to determine the effectiveness of OLT for patients with Wilson's disease, including those with neurological involvement attributed to copper accumulation in the central nervous system. OLT was performed in 45 patients (19 men [42.2%], 26 women [57.8%]) with Wilson's disease between 1971 and 1993 who were followed up for at least 4 years. The age at diagnosis of Wilson's disease ranged from 3 to 41 years (mean, 17.7 +/- 7.4 years). The age at OLT ranged from 8 to 52 years (mean, 22.3 +/- 9.4 years). Nineteen patients (42.2%) were aged younger than 18 years at OLT. The indications for OLT included chronic hepatic failure in 15 patients (33.3%) and fulminant (FHF) or subfulminant hepatic failure in 30 patients (66. 6%). All but 1 of the 19 pediatric patients (94.7%) were in the latter group. Twenty-five patients (55.5%) were receiving D-penicillamine, 9 patients for more than 1 year; none of the patients treated long term presented as FHF. Thirty-three patients (73.3%) survived more than 5 years after OLT. Fourteen patients (31%) died during the posttransplantation period; 7 of the 14 patients (50%) were aged younger than 18 years. Twelve patients died during the first 3 months after OLT of complications of disease and surgery, 10 of whom underwent transplantation for FHF. The other 2 patients died 6 and 9 years after transplantation of infectious problems. Eleven patients (24.4%) required retransplantation because of a primary nonfunctioning graft (n = 6), chronic rejection (n = 4), and hepatic artery thrombosis (n = 1). Seventeen patients (37.7%) presented with neurological abnormalities; 14 patients with Wilsonian neurological manifestations and 3 patients with components of increased intracranial pressure. Ten of the 13 surviving patients with hepatic insufficiency and neurological abnormalities at OLT showed significant neurological improvement. Our experience shows OLT is a life-saving procedure in patients with end-stage Wilson's disease and is associated with excellent long-term survival. The neurological manifestation of the disease can improve significantly after OLT. Earlier transplantation in patients with an unsatisfactory response to medical treatment may prevent irreversible neurological deterioration and less satisfactory improvement after OLT.
10529259##1999-10-21##Expression and mutagenesis of ZntA, a zinc-transporting P-type ATPase from Escherichia coli.##Cation-transporting P-type ATPases comprise a major membrane protein family, the members of which are found in eukaryotes, eubacteria, and archaea. A phylogenetically old branch of the P-type ATPase family is involved in the transport of heavy-metal ions such as copper, silver, cadmium, and zinc. In humans, two homologous P-type ATPases transport copper. Mutations in the human proteins cause disorders of copper metabolism known as Wilson and Menkes diseases. E. coli possesses two genes for heavy-metal translocating P-type ATPases. We have constructed an expression system for one of them, ZntA, which encodes a 732 amino acid residue protein capable of transporting Zn(2+). A vanadate-sensitive, Zn(2+)-dependent ATPase activity is present in the membrane fraction of our expression strain. In addition to Zn(2+), the heavy-metal ions Cd(2+), Pb(2+), and Ag(+) activate the ATPase. Incubation of membranes from the expression strain with [gamma-(33)P]ATP in the presence of Zn(2+), Cd(2+), or Pb(2+) brings about phosphorylation of two membrane proteins with molecular masses of approximately 90 and 190 kDa, most likely representing the ZntA monomer and dimer, respectively. Although Cu(2+) can stimulate phosphorylation by [gamma-(33)P]ATP, it does not activate the ATPase. Cu(2+) also prevents the Zn(2+) activation of the ATPase when present in 2-fold excess over Zn(2+). Ag(+) and Cu(+) appear not to promote phosphorylation of the enzyme. To study the effects of Wilson disease mutations, we have constructed two site-directed mutants of ZntA, His475Gln and Glu470Ala, the human counterparts of which cause Wilson disease. Both mutants show a reduced metal ion stimulated ATPase activity (about 30-40% of the wild-type activity) and are phosphorylated much less efficiently by [gamma-(33)P]ATP than the wild type. In comparison to the wild type, the Glu470Ala mutant is phosphorylated more strongly by [(33)P]P(i), whereas the His475Gln mutant is phosphorylated more weakly. These results suggest that the mutation His475Gln affects the reaction with ATP and P(i) and stabilizes the enzyme in a dephosphorylated state. The Glu470Ala mutant seems to favor the E2 state. We conclude that His475 and Glu470 play important roles in the transport cycles of both the Wilson disease ATPase and ZntA.
10553201##1999-12-20##Pediatric movement disorders.##Movement disorders in children encompass disorders of motor control--both hyperkinetic (excessive movement) and hypokinetic (decreased movement). This article focuses on the hyperkinetic movement disorders, particularly tremor, Wilson's disease, dystonia, tics and Tourette syndrome, chorea, myoclonus, neuroleptic-induced movement disorders, and psychogenic movement disorders. Phenomenology of the disorders as well as clinical presentation, basic pathophysiology, genetics, and treatment are discussed.
10497213##1999-9-25##Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p.##Wilson disease (WD) and Menkes disease (MNK) are inherited disorders of copper metabolism. The genes that mutate to give rise to these disorders encode highly homologous copper transporting ATPases. We use yeast and mammalian two-hybrid systems, along with an in vitro assay to demonstrate a specific, copper-dependent interaction between the six metal-binding domains of the WD and MNK ATPases and the cytoplasmic copper chaperone HAH1. We demonstrate that several metal-binding domains interact independently or in combination with HAH1p, although notably domains five and six of WDp do not. Alteration of either the Met or Thr residue of the HAH1p MTCXXC motif has no observable effect on the copper-dependent interaction, whereas alteration of either of the two Cys residues abolishes the interaction. Mutation of any one of the HAH1p C-terminal Lys residues (Lys(56), Lys(57), or Lys(60)) to Gly does not affect the interaction, although deletion of the 15 C-terminal residues abolishes the interaction. We show that apo-HAH1p can bind in vitro to copper-loaded WDp, suggesting reversibility of copper transfer from HAH1p to WD/MNKp. The in vitro HAH1/WDp interaction is metalospecific; HAH1 preincubated with Cu(2+) or Hg(+) but not with Zn(2+), Cd(2+), Co(2+), Ni(3+), Fe(3+), or Cr(3+) interacted with WDp. Finally, we model the protein-protein interaction and present a theoretical representation of the HAH1p.Cu.WD/MNKp complex.
10556564##1999-11-11##Cooperative binding of copper(I) to the metal binding domains in Menkes disease protein.##We have optimised the overexpression and purification of the N-terminal end of the Menkes disease protein expressed in Escherichia coli, containing one, two and six metal binding domains (MBD), respectively. The domain(s) have been characterised using circular dichroism (CD) and fluorescence spectroscopy, and their copper(I) binding properties have been determined. Structure prediction derived from far-UV CD indicates that the secondary structure is similar in the three proteins and dominated by beta-sheet. The tryptophan fluorescence maximum is blue-shifted in the constructs containing two and six MBDs relative to the monomer, suggesting more structurally buried tryptophan(s), compared to the single MBD construct. Copper(I) binding has been studied by equilibrium dialysis under anaerobic conditions. We show that the copper(I) binding to constructs containing two and six domains is cooperative, with Hill coefficients of 1.5 and 4, respectively. The apparent affinities are described by K(0.5), determined to be 65 microM and 19 microM for constructs containing two and six domains, respectively. Our data reveal a unique regulation of Menkes protein upon a change in copper(I) concentration. The regulation does not occur as an 'all-or-none' cooperativity, suggesting that the copper(I) binding domains have a basal low affinity for binding and release of copper(I) at low concentrations but are able to respond to higher copper levels by increasing the affinity, thereby contributing to prevent the copper concentration from reaching toxic levels in the cell.
10441329##1999-8-11##Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.##The Atp7b protein is a copper-transporting ATPase expressed predominantly in the liver and to a lesser extent in most other tissues. Mutations in the ATP7B gene lead to Wilson disease, a copper toxicity disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neuro-logical abnormalities. Using homologous recombination to disrupt the normal translation of ATP7B, we have generated a strain of mice that are homozygous mutants (null) for the Wilson disease gene. The ATP7B null mice display a gradual accumulation of hepatic copper that increases to a level 60-fold greater than normal by 5 months of age. An increase in copper concentration was also observed in the kidney, brain, placenta and lactating mammary glands of homo-zygous mutants, although milk from the mutant glands was copper deficient. Morphological abnormalities resembling cirrhosis developed in the majority of the livers from homozygous mutants older than 7 months of age. Progeny of the homozygous mutant females demonstrated neurological abnormalities and growth retardation characteristic of copper deficiency. Copper concentration in the livers of the newborn homozygous null mutants was decreased dramatically. In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the 'toxic milk' phenotype in the mouse.
10478876##1999-9-9##The role of transjugular liver biopsy in a liver transplant center.##Transjugular liver biopsy is a particularly useful procedure in overcoming the classic limitations of percutaneous biopsy, such as hemorrhagic diathesis or tense ascites. The authors evaluated the impact that this technique had in their liver transplant program, considering performance and safety in 160 procedures. Histologic characterization was accomplished in 75% of cirrhotic patients and in 96% of patients with acute liver disease. Confirmation of a presumptive diagnosis was made in 76% of patients and a previously unsuspected diagnosis was raised in 11%. Hemochromatosis, Wilson's disease, and acute alcoholic hepatitis were the most challenging diagnoses and, together with patients with liver failure, had the most relevant implications in transplant decisions. The availability of transjugular liver biopsy provided decisive information regarding patient selection and the best timing to proceed with transplantation.
10482318##1999-9-11##Treatment of Wilson's disease with zinc.##
10511956##1999-10-8##[Short interval change of 99mTc-ethyl cysteinate dimer single photon emission computed tomography in Wilson's disease].##We studied short interval change of cranial computed tomography (CT), magnetic resonance imaging (MRI) and 99mTc-ethyl cysteinate dimer single photon emission computed tomography (99mTc-ECD SPECT) in a case of Wilson's disease. Before treatment, CT scan showed low density changes in the bilateral thalamus and basal ganglia, and MRI demonstrated high intensity in same lesions. 99mTc-ECD SPECT study revealed a hypoperfusion in bilateral thalamus. After 2 months under D-penicillamine therapy, neurological findings had improvement. Hypoperfusion in the thalamus with 99mTc-ECD SPECT significantly improved, whereas abnormal findings of CT scan and MRI persisted. 99mTc-ECD SPECT study may be useful for the planning of the treatment of Wilson's disease.
10752277##2001-2-7##[Identification of molecular defects in liver diseases. Recent advances].##Recent molecular studies have resulted in the identification of genetic alterations underlying several hereditary disorders of the liver. Cloning of disease genes are increasing our understanding of the basic defects in liver diseases. This review focuses on selected inherited liver diseases such as hyperbilirubinemic syndromes, hemochromatosis, Wilson disease and genetic cholestatic syndromes and illustrate the knowledge gained on these disorders from molecular studies. Potential implications of the identification of disease genes such as practical applications for diagnosis, information on prognosis and the possibility to design new therapies are discussed.
10500667##1999-9-29##Indications and results of liver transplants in Wilson's disease.##
10506364##1999-10-3##[Bilateral spontaneous rupture of the quadriceps tendon in a patient with Wilson disease. A case report].##A 58-year old man with Wilson's disease sustained a bilateral spontaneous rupture of the quadriceps tendon. The histological investigation showed advanced degeneration of tendon structure and copper deposits. After tenosuture the patient had complete cure with full range of movement. We discuss about relation of Wilson's disease, copper deposits and degenerative changes of tendon tissue.
10452945##1999-8-24##Cloning and expression analysis of the sheep ceruloplasmin cDNA.##The cDNA encoding sheep ceruloplasmin (sCP) was isolated from a sheep liver cDNA library. The cDNA contig was 3530 nucleotides in length and encoded a protein of 1048 amino acids. The deduced amino acid sequence showed a high degree of conservation (87%) when compared to the human ceruloplasmin (hCP) sequence. Northern blot analysis of sheep tissue revealed that the sheep ceruloplasmin gene (sCP) was expressed primarily in the liver, but low levels of mRNA were detected in the hypothalamus, spleen and uterus. No sCP mRNA was detected in the cortex, heart, intestine or kidney. Expression was not significantly affected by hepatic copper content. Northern blot analysis of sheep liver during development demonstrated little sCP expression during fetal life, but significant levels of mRNA were observed after birth. Significantly, the developmental expression pattern of sCP was closely correlated with that of the sheep Wilson disease gene (sATP7B), suggesting that the expression of the two genes may be coordinated to ensure that copper is supplied to apoceruloplasmin. Overall, the structure and expression of sCP appeared similar to other mammals, suggesting that abnormalities in CP were not responsible for the unusual sheep copper phenotype.
10425169##1999-7-30##Molecular mechanisms of copper homeostasis.##Copper is an essential trace element which plays a pivotal role in cell physiology as it constitutes a core part of important cuproenzymes. Novel components of copper homeostasis in humans have been identified recently which have been characterised at the molecular level. These include copper-transporting P-type ATPases, Menkes and Wilson proteins, and copper chaperones. These findings have paved the way towards better understanding of the role of copper deficiency or copper toxicity in physiological and pathological conditions.
10624340##2000-1-7##Magnetic resonance imaging and proton MR spectroscopy in Wilson's disease.##MRI of the brain and liver using T2 relaxation time measurements and proton spectroscopy (1H-MRS) of the brain was performed in four siblings with Wilson's disease (one with clinical disease and three asymptomatic) as well as age- and sex-matched control subjects. The T2 values of the liver were correlated with liver biopsy results. 1H-MRS of the left and right globus pallidus was obtained. The patient with clinical disease was examined three times, and two of three asymptomatic siblings twice. MR images of the brain were abnormal in all four patients. High signal intensity areas in the posterior thalamus, general atrophy and pontine myelinolysis were present in the patient with clinical manifestations. The T2 measurements of these areas confirmed the results of image analysis. Apart from general brain atrophy, the changes in the patient with clinical disease were largely reversible. The T2 values were significantly different from those of the control subjects only in the globus pallidus. The NAA/Cho, NAA/Cr and Cho/Cr ratios from the 1H-MR spectra of globus pallidus showed no significant difference between patients and control subjects. The mean values of NAA/Cho and NAA/Cr were lower in patients with Wilson's disease than in the control subjects. One of the patients had hepatic steatosis, but the liver T2 values were no different to those of the control subjects. In conclusion, the MRI findings reflect the success of the specific therapy in patients. MRI thus seems to be useful in the follow-up of Wilson's disease.
10460447##1999-8-25##Magnetic resonance proton spectroscopy of the brain in Wilson's disease.##We studied 13 patients with Wilson's disease (WD) using localized magnetic resonance proton spectroscopy to test whether hepatic encephalopathy or impaired energy metabolism contributes to neurological dysfunction. Levels of myoinositol (MI), choline-containing compounds (Cho), creatine (Cr), N-acetyl-aspartate (NAA), Glx (unresolved resonances of glutamate, glutamine, and gamma-aminobutyric acid) and lactate were measured using a relative quantitative approach. Results were compared with those from 12 healthy controls. In one patient with de novo WD and acute hepatic disease but no neurological symptoms we found a marked decrease in the Cho/Cr and MI/Cr ratios. However, proton spectroscopy in the white matter, gray matter, and putamen of patients with treated WD showed no significant differences compared to healthy controls. In none of the subjects studied was the lactate/Cr ratio elevated. The spectroscopic findings were compatible with subclinical hepatic encephalopathy in the one patient with de novo WD and acute hepatic disease, but this does not play a major role in brain dysfunction in patients with treated WD. Additionally, there was no evidence of increased lactate concentration, indicating that cerebral energy metabolism was not grossly impaired.
10448050##1999-8-17##The role of copper in neurodegenerative disease.##Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.
10453201##1999-8-24##Intracellular localization of the Menkes and Wilson's disease proteins and their role in intracellular copper transport.##Copper is a heavy metal ion essential for the activity of a variety of enzymes in the body. In excess, copper is a very toxic ion and therefore efficient regulation of its metabolism is required. This is dramatically illustrated by the genetic disorders X-linked Menkes disease and autosomal recessive Wilson's disease. In 1993, both the Menkes and Wilson's genes were isolated and it was found that these genes encode homologous cation copper transporting P-type ATPase proteins. The Menkes protein (ATP7A) is expressed in most tissues, except liver. In contrast, the Wilson's protein (ATP7B) is abundantly expressed in liver. Intracellular localization of those proteins was investigated. Both ATP7A and ATP7B are localized in the trans-Golgi network and post-Golgi vesicular compartment (PGVC) in the cell. This intracellular localization was altered by the copper content present in the cell. This result may support the hypothesis that ATP7A and ATP7B are involved in cellular copper transport and those proteins could be suitable models for elucidating intracellular copper metabolism.
10453198##1999-8-24##Treatment and management of Wilson's disease.##Wilson's disease is an autosomal recessive disorder related to the copper metabolism. The clinical symptoms are due to copper deposition in various tissues, including liver, brain, kidney, cornea and others. The key strategy of treatment is to reduce the amount of copper in the liver and other tissues by administering both copper-chelating agents and a low copper diet. D-Penicillamine is considered to be the first choice as a copper-chelating agent. Patients require 15-25 mg/kg daily in the early stages of treatment and this drug should also be given more than 2 h before meals. Some undesirable or serious side-effects, such as systemic lupus erythematosus (SLE) and nephrotic syndrome, do occur in 20-25% of all patients. In such cases, trienthylene tetramine (trientine) appears to be as effective as penicillamine. This drug is usually used when D-penicillamine has to be withdrawn. It is also sometimes administered to patients with neurological symptoms as a first-choice drug. It is given in doses of 40-50 mg/kg daily, in the same manner as for D-penicillamine. Zinc salt administration has also emerged as an interesting supportive therapy for both treatments. A dose of 5-7.5 mg/kg daily is given before meals. The copper content of the diet should be less than 1 mg/day in the early stages of treatment. Thereafter, it can be increased to 1.0-1.5 mg/day during well-controlled periods. Liver transplantation is now performed in many countries for patients with either the fulminant or chronic progressive types of Wilson's disease.
10453197##1999-8-24##The Long-Evans Cinnamon rat: an animal model for Wilson's disease.##The Long-Evans Cinnamon (LEC) rat is known to develop hepatitis and liver cancer spontaneously, phenomena attributed to abnormal copper metabolism. This mutant strain of rat shows some clinical features that are similar to those of Wilson's disease, including excessive copper in the liver, reduced excretion of copper into bile, a reduced level of serum copper and a remarkable decrease in serum ceruloplasmin activity. Molecular studies have revealed that the copper transporting P-type ATPase, atp7b, which is the rat gene homologous to human ATP7B, was found to be defective in the LEC rat. These observations have confirmed that the LEC rat is a rodent model for Wilson's disease. In addition, recent studies have suggested that the ATP7B protein is involved in the intracellular transport of hepatic copper. The absence or diminution of ATP7B function results in abnormal copper metabolism in the LEC rat and in patients with Wilson's disease.
10453196##1999-8-24##Molecular analysis and diagnosis in Japanese patients with Wilson's disease.##
10453195##1999-8-24##Mass screening for Wilson's disease: results and recommendations.##Wilson's disease is a treatable inherited disorder of copper metabolism. Established treatments include the use of oral chelating agents and the establishment of a minimum copper diet, although prognosis mainly depends on the extent of liver or nervous system damage present before treatment. Once irreversible damage has occurred, the effect of these treatments is diminished and the patient's quality of life compromised. Therefore, the establishment of a mass screening system able to detect Wilson's disease patients presymptomatically has been discussed. Recently, a monoclonal antibody specific to holoceruloplasmin has been developed. This antibody was used in a nationwide screening trial of 126,810 newborn infants, but no Wilson's disease patients were identified. However, three patients out of 24,165 were diagnosed with Wilson's disease using this specific antibody in a screening performed during the period from late infancy to elementary school. The age of 3 years is thought to be the best point for Wilson's disease mass screening. In this paper, a review of mass screening for Wilson's disease in Japan using a specific monoclonal antibody to holoceruloplasmin is presented.
10453194##1999-8-24##Wilson's disease and Menkes disease.##
10487279##1999-9-16##Living related liver transplantation from heterozygote genetic carriers to children with Wilson's disease.##We reviewed the outcome of children undergoing living related liver transplantation (LRLT) for Wilson's disease (WD), and specifically addressed the potential risk associated with the use of donors who were heterozygous for the Wilson genetic defect. LRLTs were carried out in 11 children with WD, nine of whom presented with fulminant hepatic failure and two with end-stage hepatic insufficiency. The age of the patients ranged from 6 to 16 yr. Eight patients had hepatic encephalopathy and were plasmapheresed preoperatively. The donors (all parents: six fathers and five mothers) were all one-haplotype matched with their respective recipients, and were all therefore heterozygote carriers of the WD genetic defect. The serum ceruloplasmin levels were within normal limits in all donors (mean: 20.0 +/- 2.85 mg/dL). All recipients but one had low serum ceruloplasmin levels with a mean value of 11.6 +/- 7.36 mg/dL before transplantation. The serum ceruloplasmin levels had increased to an average of 21.0 +/- 3.76 mg/dL after LRLT at the latest evaluation, which ranged between 7 and 75 months after transplantation. A marked reduction in urinary copper excretion was observed in all recipients after transplantation. Of eight recipients presenting preoperatively with Kayser-Fleischer (K-F) rings, this abnormality resolved completely after LRLT in five patients and partially in three. All recipients are alive and remain well, and none have developed signs of recurrent WD after a mean follow-up period of 31 months (range 7-75 months). In conclusion, LRLT is an excellent choice for effective treatment of WD, and grafts chosen from heterozygote carriers of the condition do not appear to confer any risk of recurrence in the recipients.
10487274##1999-9-16##This liver is a giver: Wilson disease and living related liver transplantation.##
10536482##1999-10-28##[An infant of autoimmune hepatitis (type I) with cirrhosis].##A 6 year-old boy with autoimmune hepatitis accompanied with cirrhosis was reported. He was admitted to our hospital because of abdominal distention, high fever, and diarrhea. Laboratory examination revealed abnormalities in hepatic function, cholestasis, anemia, thrombocytopenia, hypoalbuminemia, hypocomplementemia, and low concentration of coagulation factors. Abdominal MRI, and asialoglycoprotein receptor-mediated liver scintigraphy strongly indicated liver cirrhosis. Viral hepatitis, Wilson's disease, and antitrypsin deficiency were excluded serologically. Instead, hypergammaglobulinemia, and positive antinuclear antibody suggested autoimmune hepatitis, and the survey of anti-mitochondrial antibody, anti-smooth muscle antibody, and anti-LKM-1 antibody was negative, indicating type I autoimmune hepatitis. Finally, the histology of liver biopsy specimen indicating the destruction of hepatic lobular architecture, dense mononuclear cell infiltrates, and severe fibrosis confirmed the diagnosis. He was treated firstly with methylprednisolone pulses, and then prednisolone p.o. + azathioprine p.o. All of the abnormal laboratory parameters improved to normal levels, indicating that the immunosuppressive therapy will be effective for the severe AIH with cirrhosis.
10425268##1999-7-30##Non-Indian childhood cirrhosis.##Copper is an essential trace element for sustaining life. However, copper in excess is highly toxic and elevated copper concentrations in cells have been associated with several diseases, including non-Indian childhood cirrhosis (NICC) in man and copper toxicosis in Bedlington terriers. NICC and copper toxicosis in Bedlington terriers are phenotypic very similar to Wilson disease and Indian childhood cirrhosis. Recently, the gene underlying Wilson disease (ATP7B) as well as copper transport genes hCTR1, hCTR2 and ATOX1 have been excluded as candidates for NICC in man and copper toxicosis in Bedlington terriers. Currently, a genome wide screen is being carried out to localize the NICC gene. Isolation of the NICC gene and defining its pathophysiology will significantly expand our insight into copper metabolism in man, which, at present, is largely limited. The availability of a dog mutation with phenotypic similarities to NICC will open up new lines of research for studying the disease if it proves to be homologous to NICC but will still represent an important addition to the list of genes determining copper disease in mammals if it doesn t.
10406672##1999-7-16##Detection of a rare Wilson disease mutation associated with arylsulfatase A pseudodeficiency.##We have studied a patient with Wilson disease (WD), belonging to a family segregating late-onset, dominant cerebellar ataxia. Analysis of the WD gene showed that the patient is a compound heterozygote, carrying the 14His1069Gln mutation from the father and the 8Gly710Ser mutation from the mother. The 8Gly710Ser is a mutation described previously only in a Swedish patient. Our patient is also homozygous for arylsulfatase A pseudodeficiency. This genetic defect, which has been reported in association with other neuropsychiatric syndromes, has not been described in WD.
10547896##1999-11-5##Liver transplantation in metabolic disorders.##Liver transplantation in pediatric patients represents about 10% of a total of 23,000 transplantations registered in the European Liver Transplantation Register (ELTR)since 1968. The pediatric patients show a specific spectrum of indications with cholestatic liver disorders ranking first, followed by hepatic based metabolic disorders. There has been a significant improvement of survival in transplantation since the early 80ies. The overall survival standard is nowadays in the range of 80%. There is a trend towards even better results in metabolic disorders. The clinical presentation of liver disease caused by metabolic disorders shows a wide range from acute liver, cerebral, cardiac and renal failure to chronic end stage liver, kidney and heart disease potentially complicated by hepatocellular carcinoma. In many cases, the diagnosis of a underlying metabolic disorder is very difficult and time consuming so the decision to do a liver transplantation may be necessary before a final diagnosis is established. Having these problems in mind, the consideration of absolute and relative contraindications for liver transplantation in metabolic disorders is even more difficult than it is already in cholestatic or inflammatory liver disorders. The individual evaluation of a patient suffering from a hepatic metabolic disorder must consider in addition the often dramatic restriction of quality of life due to rigorous dietary restrictions or other therapies. This makes clear that suitable methods to measure quality of life must be developed and applied in order to fulfill this goal. The extension of indications for liver transplantation even to disorders with only partial defects in otherwise healthy livers was possible by using innovative surgical techniques such as partial, living related, split, in situ split and auxiliary orthotopic transplantation. These techniques allowed to reduce the mortality on pediatric waiting lists significantly without restricting the general donor pool. However, living related liver transplantation is handicaped by the heterozygous status of the parent donor. This plays a role especially in patients with progressive familial intrahepatic cholestasis (PFIC) and Wilson's disease.
10578476##1999-12-1##Circling seizures in a case with Wilson's disease.##We report a case of Wilson's disease with circling seizures. Because of the existence of other types of frontal automatism and the EEG focus on the frontal regions, circling seizures of the patient were thought to originate from the frontal lobe. Magnetic resonance imaging demonstrated large cavitary lesions on bilateral frontal lobes. The mechanisms of circling behavior are discussed in association with Wilson's disease.
10439967##1999-8-10##Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease.##The large size of many disease genes and the multiplicity of mutations complicate the design of an adequate assay for the identification of disease-causing variants. One of the most successful methods for mutation detection is the single strand conformation polymorphism (SSCP) technique. By varying temperature, gel composition, ionic strength and additives, we optimised the sensitivity of SSCP for all 27 exons of the CFTR gene. Using simultaneously SSCP and heteroduplex (HD) analysis, a total of 80 known CF mutations (28 missense, 22 frameshift, 17 nonsense, 13 splicesite) and 20 polymorphisms was analysed resulting in a detection rate of 97.5% including the 24 most common mutations worldwide. The ability of this technique to detect mutations independent of their nature, frequency, and population specificity was confirmed by the identification of five novel mutations (420del9, 1199delG, R560S, A613T, T1299I) in Swiss CF patients, as well as by the detection of 41 different mutations in 198 patients experimentally analysed. We present a three-stage screening strategy allowing analysis of seven exons within 5 hours and analysis of the entire coding region within 1 week, including sequence analysis of the variants. Additionally, our protocol represents a general model for point mutation analysis in other genetic disorders and has already been successfully established for OTC deficiency, collagene deficiency, X-linked myotubular myopathy (XLMTM), Duchenne and Becker muscular dystrophy (DMD, BMD), Wilson disease (WD), Neurofibromatosis I and II, Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsies, and defects in mitochondrial DNA. No other protocol published so far presents standard SSCP/HD conditions for mutation screening in different disease genes.
10405226##1999-7-15##Wilson's disease: copper unfettered.##Wilson's disease is a rare autosomal recessive inherited disorder of copper metabolism. Hepatic excretion of copper is impaired due to mutation of the gene for a copper-transporting adenosine triphosphatase, ATP7B. Copper accumulation in liver, brain, and other tissues may cause a wide spectrum of hepatic, neuropsychiatric, and other clinical manifestations. The diagnosis may be supported by measurement of serum ceruloplasmin, urinary copper excretion, and hepatic copper content as well as by detection of Kayser-Fleischer rings. Several treatments are available to increase urinary excretion and decrease intestinal absorption of copper.
10424295##1999-7-29##Development of cytochrome P450 2D6-specific LKM-autoantibodies following liver transplantation for Wilson's disease -- possible association with a steroid-resistant transplant rejection episode.##
10440022##1999-8-10##Schizophrenia-like symptoms in the Westphal-Strümpell form of Wilson's disease.##
10395584##1999-7-8##A delicate balance: homeostatic control of copper uptake and distribution.##The cellular uptake and intracellular distribution of the essential but highly toxic nutrient, copper, is a precisely orchestrated process. Copper homeostasis is coordinated by several proteins to ensure that it is delivered to specific subcellular compartments and copper-requiring proteins without releasing free copper ions that will cause damage to cellular components. Genetic studies in prokaryotic organisms and yeast have identified membrane-associated proteins that mediate the uptake or export of copper from cells. Within cells, small cytosolic proteins, called copper chaperones, have been identified that bind copper ions and deliver them to specific compartments and copper-requiring proteins. The identification of mammalian homologues of these proteins reveal a remarkable structural and functional conservation of copper metabolism between bacteria, yeast and humans. Furthermore, studies on the function and localization of the products of the Menkes and Wilson's disease genes, which are defective in patients afflicted with these diseases, have provided valuable insight into the mechanisms of copper balance and their role in maintaining appropriate copper distribution in mammals.
10373684##1999-6-22##Metal ion transporters in mammals: structure, function and pathological implications.##Despite the importance of metal ions in several catalytic functions, there has been, until recently, little molecular information available on the mechanisms whereby metal ions are actively taken up by mammalian cells. The classical concept for iron uptake into mammalian cells has been the endocytosis of transferrin-bound Fe3+ by the transferrin receptor. Studies with hypotransferrinaemic mice revealed that in the intestine mucosal transferrin is derived from the plasma and that its presence is not required in the intestinal lumen for dietary iron absorption. This suggests that, at least in the intestine, other non-receptor-mediated uptake systems exist. The molecular identification of metal ion transporters is of great importance, in particular since an increasing number of human diseases are thought to be related to disturbances in metal ion homeostasis, including metal ion overload and deficiency disorders (i.e. anaemia, haemochromatosis, Menkes disease, Wilson's disease), and neurodegenerative diseases (i.e. Alzheimer's, Friedreich's ataxia and Parkinson's diseases). Furthermore, susceptibilities to mycobacterial infections are caused by metal ion transporter defects. The pathological implications of disturbed metal ion homeostasis confirm the vital roles these metal ions play in the catalytic function of many enzymes, in gene regulation (zinc-finger proteins), and in free radical homeostasis. Recent insights have significantly advanced our knowledge of how metal ions are taken up or released by mammalian cells. The purpose of this review is to summarize these advances and to give an overview on the growing number of mammalian metal ion transporters.
10435491##1999-8-6##Penicillamine as a controversial treatment for Wilson's disease.##
10435490##1999-8-6##Penicillamine should not be used as initial therapy in Wilson's disease.##
10435489##1999-8-6##Penicillamine: the treatment of first choice for patients with Wilson's disease.##
10474204##1999-9-4##Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper.##Tetrathiomolybdate (TTM) can be used as a specific chelator to remove copper (Cu) accumulating in the form bound to metallothionein (MT) in the livers of Wilson disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats). However, an adverse effect, hepatotoxicity, was observed occasionally on its clinical application. The mechanism underlying the adverse effect of TTM has been studied in comparison with dithiomolybdate (DTM), and a safer and more effective therapy by TTM was proposed based on the mechanism. The activity of glutamic-pyruvic transaminase (GPT) in serum was shown to increase significantly on the treatment of Wistar rats with sulfide produced through hydrolytic degradation of TTM and DTM, the latter being more easily degraded. The hydrolytic degradation of TTM was enhanced under acidic conditions. Cu in Cu-containing enzymes such as Cu,Zn-superoxide dismutase (SOD) in liver and ceruloplasmin (Cp) in plasma was decreased by excessive thiomolybdates, the Cu being found in the plasma in the form of a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in SOD and Cp were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Although both TTM and DTM remove Cu from MT, DTM is not appropriate as a therapeutic agent for Wilson disease due to its easy hydrolysis and production of sulfide.
10383876##1999-6-29##Chronic poisoning by copper in tap water: II. Copper intoxications with predominantly systemic symptoms.##Copper can induce acute and chronic intoxications in humans. Copper in tap water has caused a series of severe systemic diseases in Germany in recent years (chronic copper poisoning, CCuP). From the clinical point of view it has been difficult to establish the diagnosis on the basis of clinical and laboratory methods. In a retrospective study, we therefore looked for essential clinical signs as well as laboratory findings which might be typical and essential for the diagnosis of CCuP. - We observed that in patients with severe systemic CCuP not only the liver but also several other organs have been the target of copper. As a proof copper overload has been measured. The latter results are presented here. - During or shortly after exposure "free" serum copper (= non-ceruloplasmin-bound copper) was significantly elevated in all patients (range 5.1 to 47.1 micromol/l, or 25.7 to 56.2 % of total serum copper). The normal upper limits in infants according to Salmenperä (8) are: 0.3 micromol/l, or 1.6 % of total serum copper. - Total serum copper was elevated in 14/16 patients: 13.7 to 30.1 micromol/l in sick infants (normal upper level: 12.6 micromol/l), and 17.0 to 27.2 in sick children (normal upper level for children and adults: 21.4 micromol/l). - Urine copper excretion was found elevated in 9/10 patients, with a range of 11 to 456 microg/dl (normal upper level in adults: 15 microg/dl). - Our results show that patients with systemic CCuP are in a "hypercupric" state. The data thus firstly prove that indeed the putative agent copper is found in excess in the patients and secondly show that the estimation of "free" copper in serum and the measurement of copper in urine are reliable diagnostic methods. Elevation of total serum copper (even though not specific) can give a first hint to the diagnosis. - The hypercupric state of systemic CCuP can be differentiated from that of Wilson's disease by (1) normal levels of ceruloplasmin and (2) the observation that values for free copper in serum or urinary copper normalize in an environment without copper in tap water, for instance in a hospital.
10383883##1999-6-29##Treatment of copper associated liver disease in childhood.##
10450606##1999-8-18##1H NMR studies of the reactions of copper(I) and copper(II) with D-penicillamine and glutathione.##Reactions of copper ions with D-penicillamine (PSH) have been monitored by 1H NMR spectroscopy in the presence and absence of glutathione (GSH) under aerobic as well as anaerobic conditions. In D2O solution at pD = 7.4, PSH coordinates to Cu+ to form PS(-)-Cu+ under argon atmosphere as revealed from the broadening of each signal. In the presence of dioxygen, the complex was converted to the well-characterized purple cluster species consisting of Cu+, Cu2+, and PS2-. Addition of GSH into this solution quickly decomposed the cluster by the reduction of Cu2+ to Cu+. The cluster species was, however, reproduced after several hours because of the oxidation of Cu+ back to Cu2+. The solution containing both PSH and GSH formed three possible disulfides, PSSP, GSSG, and PSSG, under aerobic conditions. Addition of Cu+ to this solution again produced the purple cluster through several redox reactions. On the basis of these results, it was concluded that the co-existence of PSH and/or PSSP with Cu+ and/or Cu2+ leads to the formation of the stable cluster species regardless of the presence or absence of the other thiols such as GSH. This must be one of the reasons why PSH works in living cells as an effective drug for the Wilson disease.
10414435##1999-7-22##Cu2+ induces Ca2+-dependent neurotransmitter release from brain catecholaminergic nerve terminals.##CuCl2, ZnCl2 and NiCl2, but not CdCl2 or CoCl2, induced transmitter release from superfused rat hippocampal and striatal synaptosomes preloaded with, respectively, [3H]noradrenaline and [3H]dopamine. Cu2+ was the most potent and effective, acting in a concentration- (0.1-300 microM) and time-dependent (peak effect occurring at 2-3 min) manner. The amount of Cu2+-induced release over a 5 min period is similar to that induced by depolarization with high KCl or the K+ channel blocker 4-aminopyridine. However, the time course of the Cu2+-induced release is slower and the effect of Cu2+ is not reversed by washout. Cu2+-induced catecholamine release requires extracellular calcium (Ca2+) and is inhibited by the Ca2+ channel blocker Cd2+, and in the case of noradrenaline, by the voltage-gated Na+ channel blocker tetrodotoxin. The ability of Cu2+ to induce massive Ca2+-dependent transmitter release from brain catecholaminergic nerve terminals may contribute to the neuropathological processes associated with Cu2+ toxicity in Wilson's disease.
10357793##1999-6-5##Hepatic hyperplasia and cancer in rats: alterations in copper metabolism.##We previously demonstrated that rats exposed to the peroxisome proliferator (PP) diethylhexylphthalate (DEHP) had reduced serum ceruloplasmin (CP) oxidase activity, which suggests tissue copper deposition. Copper is highly toxic in excess, and results in cellular damage and hepatocellular carcinomas (HCC). This study addresses changes in expression of copper-related genes and metal accumulation in hyperplastic liver and tumors induced by PP. Male rats were fed diets containing DEHP or clofibrate (CLF) for 3-60 days (hyperplasia) and 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-beta-hydroxyethyl) acetamide for 10 months (HCC). During hyperplasia, an immediate and progressive decrease in serum CP activity was observed (P < 0.05), as were reductions in mRNA levels for both CP and Wilson's disease gene (WD gene, a P-type ATPase) (P < 0.05). Tumor-bearing rats had lower serum CP activity (P < 0.05), and CP and WD gene mRNA levels were reduced in tumors (P < 0.05), and in liver surrounding tumors (SL) (P < 0.05). Metallothionein mRNA showed no consistent changes during hyperplasia. Tumors showed a 2.5-fold induction of metallothionein mRNA (P < 0.05), and a 1.2-fold increase in SL. Temporal increases in liver copper content occurred during hyperplasia, with increases of 2-fold (DEHP) and 3.3-fold (CLF) at 60 days (P < 0.05). Copper content was 2.2-fold higher in tumors (P < 0.05) and 1.7-fold higher in SL; iron did not increase and zinc decreased temporally. Thus, copper accumulation and changes in copper-related gene expression may be contributing factors in liver neoplasia in PP-treated rats. Loss of CP results in decreased free radical scavenger capacity and thus may enhance oxidative damage induced by PPs.
10568054##1999-11-24##[Pregnancy, labor and early puerperium in a patient with Wilson's disease].##Pregnancy should have a successful outcome in a patient with treated Wilson's disease if complications are excluded before conception. Chelating treatment must be maintained, although there is some concern about its teratogenicity. We describe the course of pregnancy in a patient with Wilson's disease treated with D-penicillamine and zinc sulfate.
10470603##1999-9-2##Wilson's disease.##Wilson's disease is an autosomal recessive inherited disorder of copper metabolism resulting in pathological accumulation of copper in many organs and tissues. The Wilson disease gene is localized on human chromosome 13 and codes for a copper transporting P-type ATPase, -ATP7B. About one hundred mutations occurring throughout the whole gene have been documented so far. The most common is the His1069Gln point mutation. Wilson's disease may present under a variety of clinical conditions, the most common being liver disease (ranging from acute hepatitis, fulminant hepatic failure, chronic hepatitis, and cirrhosis), haemolytic anaemia, and neuropsychiatric disturbances. The diagnosis of Wilson's disease is usually made on the basis of clinical findings (Kayser-Fleischer rings, typical neurologic symptoms) and laboratory abnormalities (low serum caeruloplasmin, increased hepatic copper content). Molecular genetic testing is now the standard for testing asymptomatic siblings. Diagnosis in patients presenting with liver diseases is difficult and requires a combination of various laboratory parameters. Lifelong treatment with chelating agents (d-penicillamine, trientine) or with zinc is usually sufficient to stabilize the patient and to achieve clinical remission in most. Patients with advanced liver disease benefit from orthotopic liver transplantation.
10999174##2000-9-22##Generalized myasthenia gravis following use of D-pencillamine in Wilson's disease.##
11715435##2001-11-22##[Another hot point mutation of Wilson disease gene in Chinese: exon 12].##
10334941##1999-5-21##Cloning and characterization of the promoter region of the Wilson disease gene.##Wilson disease (WD), an autosomal recessive disorder of copper transport, is marked by impaired biliary excretion and incorporation of copper into ceruloplasmin. Molecular mechanism regulating the expression of the WD gene was studied. We isolated, sequenced, and characterized approximately 1.3 kb of the 5'-flanking region of the WD gene from the human genomic library. The approximately 1.3 kb of the WD sequence directed high level of luciferase activity in HepG2 cells. Interestingly, the 5'-flanking region contained four metal response elements (MREs) and six MRE-like sequences (MLSs), usually found in the metallothionein genes. It also contained a number of putative regulatory elements such as Sp1, AP-1, AP-2, and E-box, but lacked TATA box. The transcription start site was located at 335 base pairs upstream of the translation initiation site. Successive 5'-deletion analyses suggested that the 159-base pair region from -811 to -653, which includes MLS2 (-802 to -796) and MLS3 (-785 to -779), contained one or more positive regulatory element(s). A negative element was also identified at region -1038 to -812. A protein-MLS complex was identified through electrophoretic mobility shift and competition assay using MLS2/MLS3 and HepG2 cell nuclear proteins.
10360583##1999-6-9##Auxiliary partial orthotopic living donor liver transplantation as an aid for small-for-size grafts in larger recipients.##
10331711##1999-5-20##Oculogyric crisis as an initial manifestation of Wilson's disease.##
17023946##2006-10-7##Inherited metabolic disease.##Our understanding of the pathophysiology and of new treatments for inherited metabolic diseases that affect the liver continues to grow through the study of gene mutations and their functional effect on the proteins they encode. For genetic hemochromatosis and Wilson's disease, studies focused on the function of their respective gene products provide new insights into metal metabolism. For Crigler-Najjar syndrome, an inherited disorder that results in failure of proper bilirubin glucuronidation, the once futuristic idea of treatment by transplantation of donor hepatocytes has now proven successful in a human recipient. With continued study and experimentation, our diagnostic and therapeutic capabilities will continue to expand for these and other inherited metabolic disorders. Although this increase in new information has sparked numerous reviews of these subjects, the following are highlights from the past year that include information relative to disease diagnosis and treatment, as well as new insights into pathogenesis.
10235618##1999-5-11##Fulminant Wilsonian hepatitis unmasked by disease progression: report of a case and review of the literature.##Among various hepatic manifestations of Wilson's disease, fulminant hepatic failure is the most uncommon entity and requires a detailed clinicopathological analysis for correct diagnosis. Left unrecognized and without proper therapy, in time the disease rapidly progresses to death. We describe a 24-year-old woman who died within five weeks of the onset of Wilson's disease, which presented with a dramatic course. Discriminating features of the disease are discussed with regard to the literature.
10407761##1999-7-17##[Hemochromatosis and Wilson disease].##
10226105##1999-5-5##Living related liver transplantation for acute liver failure in children.##The mortality rate among children with acute liver failure (ALF) on the waiting list for liver transplantation is high. We present our experience with living related donor liver transplantation (LRD-LT) in children who required urgent transplantation for ALF. Between December 1995 and July 1997, 6 children underwent LRD-LT for ALF. Cause of liver failure, recipient and donor demographics, clinical and laboratory data, surgical details, complications, and 6-month and 2-year graft and patient survival were recorded. Five boys and 1 girl received left lateral segment grafts from their parents. The mean age was 4 +/- 2.8 years (range, 1 to 9 years). ALF was caused by Wilson's disease in 1 patient and sickle cell intrahepatic cholestasis syndrome in 1 patient; in 4 patients, the cause was unknown. All patients had mental status changes; 2 were on life support. Mean pretransplantation liver function test values were: alanine aminotransferase, 972 +/- 565 U/L (normal, 1 to 53 U/L), total bilirubin, 31.3 +/- 12.4 mg/dL (normal, 0.1 to 1.2 mg/dL), prothrombin time, 34.3 +/- 12.4 seconds (normal, 10.8 to 13.3 seconds), international normalized ratio, 8.46 +/- 5.4 (normal < 2), and fibrinogen, 109 +/- 23.9 mg/dL (normal, 175 to 400 mg/dL). The donors were 5 mothers and 1 father. The mean donor age was 32.5 +/- 7.6 years (range, 19 to 40 years). No donor required blood transfusion, and no donor had any early or late postoperative complications. The donors' mean hospital length of stay was 5 days. In five cases, grafts were blood group-compatible; 1 child received a blood group-incompatible graft. All grafts functioned immediately. No patient had hepatic artery or portal vein thrombosis or biliary complications. The child who received a mismatched graft died of infection of the brain caused by Aspergillus spp at 22 days posttransplantation with a functioning graft. The child with ALF caused by sickle cell intrahepatic cholestasis syndrome developed outflow obstruction 3 months posttransplantation and required retransplantation; he eventually died of vascular complications related to his primary disease. Four children are alive at a mean follow-up of 27 months (range, 14 to 36 months). LRD-LT for children with ALF facilitates timely transplantation without drawing on cadaveric donor resources. The established safety record of LRD-LT made this option appealing to both physicians and parental donors.
10361977##1999-6-11##The effect of subcutaneous tetrathiomolybdate administration on copper and iron metabolism, including their regional redistribution in the brain, in the Long-Evans Cinnamon rat, a bona fide animal model for Wilson's disease.##The present work was performed to examine the effect of tetrathiomolybdate on Cu and Fe metabolism, especially redistribution of Cu and Fe in the brains of Long-Evans Cinnamon rats, with inherently abnormal Cu deposition in the liver. The drug was injected subcutaneously at 5 mg/kg of body weight twice a week for 65 days (total dose of 20 mg) into 40-day-old Long-Evans Cinnamon rats. In Long-Evans Cinnamon rats treated with tetrathiomolybdate, the hepatic Cu concentration was 60 microg/g wet weight, compared to 170 microg/g in untreated rats. In seven brain regions (cerebellum, medulla oblongata, hypothalamus, striatum, midbrain, hippocampus and cortex) of the Long-Evans Cinnamon rats treated with tetrathiomolybdate. the Cu concentration (1.5 to 2.3 microg/g) was slightly lower (1.6 to 2.7 microg/g) than in untreated rats. A significant difference between the two groups was found only in the midbrain. Brain Fe concentrations in regions other than the striatum were not changed significantly by the tetrathiomolybdate injections. The hepatic Fe concentration was about 120 microg/g in Long-Evans Cinnamon rats without tetrathiomolybdate. Tetrathiomolybdate injection further increased the concentration to about 250 microg/g. Our results indicated that subcutaneous tetrathiomolybdate injection did not have an effect that stimulated redistribution of Cu and Fe in the seven brain regions examined, although hepatic Cu was markedly decreased and the removed Cu was deposited in kidneys, spleen and testes. The increased hepatic Fe level should be taken into account when considering side effects of the compound.
10319818##1999-5-13##RESPONSIVE-TO-ANTAGONIST1, a Menkes/Wilson disease-related copper transporter, is required for ethylene signaling in Arabidopsis.##Ethylene is an important regulator of plant growth. We identified an Arabidopsis mutant, responsive-to-antagonist1 (ran1), that shows ethylene phenotypes in response to treatment with trans-cyclooctene, a potent receptor antagonist. Genetic epistasis studies revealed an early requirement for RAN1 in the ethylene pathway. RAN1 was cloned and found to encode a protein with similarity to copper-transporting P-type ATPases, including the human Menkes/Wilson proteins and yeast Ccc2p. Expression of RAN1 complemented the defects of a ccc2delta mutant, demonstrating its function as a copper transporter. Transgenic CaMV 35S::RAN1 plants showed constitutive expression of ethylene responses, due to cosuppression of RAN1. These results provide an in planta demonstration that ethylene signaling requires copper and reveal that RAN1 acts by delivering copper to create functional hormone receptors.
10212214##1999-4-23##Role of the copper-binding domain in the copper transport function of ATP7B, the P-type ATPase defective in Wilson disease.##We have analyzed the functional effect of site-directed mutations and deletions in the copper-binding domain of ATP7B (the copper transporting P-type ATPase defective in Wilson disease) using a yeast complementation assay. We have shown that the sixth copper-binding motif alone is sufficient, but not essential, for normal ATP7B function. The N-terminal two or three copper-binding motifs alone are not sufficient for ATP7B function. The first two or three N-terminal motifs of the copper-binding domain are not equivalent to, and cannot replace, the C-terminal motifs when placed in the same sequence position with respect to the transmembrane channel. From our data, we propose that the copper-binding motifs closest to the channel are required for the copper-transport function of ATP7B. We propose that cooperative copper binding to the copper-binding domain of ATP7B is not critical for copper transport function, but that cooperative copper binding involving the N-terminal two or three copper-binding motifs may be involved in initiating copper-dependent intracellular trafficking. Our data also suggest a functional difference between the copper-binding domains of ATP7A and ATP7B.
10336172##1999-5-21##Immunohistochemical determination of the Wilson Copper-transporting P-type ATPase in the brain tissues of the rat.##Immunohistochemical localization of Copper-transporting P-type ATPase (ATP7B), a gene product responsible for Wilson disease, was visualized in the brain tissues of the Long-Evans agouti rat in detail using tissue-blotting technique and confocal laser microscopy. The ATP7B was intensely detected in neuronal cells of the hippocampal formation, olfactory bulbs, cerebellum, cerebral cortex and nuclei in the brainstem in which high amounts of copper and cuproenzymes, dopamine beta hydroxylase and Cu,Zn-superoxide dismutase (Cu,Zn-SOD) were detected. The present results suggest that ATP7B plays key roles in neurotransmissions of catecholamine pathway and preventing brain tissues from injury by superoxide radicals to regulate the cellular Cu concentration and/or activities of cuproenzymes related to neurotransmissions and a free radical metabolism. Furthermore, it is reasonable to assume that neurotoxicity due to abnormal copper accumulation or irregular regulation of cuproenzymes in the critical brain regions by mutation of the ATP7B gene leads to neurological failures of Wilson disease.
10341753##1999-5-26##[Wilson's disease. The making of a diagnosis by conventional and molecular biology methods].##
10327155##1999-5-18##Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice.##We previously reported that the common toxic gain-of-function in various mutant copper-zinc superoxide dismutases (SOD1) seen in patients with familial amyotrophic lateral sclerosis (ALS) was an abnormal copper release from the enzyme protein. In this study, trientine and ascorbate, known to have a beneficial effect in an animal model of Wilson disease, were administered to transgenic mice overexpressing a mutated human SOD1 (G93A). The onset of neurological signs in the treated group was significantly delayed compared with that in the control group, and the time to reach total paralysis in the treated group was delayed as well. Since the agents used in this study cause low toxicity in animals and humans, this treatment may be a good candidate for clinical application.
10200362##1999-4-14##[Missense mutations of exons 14 and 18 of Wilson's disease gene in Chinese patients]##OBJECTIVE: To investigate the characteristics of mutations of exons 14 and 18 of Wilson's disease (WD) gene in Chinese patients. METHODS: The subjects of study included 60 unrelated normal controls and 44 unrelated WD patients. Genomic DNA was prepared from peripheral blood leukocytes by a salt-out method. Mutations of exons 14 and 18 in these subjects were screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and further confirmed by sequencing. RESULTS: One patient was homozygous for Arg1041Pro mutation of exon 14 and another patient was heterozygous for Asn1270Ser mutation of exon 18. CONCLUSION: The mutations of exons 14 and 18 of WD gene in Chinese patients were confirmed by sequencing for the first time in China. Arg1041Pro was identified as a novel missense mutation. In addition, an Asn1270Ser, previously described mutation, was detected in this study. But exons 14 and 18 are not the hot point mutations of WD gene in Chinese patients.
10200361##1999-4-14##[Study on mutation of exon 8 of Wilson's disease gene]##OBJECTIVE: To analyze the frequency of mutation in exon 8 of Wilson's disease (WD) gene in Chinese people. METHODS: Screening for ATP7B gene mutation was conducted in 45 WD patients£® Mobility shift of exon 8 was analyzed by SSCP. Nucleotide sequence of exon 8 was analyzed, and the PCR products were cut by enzyme Msp I. The authors found G2273T mutation at codon 778, and according to this mutation sequence, made an analysis of enzyme cut by Msp I in all patients. 2 WD families were analyzed. RESULTS: No abnormality was found in 20 controls. In 45 patients, 2 were homozygous (4.4%) and 11 heterozygous (12.2%). The positive rate of mutation was 16.67%. The Arg778Leu mutation was validated by this study. CONCLUSION: The mutation in exon 8 of WD gene may play an important role in pathogenesis of Wilson's disease in Chinese.
10217409##1999-4-27##Biliary excretion of copper in LEC rat after introduction of copper transporting P-type ATPase, ATP7B.##Wilson's disease, an autosomal recessive disorder, is characterized by the excessive accumulation of hepatic copper that results from reduced biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. The ATP7B gene, responsible for the disease, encodes a copper transporting P-type ATPase. We previously demonstrated the involvement of ATP7B in hepatic copper secretion into plasma after the introduction of ATP7B into the Long-Evans Cinnamon (LEC) rat, a rodent model of Wilson's disease. In this study we found the increased copper contents of the hepatic lysosomal fractions and bile in the LEC rats after ATP7B introduction, indicating the participation of ATP7B in the biliary excretory pathway for copper.
10717692##2000-3-16##Need for liver transplantation in Indian children.##
11045182##2000-10-25##[Serum levels of zinc, copper and selenium in patients with Wilson's disease treated with zinc].##Zinc administered on a long-term basis in excess to patients with Wilson a disease blocks in a significant way copper absorption from the gut, prevents its accumulation and toxic action in the organism. The authors investigated the effect of its long-term administration on the plasma concentration of copper, zinc, and selenium, on the superoxide dismutase activity in red blood cells and glutathione peroxidase activity in whole blood. In seven patients with Wilson a disease treated with zinc sulphate, 136 mg of elemental zinc for 1.5 years (18 months), the authors assessed the plasma concentration of zinc, copper, selenium and ceruloplasmin, the activity of superoxide dismutase in red blood cells, the activity of glutathione peroxidase in whole blood and the urinary excretion of zinc and copper in 24 hours. Envisaged findings with regard to the diagnosis of the investigated patients and their treatment: elevated plasma zinc concentration and increased urinary excretion, reduced copper and ceruloplasmin plasma concentration and increased urinary copper excretion. The authors recorded also a significantly elevated selenium plasma concentration and a significantly higher concentration of superoxide dismutase in red blood cells (p < 0.05). The increase of the glutathione peroxidase activity in whole blood in the investigated patients was not significant (p < 0.05). Changes in the values of the investigated parameters in patients with Wilson s disease treated on a long-term basis with zinc indicate the possible mutual interaction of zinc with other trace elements with an impact on the activity of the corresponding metalloenzymes, i.e. in the sphere in antioxidant systems.
10378366##1999-6-23##[Therapy of Wilson disease].##Wilson disease is a copper storage disease with autosomal-recessive trait that is predominantly a disorder of the adolescent and young adult. Clinical manifestations are dominated by hepatic and/or neurological symptoms. Diagnostic procedures include determination of total serum copper, free serum copper and serum ceruloplamin concentrations as well as urinary copper excretion. Confirmation of diagnosis may be achieved by liver biopsy and histological determination of copper content. The aim of treatment is reduction of tissue copper concentration and detoxification of copper. Drugs applied are the chelating agents. D-penicillamine and trientine, or zinc. The chelating agents induce renal and biliary copper excretion and increased synthesis of metallothionein, which attaches and detoxifies intracellular copper, leading to impaired absorption and binding of excess intracellular copper. Treatment with zinc results in induction of hepatic and intestinal metallothionein synthesis. Regular examinations of the parameters of copper metabolism are necessary in order to control the therapeutic effect. Free copper serum concentrations and urinary copper excretion should reach values below 10 micrograms/dl and 80 micrograms/day, respectively. A significant improvement of clinical symptoms and normalization of parameters of copper metabolism can be expected earliest six months after onset of therapy. Anti-copper treatment may be accompanied by copper-reduced diet. Lifelong therapy is required and provides life-expectancy near to normal. Interruption of treatment leads to reaccumulation of copper, often resulting in fulminant hepatic failure. This can also be observed as initial presentation in 5% of cases (predominant age 12 to 25 years). End stage liver disease and fulminant hepatic failure are indications for liver transplantation by which the genetic defect is phenotypically cured. Here decoppering treatment is no longer required. Whether severe neurological disorders may also be improved is not clear until today.
10194254##2000-4-29##[Missense mutations of exons 14 and 18 of Wilson's disease gene in Chinese patients].##
10194253##2000-4-29##[Study on mutation of exon 8 of Wilson's disease gene].##
10064850##1999-3-5##Etheno DNA-base adducts from endogenous reactive species.##Promutagenic etheno (epsilon) adducts in DNA are generated through reactions of DNA bases with LPO products derived from endogenous sources or from exposure to several xenobiotics. The availability of sensitive methods has made it possible to detect three epsilon-adducts in vivo, namely epsilon dA, epsilon dC and N2,3-epsilon dG. One probable endogenous source for the formation of these adducts arises from LPO products such as trans-4-hydroxy-2-nonenal (HNE), resulting in highly variable background epsilon-adduct levels in tissues from unexposed humans and rodents. The range of background levels of epsilon dAx10-8dA detected inhuman tissues was <0.05 to 25 and in rodent tissues 0.02 to 10; the corresponding values for epsilon dCx10-8dC were 0.01 to 11 and 0.03 to 24, respectively. Part of this variability may be associated with different dietary intake of antioxidants and/or omega-6 PUFAs which oxidize readily to form 4-hydroxyalkenals, as epsilon dA and epsilon dC levels in WBC-DNA of female volunteers on a high omega-6 PUFA diet were drastically elevated. Increased levels of etheno adducts were also found in the liver of cancer-prone patients suffering from hereditary metal storage diseases, i.e., Wilson's disease (WD) and primary hemochromatosis (PH) as well as in Long-Evans Cinnamon rats, an animal model for WD. Increased metal-induced oxidative stress and LPO-derive epsilon-adducts, along with other oxidative damage, may trigger this hereditary liver cancer. Epsilon-Adducts could hence be explored as biomarkers (i) to ascertain the role of LPO mediated DNA damage in human cancers associated with oxidative stress imposed by certain lifestyle patterns, chronic infections and inflammations, and (ii) to verify the reduction of these epsilon-adducts by cancer chemopreventive agents. This article summarizes recent results on the formation, occurrence and possible role of epsilon-DNA adducts in carcinogenesis and mutagenesis.
10321258##1999-5-13##[Management of asymptomatic elevated serum aminotransferase levels, particularly in nonalcoholic steatohepatitis].##At routine determination of serum activities of transaminases (aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) increased levels are frequently found. An algorithm may be used in the analysis of elevated transaminase levels: after elimination of the most frequent causes of hepatitis (alcoholic hepatitis, chronic hepatitis B and C) and some rare conditions (autoimmune hepatitis, alpha 1-antitrypsin deficiency, haemochromatosis and Wilson's disease), the diagnosis will often be nonalcoholic steatohepatitis. Although nonalcoholic steatohepatitis is considered a stable disease, recent literature shows a progression to cirrhosis in 8-17%. So far, no effective therapeutic strategies are available for nonalcoholic steatohepatitis.
10070040##1999-3-10##Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver.##Wilson's disease is an inherited disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration. In this current study, a polyclonal antiserum specific for the Wilson's disease ATPase was used to examine the hepatic expression of this protein. Immunoblot analysis of lysates from human and rat liver detected a single 165-kDa protein, which by immunofluorescence was present only in hepatocytes and localized predominantly to the trans-Golgi network and exclusively in this compartment under low hepatic copper concentrations. Although hepatic copper concentration had no effect on the steady-state levels of the Wilson's disease protein, copper administration in vivo resulted in redistribution of this protein to a cytoplasmic vesicular compartment localized toward the hepatocyte canalicular membrane. The relative abundance of the Wilson's disease protein in the liver was found to be greatest in the fetus before the onset of biliary copper excretion. Taken together, these studies reveal a novel posttranslational mechanism of copper homeostasis in vivo consistent with the proposed function of the Wilson's disease protein in holoceruloplasmin biosynthesis and biliary copper excretion and of relevance to the broad clinical heterogeneity observed in this disease.
10192421##1999-4-7##Heinz body haemolytic anaemia in Wilson's disease.##
9949209##1999-2-9##Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16.##Abnormal hepatic copper accumulation is recognized as an inherited disorder in man, mouse, rat and dog. The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene, causing Wilson disease (WD). Mutations in the ATP7B genes have also been demonstrated in mouse and rat. The ATP7B gene has been excluded in the much rarer human copper overload disease non-Indian childhood cirrhosis, indicating genetic heterogeneity. By investigating the common autosomal recessive copper toxicosis (CT) in Bedlington terriers, we have identified a new locus involved in progressive liver disease. We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co-localization of ATP7B and C04107, using fluorescence in situ hybridization (FISH). C04107 is an anonymous microsatellite marker closely linked to CT. However, BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respectively, demonstrating that WD cannot be homologous to CT. The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22. 2-22.5. A transcribed sequence identified from the C04107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p13-p16, a region devoid of any positional candidate genes.
10457341##1999-8-24##Distal splenorenal shunts for the treatment of severe thrombocytopenia from portal hypertension in children.##Profound thrombocytopenia resulting from portal hypertension may exacerbate gastrointestinal bleeding, precipitate spontaneous bleeding, preclude surgical intervention for associated disorders, and severely limit life-style because of the danger of splenic injury. Although splenectomy can reverse the thrombocytopenia, the procedure should be avoided in children. We reviewed our experience with distal splenorenal shunting (DSRS) in children, particularly when performed for the sole purpose of reversing severe thrombocytopenia resulting from portal hypertension. DSRS was performed in 11 children between the ages of 7 and 15 years: five for severe thrombocytopenia (group 1), four for advanced hypersplenism and congenital hepatic fibrosis prior to renal transplantation (group 2), and two for esophageal bleeding (group 3). One child in group 1 with severe heart disease and Child's class C cirrhosis due to hepatitis C died of progressive cardiac failure and was excluded from further analysis. Of the eight remaining patients in groups 1 and 2, four children had congenital hepatic fibrosis, two had portal vein thrombosis, one had hepatitis B, and one had Wilson's disease. After DSRS, the mean platelet count increased from 37,000 +/- 18,000 to 137,600 +/- 81,000 (P = 0.01). The platelet count improved significantly in all seven children with presinusoidal portal hypertension or stable cirrhosis but did not increase in the child with hepatitis B and Child's class B cirrhosis. The white blood cell count increased from an average of 3.3 +/- 1.1 to 5.4 +/- 2.6 (P= 0.02). There were no postoperative complications in this group. The improved platelet count allowed the four children with congenital hepatic fibrosis and renal failure to undergo renal transplantation with full posttransplant immunosuppression including azathioprine. Postoperative Doppler ultrasound examination demonstrated shunt patency at 6 months in all cases. Spleen size decreased appreciably in all children in groups 1 and 2. All children were able to resume full activity including contact sports. In summary, DSRS effectively controls profound thrombocytopenia resulting from presinusoidal portal hypertension or stable cirrhosis without sacrificing the spleen and should be the treatment of choice for this condition.
10344628##1999-5-27##The presence of an Na+/spermine antiporter in the rat renal brush-border membrane.##This study was aimed at determining the driving force for spermine transport in rat renal proximal tubular brush-border membrane. The uptake of spermine and trientine, a spermine-like drug used for treating Wilson's disease, into rat renal brush-border membrane vesicles was significantly stimulated by an outwardly directed Na+ gradient. The Na+-dependent uptake was temperature dependent and saturable. A kinetic analysis of the initial uptake of spermine with an Na+ gradient gave a Km value of 1.44 microM and a Vmax value of 6.31 pmol (mg protein)(-1)/30s. The Na+ dependent uptake of [3H]spermine was inhibited by spermine, trientine and tetraethylene-pentamine. Substrates of the H+/organic cation transporter (cimetidine and tetraethyl-ammonium), physiological polyamines (putrescine and spermidine) with 2 or 3 amino groups and aminoglycosides (amikacin and tobramicin) with 4 or 5 cationic amines did not affect the uptake of spermine in the presence of an outwardly directed Na+ gradient. These results suggest that the renal tubular secretion of spermine is mediated by an Na+/spermine antiport system which is specific for a straight-chain polyamine compound with more than 4 amino groups.
10433383##1999-8-5##Mechanism of hepatorenal syndrome in rats of Long-Evans Cinnamon strain, an animal model of fulminant Wilson's disease.##Rats of Long-Evans Cinnamon (LEC) strain were used as a hepatorenal syndrome model of fulminant Wilson's disease. Copper levels in the kidneys increased markedly from 16 to 126 microg Cu/g from 12 to 16 weeks, and remained at the same level at 16 and 19 weeks when the rats suffered from severe renal dysfunction and also at 20 weeks in some other normal rats. The above findings imply that the renal dysfunction may have been induced independently of the copper level in the kidneys. The present study suggested the following mechanism: immediately after copper-induced hepatic dysfunction, plasma copper-metallothionein (CuMT), which was released from the liver, became elevated. The elevation was closely related to the increases in alkaline phosphatase, glucose and amino acids, all in the urine. The above findings suggest that plasma CuMT, which was released from the liver into the blood upon copper-induced hepatic dysfunction, was subsequently filtered at the glomeruli due to its smaller molecular weight, and then caused dysfunction of the brush border membrane of the renal proximal tubules probably after splitting into radical copper and amino acids in acidic vesicles close to the membrane. The critical concentration of plasma CuMT required to induce renal dysfunction was estimated as 1 microg Cu/l.
9950703##1999-2-9##[Clinical application of chromosome haplotype analysis and mutation analysis to the diagnosis of Wilson's disease].##
10022651##1999-2-18##Prevalence of GB virus-C/hepatitis G virus infection in patients with cryptogenic chronic liver disease and in patients with primary biliary cirrhosis or Wilson's disease.##
10022625##1999-2-18##Zinc therapy increases duodenal concentrations of metallothionein and iron in Wilson's disease patients.##
10022620##1999-2-18##Zinc therapy induction of intestinal metallothionein in Wilson's disease.##
9950803##1999-2-10##Genetic disorders of membrane transport. IV. Wilson's disease and Menkes disease.##Copper is an essential transition metal that permits the facile transfer of electrons in a series of critical biochemical pathways. Menkes disease and Wilson's disease are inherited disorders of copper metabolism resulting from the absence or dysfunction of homologous copper-transporting ATPases that reside in the trans-Golgi network of all cells. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same manner within the cell and the unique clinical features of each disease are entirely the result of the tissue-specific expression of each protein. Elucidation of the basic defect in these rare genetic disorders has provided a valuable heuristic paradigm for understanding the mechanisms of cellular copper homeostasis.
11096575##2000-11-30##Wilson's Disease.##Early diagnosis permits preventive therapy to preempt development of organ damage. In all diagnosed patients, both symptomatic and asymptomatic, pharmacologic therapy is lifelong, and maintenance treatment to prevent copper toxicity is mandatory. Patients with either fulminant hepatic failure or hepatic insufficiency unresponsive to medical therapy should be considered for orthotopic liver transplantation, which effectively cures Wilson's disease. Prognosis is excellent for compliant patients receiving pharmacologic therapy.
10933485##2000-8-10##Psychiatric symptoms as late onset of Wilson's disease: neuroradiological findings, clinical features and treatment.##We describe a case of Wilson's disease with late psychiatric onset. Major depressive disorder was the first clinical manifestation at the age of 38 years. After pharmacotherapy with antidepressive agents, a manic episode was observed. Extrapyramidal hand tremor and micrography were the first neurological signs. Emotional lability occurred during worsening of extrapyramidal signs. Diagnosis was based on urinary and serum copper levels, ceruloplasmin serum level, Kayser-Fleischer ring, and liver biopsy that detected cirrhosis. Magnetic resonance imaging revealed basal ganglia hyperintensity on T1-weighted images, and hypodensity in the central part and hyperintensity in the peripheral part of the lentiform nucleus on T2-weighted images. Hyperintensity on T2-weighted images was also observed in the dorsal part of the midbrain. 123I-iodobenzamide single photon emission computed tomography (IBZM-SPECT) detected a normal distribution of the drug in the brain, with better signal in the right side and deficit of D2-dopaminergic receptors in the basal ganglia. Abnormal manganese erythrocyte level was observed. Treatment was based on penicillamine, zinc salts, low-copper diet, antidepressant agents, interpersonal psychotherapy and neurorehabilitation.
10070620##1999-3-10##Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics.##Wilson disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. In this paper, we describe the results of a pilot study of screening for WD using ceruloplasmin determinations in dried blood samples. Specimens were collected from children aged 1 to 6 years who were seen at local paediatric outpatient clinics in the Miyagi Prefecture. We measured ceruloplasmin (CP) concentrations in 2789 children using an enzyme-linked immunosorbent assay. The mean value was 12.4 +/- 3.95 mg/dl blood. Among these children, we identified two (case 1, male, 2 years old; case 2, female, 3 years old) with markedly reduced CP concentrations. Apart from low serum copper concentrations, their biochemical findings were almost normal, as were growth and development. To confirm the diagnosis, we analysed the WD gene and detected A803T/2871delC mutations in case 1 and R778L/G1035V mutations in case 2. We conclude that these children were presymptomatic WD patients. The CP level in dried blood samples from children aged 1 to 6 years appears to be a reliable marker for early detection of WD.
10051024##1999-3-2##The His1069Gln mutation in the ATP7B gene in Russian patients with Wilson disease.##
9920665##1999-1-27##A novel pineal night-specific ATPase encoded by the Wilson disease gene.##We have identified a pineal night-specific ATPase (PINA), a novel splice variant of the ATP7B gene disrupted in Wilson disease (WD). PINA expression exhibits a dramatic diurnal rhythm in both pineal gland and retina with 100-fold greater expression at night than at day. PINA is expressed in pinealocytes and a subset of photoreceptors in adult rats and is transiently expressed in the retinal pigment epithelium and the ciliary body during retinal development. Nocturnal pineal expression of PINA is under the control of a suprachiasmatic nucleus clock mediated by superior cervical ganglion innervation of the pineal. In vitro, PINA expression in pineal cells can be stimulated by agents activating the cAMP signal transduction pathway. PINA is able to restore copper transport activity in Saccharomyces cerevisiae deficient in the homologous copper-transporting ATPase CCC2, suggesting that this protein may function as a copper transporter in rat pinealocytes. These studies suggest a potential role of rhythmic copper metabolism in pineal and/or retina circadian function.
9932853##1999-2-5##A high index of suspicion: the key to an early diagnosis of Wilson's disease in childhood.##
10461685##1999-8-26##Copper increases in both plasma and red blood cells at the onset of acute hepatitis in LEC rats.##Ceruloplasmin is excreted mostly in the apo-form in Wilson's disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model for Wilson's disease, and hence the concentration of Cu in the plasma is low. However, it increases toward and at the onset of acute hepatitis in LEC rats, the increased Cu in the plasma being bound to ceruloplasmin, metallothionein and albumin. Changes in the concentration of Cu in red blood cells (RBCs) were monitored with age for the first time together with that in the plasma in LEC rats. Cu in the RBCs was found to increase to a 5-7 times higher level than that in the plasma toward the onset and peaked at the onset, the pattern being similar to that in the plasma. The source of the Cu increase in the RBCs was discussed, and it was assumed that the so-called free Cu ions that leak from the damaged hepatocytes are bound to albumin and/or taken up by the RBCs.
10461684##1999-8-26##Therapeutic effects of tetrathiomolybdate on hepatic dysfunction occurring naturally in Long-Evans Cinnamon (LEC) rats: a bona fide animal model for Wilson's disease.##Long-Evans Cinnamon (LEC) rats were fed a diet containing 7 ppm Cu and 30 ppm Cu from 60 days after birth. Fischer (Fischer group) and LEC (LEC-control group) rats fed a 7 ppm Cu diet showed normal growth throughout the whole period (60 to 125 days after birth). On the other hand, LEC rats fed the 30 ppm Cu diet had decreased body weight and showed slight jaundice at around 100 days after birth. Tetrathiomolybdate (TTM, 10 mg/kg bw) was injected sub-cutaneously at 101 and 105 days after birth into half of the LEC rats fed the 30 ppm Cu diet. LEC rats given TTM (LEC+TTM group) recovered their body weight and the jaundice rapidly disappeared. However, LEC rats without TTM (LEC-TTM group) had sharply decreased body weight and showed severe jaundice at 103 days after birth. The hepatic Cu concentration in LEC+TTM rats (460 micrograms/g) exceeded that of LEC-control rats (330 micrograms/g) at 125 days after birth. Our data suggest that TTM is effective for treatment of acute hepatic injury in the LEC rat.
10461683##1999-8-26##Preventive effect of zinc compounds, polaprezinc and zinc acetate against the onset of hepatitis in Long-Evans Cinnamon rat.##It is known that Long-Evans Cinnamon (LEC) rats are characterized by the fulminant hepatitis occurring as a result of an abnormal hepatic deposition of Cu due to the lack of the Cu-transporter p-type ATPase. To prevent the hepatitis, two Zn compounds, Zn acetate and polaprezinc were given orally to LEC rats aged 30 days. At 100 days after birth, the control group composed of LEC rats fed a basal diet (Cu, 17 ppm; Zn, 50 ppm; Fe, 150 ppm) exhibited slight jaundice and showed high activities of serum enzymes related to hepatic function. The groups fed the diet fortified (1000 ppm as Zn) with Zn acetate or polaprezinc did not have jaundice. The hepatic Cu concentrations were 174 +/- 34 micrograms/g and 156 +/- 23 micrograms/g in the polaplezinc group and Zn acetate group, respectively. The control group showed 267 +/- 17 micrograms Cu/g and 298 +/- 62 micrograms Fe/g in the liver. The Fe concentration was about 1.7 times the concentration in the two Zn groups. Hepatic free Cu and Fe concentrations were 2.6 +/- 0.3 and 21.4 +/- 5.8 micrograms/g, 1.7 +/- 0.7 and 6.8 +/- 1.1 micrograms/g, and 1.3 +/- 0.1 and 6.2 +/- 0.8 micrograms/g in the control, polaprezinc and zinc acetate groups, respectively. Intestinal metallothionein (MT) concentrations were not increased significantly by the Zn diets. The two Zn compounds inhibit Cu absorption from the intestinal tract, resulting in a decrease of hepatic Cu deposition. The new Zn compound as well as Zn acetate is categorized as a therapeutic drug for Cu poisoning, including Wilson's disease.
10216413##1999-4-27##[Acute hemolytic anemia associated with D-penicillamine absorption deficiency in Wilson's disease].##
10073187##1999-3-12##Liver transplantation for metabolic liver diseases.##Liver transplantation has revolutionized the outcome of metabolic liver diseases that are caused by defects in hepatocytes (e.g., Wilson's disease) or by excessive deposition of substrates secondary to their increased absorption (e.g., hemochromatosis). Early diagnosis and referral are the keys to successful outcome. The timing of liver transplantation for patients on medical therapy depends on a lack of biochemical and clinical evidence of improvement. Overall outcome following liver transplantation depends on the severity of multisystem involvement and preoperative decompensation.
11783297##2002-1-11##[Comparative study on therapeutic effects of gandou tablet I and dimercaptosuccinate acid in treating Wilson disease].##
9878778##1999-1-8##Increased abundance of GABAA receptor subunit mRNAs in the brain of Long-Evans Cinnamon rats, an animal model of Wilson's disease.##The abundance of mRNAs encoding various subunits of the gamma-aminobutyric acid type A (GABAA) receptor was examined in different regions of the brain of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease (WD). The measurements were performed at two different stages of disease: at 9 weeks of age, when no symptoms are evident, and at 15 weeks of age, when 90% of the animals develop jaundice. The amounts of the gamma2L and gamma2S subunit mRNAs in the striatum, cerebellum, and cerebral cortex of LEC rats at 9 weeks of age were increased (+25 to +35%) compared with those in LE rats of the same age; these differences were no longer apparent in 15-week old animals. The amount of alpha1 subunit mRNA was also significantly increased (+30%) in the cerebellum of LEC rats at 9 weeks of age; although a smaller increase (+20%) was still evident at 15 weeks of age, this was not statistically significant. The amount of beta2 subunit mRNA was increased in the cerebellum (+32%) and hippocampus (+21%) of LEC rats at 9 weeks of age, but no differences with LE rats were apparent at 15 weeks. The onset of isoniazid-induced seizures in LEC rats at 9 weeks of age was significantly delayed compared with that in LE rats. These results demonstrate abnormal expression of GABAA receptor subunit genes in the brain of LEC rats, and they suggest that this altered expression is associated with an increase in GABAergic tone.
10547036##1999-11-5##Variability of human hepatic UDP-glucuronosyltransferase activity.##The availability of a unique series of liver samples from human subjects, both control patients (9) and those with liver disease (6; biliary atresia (2), retransplant, chronic tyrosinemia type I, tyrosinemia, Wilson's disease) allowed us to characterize human hepatic UDP-glucuronosyltransferases using photoaffinity labeling, immunoblotting and enzymatic assays. There was wide inter-individual variation in photoincorporation of the photoaffinity analogs, [32P]5-azido-UDP-glucuronic acid and [32P]5-azido-UDP-glucose and enzymatic glucuronidation of substrates specific to the two subfamilies of UDP-glucuronosyltransferases. However, the largest differences were between subjects with liver disease. Glucuronidation activities toward one substrate from each of the UDP-glucuronosyltransferases subfamilies, 1A and 2B, for control and liver disease, respectively, were 1.7-4.5 vs 0.4-4.7 nmol/mg x min for hyodeoxycholic acid (2B substrate) and 9.2-27.9 vs 8.1-75 nmol/mg x min for pchloro-m-xylenol (1A substrate). Microsomes from a patient with chronic tyrosinemia (HL32) photoincorporated [32P]5-azido-UDP-glucuronic acid at a level 1.5 times higher than the other samples, was intensely photolabeled by [32P]5-azido-UDP-glucose and had significantly higher enzymatic activity toward p-chloro-m-xylenol. Immunoblot analysis using anti-UDP-glucuronosyltransferase antibodies demonstrated wide inter-individual variations in UDP-glucuronosyltransferase protein with increased UDP-glucuronosyltransferase protein in HL32 microsomes, corresponding to one of the bands photolabeled by both probes. Detailed investigation of substrate specificity, using substrates representative of both the 1A (bilirubin, 4-nitrophenol) and 2B (androsterone, testosterone) families was carried out with HL32, HL38 (age and sex matched control) and HL18 (older control). Strikingly increased (5-8-fold) glucuronidation activity was seen in comparison to HL18 only with the phenolic substrates. The results indicate that one or more phenol-specific UDP-glucuronosyltransferase 1A isoforms are expressed at above normal levels in this tyrosinemic subject.
10079824##1999-3-18##Expression, purification, and metal binding characteristics of the putative copper binding domain from the Wilson disease copper transporting ATPase (ATP7B).##
10079822##1999-3-18##Animal models of Wilson's disease.##
10079820##1999-3-18##The treatment of Wilson's disease.##
10079819##1999-3-18##Developmental expression of the mouse mottled and toxic milk genes.##
10079817##1999-3-18##Mutation spectrum of ATP7A, the gene defective in Menkes disease.##Our knowledge about Menkes disease (MD) has expanded greatly since its description in 1962 as a new X-linked recessive neurodegenerative disorder of early infancy. Ten years later a defect in copper metabolism was established as the underlying biochemical deficiency. In the beginning of 1990s efforts were concentrated on the molecular genetic aspects. The disease locus was mapped to Xq13.3 and the gene has been isolated by means of positional cloning. This was the beginning of a series of new findings which have greatly enhanced our understanding of copper metabolism not only in human, but also in other species. This review will focus on the molecular genetic aspects of Menkes disease and its allelic form occipital horn syndrome. The mutations will be compared briefly with those described in the animal model mottled mouse, and in Wilson disease, the autosomal recessive disorder of copper metabolism.
10079814##1999-3-18##Multiple forms of the Menkes Cu-ATPase.##The 5' region of MNK cDNAs has a 45 bp insert terminating at the 5'end with an AGATG sequence. The ATG in the sequence is in-frame with the ATG downstream identified by Vulpe et al (1993) as a translation start site for MNK mRNA. Inserts of 192 bp and 45 bp have been found in the 5' region of MNK mRNAs from BeWo cells, Caco-2 cells and normal human fibroblasts. Extensions to the 5' end of these mRNAs could foretell a modified N-termini in certain forms of the Menkes Cu-ATPase. These modified H2N-terminal extensions are postulated to be targeting signals for post-translational processing and cellular localization. In this report, we provide evidence that the primary Menkes transcript in non-Menkes cells undergoes post-transcriptional splicing that gives rise to multiple transcripts. The data suggest that the Menkes gene is a copper locus that codes for more than one form of the Menkes Cu-ATPase and one of these forms could be a small Cu transport protein.
10079813##1999-3-18##Cu metabolism in the liver.##This paper has, given some idea of our concepts of the processes involved in the transport of Cu across cell membranes in the liver, which we have summarised in Fig 1. Cu(II)His2 is reduced to Cu(I). This is transported across the membrane, re-oxidised, either before or after binding to glutathione (Freedman et al., 1989) or HAH1 (Klomp et al., 1997), binds to SAHH, and donates Cu(II) to the ATPase. It is very interesting that cells which are very diverse from an evolutionary point of view still use very similar methods to handle the metal. Whether regulation of transport is also the sam remains to be seen. We would guess that, although there will be strong similarities, there will also be very significant differences, reflecting the different environments seen by different tissues in mammalian cells and given the different requirements of the tissues.
9929706##1999-2-4##New knowledge of genetic pathogenesis of hemochromatosis and Wilson's disease.##Discovery of the gene for WD has greatly enhanced our understanding of this disorder at the cellular level and has set the stage for future testing of new modes of therapy. Improvements in analytic methods for detecting mutations in genomic DNA will someday enable a rapid and cost-effective method of screening for this disorder. Until then, the time-tested clinical and biochemical evaluation, including measurement of ceruloplasmin oxidase activity, slit-lamp examination for Kayser-Fleischer rings, and measurement of hepatic copper content, will continue to remain the standard for establishing the diagnosis of WD.
10083649##1999-3-20##[Type-III hyperlipoproteinemia in a girl with Wilson's disease].##
10470438##1999-9-2##Involvement of Fas/FasL system in the pathogenesis of autoimmune diseases and Wilson's disease.##The interaction of Fas with FasL has been demonstrated to be implicated in the pathogenesis of several autoimmune and liver diseases. Recently, attention has been focused on the hypothesis that thyrocytes and beta cells undergo massive Fas/FasL-mediated apoptosis during autoimmune response. Similarly, hepatocyte cell death occurring following copper accumulation points towards the same mechanism.
10746345##2000-4-4##Disorders of copper transport.##Copper is an essential component of a number of important enzymes. Efficient systems have developed for providing sufficient copper for essential functions, while eliminating excess to avoid tissue toxicity. Copper transport is disrupted in two human diseases: Wilson disease and Menkes disease. Both have defects in copper transporting membrane proteins. Many other proteins are involved in copper transport. Some of these proteins have been identified through a study of the similar copper pathway in yeast. This suggests other copper transport diseases are yet to be discovered. Molecular diagnosis holds promise for reliable diagnosis of patients. Testing of flanking markers is a reliable way to detect presymptomatic sibs of a definite patient.
10492993##1999-9-24##[Monoethylglycinexylidide--a metabolite of lidocaine--as an index of liver function in chronic hepatic parenchymal diseases].##The changes of biotransformation enzyme system (b.e.s.) activity and capacity in liver diseases significantly influence the metabolism of various xenobiotics. Lidocaine is metabolised through oxidative N-deethylation by b.e.s. resulting in the production of monoethylglycinexylide (MEGX). The aim of this study was the determination of serum MEGX concentration as a model substance for indirect evaluation of liver b.e.s. function in patients with liver steatofibrosis and cirrhosis and the assessment of the possibilities to use it as a quantitave test of liver functional state. The study group consisted of 53 patients, 36 of them with liver disease of different etiology (postviral, ethyltoxic, cryptogenic, liver cirrhosis on the basis of autoimmune hepatitis, liver cirrhosis induced by primary sclerosing cholangitis, primary biliary cirrhosis in the stage of cirrhosis, Wilson's disease in the stage of cirrhosis), 7 patients with liver steatofibrosis and 10 control persons. After intravenous administration of lidocaine (1 mg/kg of body weight), concentration of MEGX was assessed by fluorescence polarization immunoassay (FPIA) using Tdx system in venous blood. The concentration was assesed prior to administration of lidocaine and 15 and 30 minutes after. In the group of liver steatofibrosis the concentrations in the 15th minute after administration were lower comparing to controls, in the 30th minute the difference was less significant. The values of MEGX in cirrhosis group were significantly decreased 15 and 30 minutes after lidocaine administration in comparison with control group. The cirrhosis group was divided into two subgroups: compensated (Ci c) and decompensated (Ci d) and independently of this division into three parts according to score system of Child-Pugh classification (Ci A, Ci B, Ci C). The concentrations 15 and 30 minutes after lidocaine administration in patients with Ci c and Ci d were significantly different, similarly there were statistically significant differences among Ci A, Ci B and Ci C. Statistically significant differences were also between the group of steatofibrosis and whole group of cirrhosis. The concentration of MEGX 15 and 30 minutes after lidocaine administration correlated significantly with the values of albumin, prothrombin time, cholinesterase, Child-Plugh score and bilirubin. MEGX test represents an appropriate and rapid method for the determination of functional liver capacity in patients with liver cirrhosis and liver steatofibrosis, not yet used in Slovak republic. It is a noninvasive test, low time consuming, and when repeated it may provide prognostic information about further development of the disease. MEGX test is an appropriate index of liver function and may contribute to early treatment of chronic liver diseases. (Tab. 9, Fig. 10, Ref. 47.)
10195339##1999-4-9##Generators of brain electrical activity in patients with Wilson's disease.##Electroencephalographic (EEG) generators were investigated in 13 patients suffering from hepatolenticular degeneration with and without neurological symptoms and in 13 healthy subjects for comparison by the use of FFT approximation. Quantitative assessment of motor deficits and psychiatric disturbances was correlated with EEG features. We found mainly an increase in delta activity, a decrease in alpha activity combined with a more posterior localisation of the EEG generators in the delta band and a more anterior one in the alpha band in patients compared with healthy controls. The localisation of the EEG generators in the patients with clinical apparent neurological symptoms were in all frequency bands more superficial compared with controls and patients without neurological symptoms. With longer duration of the disease, the lower the premorbid intelligence the more posterior was the delta EEG generator localised. Although the alpha EEG generator was more anteriorly localised with longer duration of the disease and more severe cognitive deficits, it was more superficial with more pronounced psychiatric symptoms, more severe cognitive deficits, lower premorbid intelligence and more pronounced motor disabilities. With more pronounced psychiatric symptoms and cognitive deficits, the beta EEG generator was more anteriorly localised. The present study demonstrated that a significant deviant EEG pattern exists between patients with and without clinical neurological symptoms and that stage-dependent alterations in psychiatric symptoms and cognitive ability are reflected on the EEG.
10595669##1999-12-14##Menkes disease and Wilson disease: two sides of the same copper coin. Part II: Wilson disease.##
10476363##1999-9-7##Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease.##
10502777##1999-9-30##A study of Wilson disease mutations in Britain.##Wilson disease (WD) is an autosomal recessive disease of copper transport. The disease is caused by a large number of mutations in the ATP7B gene, some of which appear to be population specific, whereas others are found in probands from a variety of different ethnic backgrounds. This study presents the results of screening the ATP7B gene by SSCP and sequencing in order to define the spectrum of mutations seen in British referrals for WD. The 52 patients screened included 10 with a non-British mixed ethnicity origin. This study identified 19 novel mutations and 18 mutations that had been previously described. The novel mutations included seven nonconservative missense mutations, eight small insertions, or deletions causing frameshift, two nonsense mutations, and two splice-site mutations. Seven of the 10 mixed ethnicity patients harboured homozygous mutations, whereas only four of the larger British group were homozygotes. The detection rate by SSCP analysis in the British group of 42 consecutive unrelated WD probands was 70%. However, SSCP screening of just three exons (exons 8, 14, and 18) is predicted to identify 60% of mutations present in WD referrals.
10502776##1999-9-30##Molecular characterization of wilson disease in the Sardinian population--evidence of a founder effect.##Wilson disease (WD) in the Sardinian population has an approximate incidence of 1:7,000 live births. Mutation analysis of the WD gene in this population reported in our previous articles led us to the characterization of two common mutations and a group of 13 rare mutations accounting for the molecular defect of 8.5, 7.9, and 15.1% of the WD chromosomes. However, molecular analysis of the WD chromosomes containing the most common haplotype, which accounts for 60.5% of the WD chromosomes, failed to define the disease-causing mutation. In this study, we characterized the promoter and the 5' UTR of the WD gene sequence and carried out a mutation analysis in this DNA region from patients with the most common haplotype. The promoter is contained in a GC-rich island and shows a TATA and a CAAT consensus sequence as well as potential binding sites for transcription factors and metal response elements. In all the analyzed 92 chromosomes with this haplotype, we detected a single mutation consisting of a 15-nt deletion from position -441 to position -427 relative to the translation start site. Expression assays demonstrated a 75% reduction in the transcriptional activity of the mutated sequence compared to the normal control. By adding this mutation to those that have been already characterized, we have now defined the molecular defect in 92% of the WD chromosomes in Sardinians. The high frequency, the expected prevention by preclinical diagnosis and early treatment of the devastating effect of WD on the nervous system and liver tissue, and the feasibility to detect most of molecular defects by DNA analysis indicate that WD in the Sardinian population should be added to the list of diseases currently detected by newborn screening.
10447265##1999-8-14##Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online.##In order to obtain novel mutations in the recently discovered Wilson disease gene, we screened 5 unrelated German individuals for mutations in the 21 exons and their flanking intronic sequences. We detected 9 mutations affecting the Wilson disease gene. Four of those, designated 802-808delTGTAAGT, 2008-2013delTATATG, Cys985Thr, and Ile1148Thr have not yet been reported. One patient had a homozygous mutation whereas the remaining four subjects were compound heterozygous. Therefore these data confirm, that mutations causing Wilson disease are frequently found in affected subjects and they are very heterogenous.
10626229##2000-1-8##Cancer-prone oxyradical overload disease.##Oxyradical overload disease develops in conditions involving chronic inflammation and may be of inherited etiology, e.g. haemochromatosis and Wilson disease, be acquired, e.g. infection with hepatitis B or C virus or Helicobactor pylori, or be chemically induced, e.g. acid reflux in Barrett oesophagus. Susceptibility to cancer is frequently a pathological consequence of extensive oxyradical damage that leads to a cycle of cell death and regeneration and causes mutations in cancer-related genes. In this brief review, we focus on the possible interactive effects of nitric oxide and the p53 tumour suppressor gene in human carcinogenesis.
10626208##2000-1-8##Lipid peroxidation-induced etheno-DNA adducts in humans.##Increased oxidative stress and lipid peroxidation are implicated at various stages of carcinogenic processes. Recent studies have shown that reactive hydroxyalkenals derived from lipid peroxidation form the promutagenic exocyclic etheno DNA adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytidine (epsilon dC). A highly selective and sensitive immunoaffinity 32P-postlabelling method has been developed to detect epsilon dA and epsilon dC, with a detection limit of about 5 adducts per 10(10) parent nucleotides, which permitted their measurement in small amounts of human DNA. Background levels of epsilon dA and epsilon dC were detected in normal human tissue DNA, apparently as a result of lipid peroxidation under normal physiological conditions. High levels of epsilon dA and epsilon dC were found in the liver DNA of cancer-prone patients with Wilson disease or primary haemochromatosis. High dietary intake of omega-6 polyunsaturated fatty acids, which are readily oxidized to form enals, increased the epsilon dA and epsilon dC levels in DNA from leukocytes of women. An immunoaffinity-high-performance liquid chromatography-fluorescence method has been developed to measure epsilon dA in human urine. Etheno DNA adducts can now be used as biomarkers to investigate the potential role of oxidative stress and lipid peroxidation in human cancers associated with certain lifestyles or chronic infections and to verify whether the levels of these adducts can be reduced by chemopreventive regimens.
11138559##2001-1-4##Metabolic liver diseases in childhood: Indian scenario.##The present survey was undertaken to ascertain the spectrum of childhood metabolic liver diseases (MLD) and diagnostic methods available in teaching medical institutions in India. Out of 17 medical colleges approached in different parts of the country, pediatricians from 11 institutions agreed to participate. Six colleges had organised pediatric gastroenterology & hepatology services (category I) and five were not having such services (category II). The participants provided information regarding the number of chronic liver disease patients seen at their centres during the past 5-10 years with their etiological diagnosis, the proportion of metabolic liver diseases in these children and the methods used to label etiology. Patients with acute hepatitis B infection and neonatal cholestasis were excluded. In the past 1-9 years, (38-236) and (4-57) children with chronic liver disease (CLD) were seen in category I and category II centres respectively. Chronic hepatitis B and C and metabolic liver diseases were being diagnosed in most of the centres, though in category I other causes of chronic liver diseases were also reported. Metabolic liver diseases constituted 8 to 43% of the reported CLD in category I colleges and 0-46% in the other pediatric centres. Most major categories of metabolic liver diseases were seen at various centres. Indian Childhood Cirrhosis (ICC) was very infrequently reported even in the large hospitals and Wilson's disease was the most frequently diagnosed metabolic liver disease. Reference diagnostic tests for most of the metabolic liver disorders were not accessible to majority of participating institutions. Metabolic liver diseases constitute a significant proportion of childhood chronic liver diseases in our country. There is an important need to set up reference laboratories in the country to facilitate diagnostic work up of metabolic liver diseases at affordable costs.
11132457##2001-1-2##Management of chronic liver disease.##Childhood liver disorders have, in general, mode of presentations which are distinct from that in adult population. It is due to varying etiology and natural history of the liver diseases in childhood. Chronic hepatitis B and C can be managed with alpha interferon. Remission rates in children have been reported to be between 20-58%. Recently available lamuvidine has also been used in combination with interferon therapy. Oral chelation therapy and liver transplantation have radically affected the outcome of patients with Wilson's disease. Corticosteroids and immunosuppressive therapy are effective in reducing both morbidity and mortality due to auto-immune hepatitis. Offending carbohydrates are eliminated from the diet of patients with galactosemia and hereditary fructose intolerance. The most important and often neglected component of management of chronic liver diseases in childhood are nutritional management and prompt interventions for ascites, spontaneous bacterial peritonitis, portal hypertension and hepatic encephalopathy. With definitive etiological and histological assessment and institution of specific as well as supportive therapy, children with chronic liver disease can have a prolonged survival with improved quality of life. Several of them can potentially receive the liver transplant as and when it becomes available.
12840876##2003-7-5##Carrier detection and presymptomatic identification of Wilson disease in Chinese by non-isotopic linkage analysis with four short tandem repeat polymorphisms.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. To establish an efficient, accurate and fast diagnostic method for carrier detection and presymptomatic identification of WD in Chinese population, we studied haplotypes of short tandem repeat (STR) polymorphisms flanking the WD gene in 40 Chinese WD families. The results suggested that this genetic diagnosis system based on the four STR polymorphisms is of high value for the detection of potential carriers and WD homozygotes in families with at least one previously affected child. It is an efficient, accurate and fast diagnostic method that can be well suited for routine use in clinical laboratories.
10382558##1999-6-26##Molybdenum.##Molybdenum does not exist naturally in the pure metallic form and of the 5 oxidation states (2-6) the predominant species are Mo(IV) and Mo(VI). Molybdenum rapidly polymerizes to a wide variety of complex polymolybdate compounds in solution. The vast majority of molybdenum is used in metallurgical applications (stainless steel, cast-iron alloys). Ammonium tetrathiomolybdate is an experimental chelating agent for Wilson's disease. For the general population, the diet is the most important source of molybdenum and concentrations in water and air usually are negligible. The average daily dietary intake is about 0.1-0.5 mg m.o. Molybdenum is an essential element with relatively low toxicity. Enzymes containing molybdenum catalyze basic metabolic reactions in the carbon, sulfur, and nitrogen cycles. Elimination of molybdenum occurs via the kidney and usually is complete within several weeks. Molybdenosis (teart) is a form of molybdenum toxicity that produces a disease in ruminants similar to copper-deficiency. Little data are available on the human toxicity of molybdenum. A gout-like syndrome and pneumoconiosis have been associated with excessive concentrations of molybdenum, but the inadequate design of the studies prevents an adequate determination of the etiology of these effects.
10382557##1999-6-26##Copper.##Copper is an essential trace element, which is an important catalyst for heme synthesis and iron absorption. Following zinc and iron, copper is the third most abundant trace element in the body. Copper is a noble metal, like silver and gold. Useful industrial properties include high thermal and electrical conductivity, low corrosion, alloying ability, and malleability. Most of the metallic copper appears in electrical applications. Copper is a constituent of intrauterine contraceptive devices and the release of copper is necessary for their contraceptive effects. The average daily intake of copper in the US is about 1 mg Cu with the primary source being the diet. The bioavailability of copper from the diet is about 65-70% depending on a variety of factors including chemical form, interaction with other metals, and dietary components. The biological half-life of copper from the diet is 13-33 days with bilary excretion being the major route of elimination. Copper sulfate is a gastric irritant that produces erosion of the lining of the gastrointestinal tract. Chronic copper toxicity is rare and primarily affects the liver. Wilson's disease and Indian childhood cirrhosis are examples of severe chronic liver disease that results from the genetic predisposition to the hepatic accumulation of copper. The serum copper concentration ranges up to approximately 1.5 mg/L in healthy persons. Gastrointestinal symptoms occur at whole blood concentrations near 3 mg Cu/L. Chelating agents (CaNa2EDTA, BAL) are recommended in severe poisoning, but there are little pharmacokinetic data to evaluate the effectiveness of these agents.
10198883##1999-4-13##[Eye movement abnormalities as a sign for the diagnosis in Niemann-Pick disease type C].##
10503961##1999-9-30##Iron depletion prevents adenine nucleotide decomposition and an increase of xanthine oxidase activity in the liver of the Long Evans Cinnamon (LEC) rat, an animal model of Wilson's disease.##The Long Evans Cinnamon (LEC) rat, which accumulates excess Cu in the liver as in patients with Wilson's disease, is a mutant strain displaying spontaneous hepatitis. It was reported that Fe, like Cu, increases in the liver and that the severity of hepatitis is modified by Fe in the diet. In this experiment, oxidative stress increased by Fe was investigated before the onset of hepatitis. To examine the effect of Fe on the progress into hepatitis, LEC female rats were fed an Fe-regular (Fe 214 microg/g; Fe(+) group) or an Fe-restricted (Fe 14 microg/g; Fe(-) group) diet from 53 days of age for 35 days. Fischer rats were also fed as control animals. Adenine nucleotide decomposition was determined as an index of oxidative stress based on xanthine oxidase activity. The size of the hepatic pool of adenine nucleotides (ATP+ADP+AMP) was significantly smaller in LEC rats than Fischer rats. The energy charge (ATP+0.5ADP)/(ATP+ADP+AMP) was smaller in Fe(+) groups than in Fe(-) groups. In the LEC rat liver, the Fe concentration in the Fe(+) group was 160% of that in Fe(-) group and the correlation coefficient between the hepatic Fe concentration and the energy charge was significant. In this strain, an increase of xanthine oxidase activity resulted in an increase of xanthine, an oxidized metabolite of hypoxanthine in the liver. The results suggest the involvement of the Fe in the progression into hepatitis in the LEC rat, even if the dietary Fe concentration is similar to that of commercial diet.
9873089##1999-1-5##Etiology and outcome for 295 patients with acute liver failure in the United States.##Little information is available on acute liver failure (ALF) in the United States. We gathered demographic data retrospectively for a 2-year period from July 1994 to June 1996 on all cases of ALF from 13 hospitals (12 liver transplant centers). Data on the patients included age, hepatic coma grade on admission, presumed cause, transplantation, and outcome. Among 295 patients, 74 (25%) survived spontaneously, 121 (41%) underwent transplantation, and 99 (34%) died without undergoing transplantation. Ninety-two of 121 patients (76%) survived 1 year after transplantation. Acetaminophen overdose was the most frequent cause (60 patients; 20%), followed by cryptogenic/non A non B non C (NANBNC; 15%), idiosyncratic drug reactions (12%), hepatitis B (10%), and hepatitis A (7%). Spontaneous survival rates were highest for patients with acetaminophen overdose (57%) and hepatitis A (40%) and lowest for those with Wilson's disease (no survivors of 18 patients). The transplantation rate was highest for Wilson's disease (17 of 18 patients; 94%) and lowest for autoimmune hepatitis (29%) and acetaminophen overdose (12%). Age did not differ between survivors and nonsurvivors, perhaps reflecting a selection bias for patients transferred to liver transplant centers. Coma grade on admission was not a significant determinant of outcome, but showed a trend toward affecting both survival and transplantation rate. These findings on retrospectively studied patients from the United States differ from those previously gathered in the United Kingdom and France, highlighting the need for further study of trends in each country.
10667744##2000-2-10##Tardive dystonia.##This paper provides an overview of the phenomenology, epidemiology, and treatment of tardive dystonia. Tardive dystonia is one of the extrapyramidal syndromes that starts after long-term use of dopamine receptor antagonists. The diagnosis is based on the presence of chronic dystonia, defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Furthermore, dystonia must develop either during or within 3 months of a course of antipsychotic treatment, and other causes such as Wilson's disease, acute dystonia, or a conversion reaction must be ruled out. Tardive dystonia occurs in about 3 percent of patients on long-term antipsychotic treatment. Some probable risk factors for tardive dystonia are younger age, male, and the presence of tardive dyskinesia. The treatment of tardive dystonia starts with an evaluation of the need for using the causative drug. If antipsychotics must be continued, a switch to an atypical antipsychotic, particularly clozapine, may be helpful. If the dystonia is relatively localized, botulinum toxin is an effective but not well-known treatment possibility. If tardive dystonia is more extensive, either dopamine-depleting drugs or high dosages of anticholinergics can be tried.
12194382##2002-8-27##Diagnosis and treatment of Wilson's disease.##Wilson's disease is due to an inherited defect in copper excretion into the bile by the liver. The resulting copper accumulation and copper toxicity results in liver disease, and in some patients, brain damage. Patients present, generally between the ages of 10 and 40 years, with liver disease, neurological disease of a movement disorder type, or behavioral abnormalities, and often with a combination of these. Because Wilson's disease is effectively treated, it is extremely important for physicians to learn to recognize and diagnose the disease. Treatment options have evolved rapidly in the last few years, with zinc now being the drug of choice in most situations.
11400755##2001-6-13##Studies of mass infant screening for Wilson disease by urinary ceruloplasmin.##We found a 4-year-old boy in the screened cohort, who showed a low ceruloplasmin (CP) in urine (17 ng/mg-creatinine) and in blood (0.6 mg/dl), but his urine copper was in the normal range. Furthermore this child was diagnosed as Wilson disease (WD) by genetic analysis. Although no significant correlation was observed between urine and blood levels of CP, it is conceivable that WD may be accompanied by very low concentration of urine CP.
10770682##2000-4-19##Wilson's disease patients with normal ceruloplasmin levels.##Wilson's disease, an inborn defect of copper metabolism, is a fatal disease unless specific treatment is given. Hepatic presentation mimics almost all kinds of liver disease and the diagnosis is sometimes problematic. The diagnosis is based on clinical findings, family history, presence of Kayser-Fleischer rings, and results of key laboratory tests such as low serum ceruloplasmin level, increased urinary copper excretion and hepatic copper content. We report four patients with Wilson's disease with hepatic manifestations with unknown there were difficulties in making the diagnosis because of normal serum ceruloplasmin levels. Inspite of normal ceruloplasmin levels and absence of Kayser-Fleischer rings, strong family history suggested Wilson's disease and the diagnosis was confirmed by increased urinary and hepatic copper amounts.
10086916##1999-3-23##Wilson's disease coexisting with viral hepatitis type C: a case report with histological and ultrastructural studies of the liver.##Histopathological and ultrastructural findings in the liver of a female patient who suffered from Wilson's disease (WD) and viral hepatitis type C (HCV) are reported. Light and electron microscopy examinations demonstrated a variety of morphological alterations--many of them frequently seen in livers of patients with WD and others that can be found in cases presenting HCV infection. The influence of coexistence of these two diseases on morphological changes is discussed.
9860458##1998-12-22##Sherlock Holmes' magnifying glass to identify Wilson's disease?##
9860423##1998-12-22##Early onset of nephrotic syndrome after treatment with D-penicillamine in a patient with Wilson's disease.##Wilson's disease responds to a variety of treatments including D-penicillamine and trientene. Nephrotic syndrome is a late complication of D-penicillamine treatment. We report a pediatric patient with Wilson's disease who developed nephrotic syndrome 2 wk after beginning D-penicillamine. His nephrosis resolved and his disease is quiescent with trientene treatment.
9837819##1998-12-5##Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant?##Wilson disease is an autosomal recessive disorder of copper transport that causes hepatic and/or neurological disease resulting from copper accumulation in the liver and brain. The protein defective in this disorder is a putative copper-transporting P-type ATPase, ATP7B. More than 100 mutations have been identified in the ATP7B gene of patients with Wilson disease. To determine the effect of Wilson disease missense mutations on ATP7B function, we have developed a yeast complementation assay based on the ability of ATP7B to complement the high-affinity iron-uptake deficiency of the yeast mutant ccc2. We characterized missense mutations found in the predicted membrane-spanning segments of ATP7B. Ten mutations have been made in the ATP7B cDNA by site-directed mutagenesis: five Wilson disease missense mutations, two mutations originally classified as possible disease-causing mutations, two putative ATP7B normal variants, and mutation of the cysteine-proline-cysteine (CPC) motif conserved in heavy-metal-transporting P-type ATPases. All seven putative Wilson disease mutants tested were able to at least partially complement ccc2 mutant yeast, indicating that they retain some ability to transport copper. One mutation was a temperature-sensitive mutation that was able to complement ccc2 mutant yeast at 30 degreesC but was unable to complement at 37 degreesC. Mutation of the CPC motif resulted in a nonfunctional protein, which demonstrates that this motif is essential for copper transport by ATP7B. Of the two putative ATP7B normal variants tested, one resulted in a nonfunctional protein, which suggests that it is a disease-causing mutation.
9844057##1998-12-9##Argininosuccinate lyase: a new autoantigen in liver disease.##Anti-liver cytosol 1 autoantibody (LC1) characterizes a severe form of autoimmune hepatitis (AIH), staining the cytoplasm of periportal hepatocytes and targeting an unidentified 60-kD liver cytosolic antigen. To identify its target, we used high-titre anti-LCI+ sera from two patients with AIH to screen 18 cytoplasm enzymes with periportal location by double immunodiffusion (DDI). Both sera gave a broad precipitin line against human liver cytosol, suggesting that they may recognize two distinct antigens, a possibility confirmed by the appearance of two precipitin lines when DDI conditions were optimized (0.8% agarose and 3% polyethylene glycol (PEG)). Experiments by DDI and Western blot (WB) identified a liver cytosolic autoantigen of 50 kD, different from LC1, giving a line of identity with argininosuccinate lyase (ASL). Reactivity to ASL was then investigated by DDI and WB in 57 patients with AIH, 17 with primary biliary cirrhosis (PBC), 15 with chronic hepatitis B virus (HBV) infection, 13 with alphal-antitrypsin deficiency, 17 with Wilson's disease, 18 with extrahepatic autoimmune disorders, and in 48 healthy controls. Anti-ASL was found in 16% of AIH and 23% of PBC patients by DDI and in 14% of AIH, 23% of PBC and 20% of HBV patients by WB. No argininosuccinate was present in the urine of four anti-ASL+ patients tested, excluding an inhibition of enzymatic activity by anti-ASL. The addition of anti-ASL+ serum to human fibroblast cultures induced a significant increase in ASL activity. ASL is a new autoantigen in liver disease and its clinical relevance warrants further investigation.
9837698##1998-12-5##D-penicillamine-induced pancreatic islet autoantibody production is independent of the immunogenetic background: a lesson from patients with Wilson's disease.##D-penicillamine (d-PA) was reported to induce various immunological abnormalities including production of autoantibodies to insulin. These abnormalities were mainly described in patients with primary immunological disorders such as rheumatoid arthritis. In order to clarify whether d-PA-induced immune disorders are restricted to patients genetically prone to develop autoimmune diseases or to a direct drug effect, we tested for the presence of various autoantibodies and for molecular HLA typing in 17 patients with Wilson's disease treated with this drug. In 2/17 patients, low-titer (10 JDFU) circulating islet cell autoantibodies (ICA) were detected, while another patient was positive for the presence of insulin autoantibodies. None of the sera tested showed reactivity for glutamic acid decarboxylase or ICA512. Five of twelve patients were positive for anti-single-stranded DNA autoantibody. Molecular HLA typing of the autoantibody-positive subjects showed that they carry HLA haplotypes not associated with insulin-dependent diabetes. The insulin response to intravenous glucose tolerance test in two patients with autoantibodies was found to be normal. A second blood testing of the autoantibody-positive patients 5 months following initial evaluation revealed conversion to negativity in all three. Our results suggest that d-PA-induced autoantibodies in patients with Wilson's disease are independent of the immunogenetic background characteristics of diabetes.
10076789##1999-3-17##Wilson's disease with concomitant beta thalassaemia and factor V deficiency.##A case of late presentation of Wilson's disease in a female with a thalassaemic trait is reported in whom diagnosis of Factor V deficiency was made. Despite ignoring the disease for years the patient had compensated cirrhosis. She had a dramatic family history of Wilson's disease affecting at least two brothers and two sisters. Moreover, her haematologic problems were not clinically revealed until diagnosis had been made on the basis of suspicions arising from laboratory results. The therapy of choice for hepatolenticular degeneration was not feasible due to the patient's refusal. Zinc salts were, therefore, administered. To our knowledge the association of such rare genetic disorders has not been reported.
9895248##1999-1-23##Wilson's disease: presymptomatic patients and Kayser-Fleischer rings.##
10220997##1999-4-30##[Multiple histochemical methods in the diagnosis of Wilson's disease. (Presentation of 74 cases and review of the literature)].##Conflicting results have been reported on the usefulness of histochemistry for copper in the diagnosis of Wilson's Disease (W.D.). In spite of the high number of methods proposed in the literature, no-one has shown to have the characteristics typical of a good histochemical method: high sensitivity associated with high specificity. On this basis, it seemed of interest to evaluate, in a large series of patients with W.D., the diagnostic value of the most commonly used histochemical methods for copper (rhodanine, orcein and Timm's method). To this end, 74 liver needle biopsies from patients affected by W.D., 39 males and 35 females, aged 4-60 years (mean age 28.5 years), were stained with rhodanine (R), orcein (O) and Timm's (T) methods. On the basis of the histological picture, liver biopsies were subdivided in four evolutive stages: stage I = steatosis; stage II = interface hepatitis; stage III = bridging fibrosis; stage IV = cirrhosis. In stage I, histochemistry for copper was positive in 11 out of 21 cases: 6 cases were T+; 1 case R+ and 2 cases O+; 2 cases were T+, R+, O+. In stage II, 11 out of 14 cases were positive for copper staining: 4 T+, 2 R+ and 2 O+; 3 cases were contemporary positives for T, R, O. In stage III, 22 out of 25 cases resulted positive: 8 T+, 3 R+ and 1 O+; 10 cases were positives, in the mean time, for more of one method. In stage IV, 12 of 14 cases were positives: 5 T+, 2 R+, 2 O+ and 3 cases were contemporaneously positives for multiple methods. Our data show that: 1) the percentage of positivity obtained using three histochemical methods for copper is higher than using only one method. From a practical point of view, it is mandatory to utilize, in clinical practice, multiple histochemical stains in order to increase the diagnostic utility of histochemistry for copper; 2) the Timm's method appears to be the most sensitive method for the demonstration of copper in all stages of W.D.; 3) even though hepatic copper already abounds in the early stages of W.D., this pool of intrahepatic copper is not yet demonstrable with any of the three histochemical techniques utilized.
9813047##1998-11-13##Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases.##Menkes' disease is a fatal, X-linked, copper deficiency disorder that results from defective copper efflux from intestinal cells and inadequate copper delivery to other tissues, leading to deficiencies of critical copper-dependent enzymes. Wilson's disease is an autosomally inherited, copper toxicosis disorder resulting from defective biliary excretion of copper, which leads to copper accumulation in the liver. The ATP7A and ATP7B genes that are defective in patients with Menkes' and Wilson's diseases, respectively, encode transmembrane, P-type ATPase proteins (ATP7A or MNK and ATP7B or WND, respectively) that function to translocate copper across cellular membranes. In this study, the cDNAs derived from a normal human ATP7A gene and the murine ATP7B homologue, Atp7b, were separately transfected into an immortalized fibroblast cell line obtained from a Menkes' disease patient. Both MNK and WND expressed from plasmid constructs were able to correct the copper accumulation and copper retention phenotype of these cells. However, the two proteins responded differently to elevated extracellular copper levels. Although MNK showed copper-induced trafficking from the trans-Golgi network to the plasma membrane, in the same cell line the intracellular location of WND did not appear to be affected by elevated copper.
10194991##1999-4-9##Caeruloplasmin isoforms in Wilson's disease in neonates.##
9881519##1999-1-9##A critical evaluation of copper metabolism in Indian Wilson's disease children with special reference to their phenotypes and relatives.##Wilson's disease is an autosomal recessive disorder of copper accumulation in various organs, with most common clinical manifestations such as hepatic, neurological, and renal dysfunctions. Serum copper and ceruloplasmin in Wilson's disease were significantly lower as compared to normals, controls, and relatives of Wilson's disease patients, whereas marked hypercupriuria (145+/-7 microg/24 h) was observed in Wilson's children only. A good correlation (r=0.92) was found between non-ceruloplasmin-bound copper and 24-h urinary copper excretion in Wilson's disease patients. Further, copper studies among the different phenotypes of Wilson's disease revealed substantially low serum ceruloplasmin and a marked hypercupriuria in Wilson's disease children associated with renal tubular acidosis as compared to the patients with either hepatological or neurological manifestations. Serum ceruloplasmin levels in 14 patients of Wilson's disease were between 14 and 20 mg/dL. These patients of Wilson's disease were confirmed by measuring liver biopsy copper, which was about nine times higher than normal hepatic copper content. During the family screening by copper studies, four asymptomatic siblings were diagnosed for Wilson's disease. These subjects were then started on D-penicillamine therapy because presymptomatic treatment prevents progression of the disease complications.
9887382##1999-1-15##Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease.##Recently, 138 cases of infantile cirrhosis originating in several families in the Austrian province of the Tyrol were reported. This endemic Tyrolean infantile cirrhosis (ETIC) is indistinguishable from Indian childhood cirrhosis (ICC), idiopathic copper toxicosis (ICT), and resembles the early forms of Wilson's disease (WND). It has been argued that ETIC might represent an allelic variant of the WND gene, which is a copper transporting P-type ATPase (ATP7B). Assuming that ETIC results from a founder effect, a possible role for ATP7B in ETIC was investigated by association studies and haplotype sharing. Because of its lethality, the mapping of ETIC was focused on obligate gene carriers, i.e. the patients' parents. Our data indicate that ETIC is a separate genetic entity, distinct from WND.
9887381##1999-1-15##His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype.##In the present study we examined 33 German and 10 Cuban unrelated Wilson disease (WND) index patients and their relatives. The common His1069Gln mutation accounted for 42% of all WND chromosomes in the German series and the haplotype C was found to be highly predictive for this mutation. Six WND gene mutations have not been described previously and involved a splice site at intron 18 (3903 + del1G), a termination codon in the copper-binding region of exon 2 (Cys271X), and missense mutations in transmembrane region 2 (Gly710Ala), in transmembrane region 3 (Tyr741Cys), in the DKTGT motif (Thr1031Ile) and in the ATP loop region (Gly1176Arg). In 15 German WND index patients and three sibs both WND mutations could be determined and a genotype-phenotype correlation was attempted. Patients homozygous for the His1069Gln mutation showed almost the complete range of clinical presentations, and thus in our study this mutation is not associated with a late, neurological presentation.
9794921##1998-10-31##Copper resistant human hepatoblastoma mutant cell lines without metallothionein induction overexpress ATP7B.##Mutant human hepatoblastoma cell lines resistant to copper toxicity were isolated from mutagenized HuH7. Two copper resistant cell lines (CuR), CuR 23 and CuR 27, had reduced basal expression of metallothionein (MT) messenger RNA (mRNA) and exhibited minimal or no increase in resistance to cadmium or zinc toxicity. Copper uptake, efflux of newly transported copper, glutathione content, and efflux rate were comparable with HuH7, whereas holoceruloplasmin synthesis and secretion were slightly decreased. Subcellular distribution of copper at steady-state showed an increase in organelle and membrane fractions with a reduction in cytosol. Expression of ATP7B mRNA was fivefold increased, and ATP7B protein approximately threefold increased in both CuR 23 and 27. Another cell line, CuR 41, showed increased basal expression of MT and ATP7B mRNA but not ATP7B protein, and resistance to cadmium and zinc toxicity. Copper uptake in CuR 41 was comparable with HuH7, but initial rates of efflux of copper and glutathione were reduced. The synthesis of holoceruloplasmin but not ceruloplasmin peptide was markedly diminished in CuR 41. Subcellular distribution of copper showed an increase in cytosolic and decreased organelle and membrane-associated copper. These data suggest that cellular resistance to copper toxicity was achieved in two independent cell lines without MT induction and that the induction of ATP7B may lead to the enhanced intracellular sequestration of copper by organelles.
9823011##1998-11-21##Genes regulating copper metabolism.##The metabolism of Cu is intimately linked with its nutrition. From gut to enzymes, Cu bioavailability to key enzymes and other components operates through a complex mechanism that uses transport proteins as well as small molecular weight ligands. Steps in Cu transport through the blood, absorption by cells, and incorporation into enzymes are slowly being understood. Cloning and sequencing of the genes for Menkes disease and Wilson disease has shown that membrane-bound enzymes analogous to Cu-ATPases in prokaryotes are equally important to Cu transport and homeostasis in mammalian cells. The primary structure of the mammalian Cu-ATPases has been deduced from cDNAs from tissues and organs. It now appears that mammalian Cu-ATPase have tissue and developmental specificity. In this review, we will focus on the Cu-ATPase that has been identified with Menkes disease. An emphasis will be placed on the existence of multiple forms of the ATPase and some indication as to how the different isoforms befit their role in the normal physiology of copper, specifically transmembrane transport and maintenance of a favorable internal cellular environment.
9838469##1998-12-5##Recovery of neurological deficits in a case of Wilson's disease after liver transplantation.##
9838442##1998-12-5##Differential expression of proteins associated with liver transplantation in Wilson's disease patients.##
11477856##2001-8-2##[Curative effect of TCM-WM therapy on Wilson disease with different clinical phenotypes and polymorphisms of ATP7B gene].##
9824945##1998-11-24##[Molecular biology analysis: hereditary hemochromatosis, Wilson disease, alpha 1-antitrypsin deficiency and Dubin-Johnson syndrome].##The molecular pathology of hereditary hemochromatosis, Wilson's disease, alpha 1-antitrypsin-deficiency and Dubin-Johnson syndrome could be well characterised during the last years. Diagnosis of hereditary hemochromatosis is reliably confirmed by PCR-augmentation and restriction-analysis. Wilson's disease is a monogenetic disease, which is characterised by over 50 mutations. Molecular diagnosis is complicated by the lack of a single specific mutation. Diagnosis of Dubin-Johnson syndrome and alpha 1-antitrypsin-deficiency is possible by PCR-analysis and hybridisation with specific oligonucleotides.
9758874##1998-10-6##[Identification of a mutation hotspot in exon 8 of Wilson's disease gene by cycle sequencing].##
9781683##1998-10-22##Characterization of a heavy metal ion transporter in the lysosomal membrane.##Lysosomes are thought to play a role in various aspects of heavy metal metabolism. In the present study we demonstrate for the first time the presence of a heavy metal ion transport protein in the lysosomal membrane. Uptake of radioactive silver both in highly purified lysosomal membrane vesicles and in purified intact lysosomes showed the typical kinetics of a carrier-mediated process. This transport was stimulated by ATP hydrolysis, and showed specificity for Ag+, Cu2+, and Cd2+. All biochemical properties of this lysosomal metal ion transporter could classify it as a heavy metal transporting P-type ATPase. Long Evans Cinnamon (LEC) rats, an animal model for the copper transport disorder Wilson disease, showed normal lysosomal silver transport.
9785470##1998-10-24##ATP7B (WND) protein.##Wilson's disease is a genetic disorder of copper metabolism characterized by the excessive accumulation of this metal in the liver. The gene for Wilson's disease, designated ATP7B, encodes a copper transporting P-type ATPase expressed predominantly in the liver. Over 60 disease specific mutations of ATP7B have now been reported in patients with Wilson's disease. The gene for ATP7B is approximately 80 kb and contains 21 exons that encode an approximately 7.5 kb transcript. Recent studies that focus on the structure and expression of the ATP7B protein support its role as a copper transporter involved in the intracellular trafficking of copper in hepatocytes. The introduction of functional ATP7B protein by recombinant adenovirus mediated gene delivery will be a potential approach for correcting Wilson's disease.
9824280##1998-11-21##Inverse correlation of serum bilirubin and alkaline phosphatase in fulminant Wilson's disease.##
9811188##1998-11-12##Acute hemolytic crisis with fulminant hepatic failure as the first manifestation of Wilson's disease: a case report.##We report a 27-year-old woman who developed Coombs' negative hemolytic anemia and fulminant hepatic failure as the initial manifestation of Wilson's disease. Unmeasurably low level of serum alkaline phosphatase provided a clue to the diagnosis of Wilson's disease. The diagnosis was established with the presence of Kayser-Fleischer ring, decreased serum ceruloplasmin level, and elevated urine and serum copper levels. In spite of repeated plasmapheresis, she died of multiorgan failure on the fifth hospital day.
9794697##1998-10-30##Treatment of Wilson's disease with zinc: XV long-term follow-up studies.##Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.
9794692##1998-10-30##Zinc treatment of Wilson's disease.##
9836186##1998-12-4##Subacute and chronic toxicity studies of triethylenetetramine dihydrochloride (TJA-250) by oral administration to F-344 rats.##Triethylenetetramine dihydrochloride (trientine-2HCl, TJA-250), a copper chelating agent used to treat Wilson's disease, was administered orally to male and female F-344 rats for 4 or 8 weeks at dosages of 0, 100, 350 or 1200 mg/kg/day or for 26 weeks at dosages of 50, 175 or 600 mg/kg/day. 4 or 8-week study. Two males receiving 1200 mg/kg/day died during week 8 of treatment. In males receiving 1200 mg/kg/day during weeks 5 to 8 of treatment, body weight gain and food consumption were decreased and hunched posture and thin build were observed. During week 4 or 8 of treatment urinalysis revealed, for males receiving 100 mg/kg/day or animals receiving 350 mg/kg/day or more, increased electrolyte outputs possibly due to the hydrochloride nature of trientine-2HCl, with low plasma alkaline phosphatase activities evident in animals receiving 350 or 1200 mg/kg/day. After 4 and 8 weeks, and during 8 weeks of treatment, high lung weights and bronchiolar epithelium hypertrophy and broncho-alveolar pneumonia were recorded for animals receiving 1200 mg/kg/day, and submucosal acute inflammation within the glandular region of the stomach was recorded for males receiving 350 or 1200 mg/kg/day and in all treated female groups. 26-week study. One male receiving 175 mg/kg/day and three males receiving 600 mg/kg/day died, showing lung changes. The body weight gain of animals receiving 600 mg/kg/day was slightly decreased. Blood chemistry and urinalysis examinations showed changes similar to those indicated in the 4- or 8-week study. The low plasma copper concentrations seen in males receiving 600 mg/kg/day, the slightly low liver copper concentrations found in animals receiving 600 or 175 mg/kg/day and the high urinary copper concentrations found in all treated groups, are attributed to the pharmacological action of trientine-2HCl. Histopathology revealed a dosage-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups, but no significant pathological changes in the stomach. Apart from the histological changes found in the lung, all the above changes were reversible. In conclusion, the NOAEL of trientine-2HCl in this 26-week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males.
9768338##1998-10-13##Wilson's disease: gall stone copper following liver transplantation.##
9801873##1998-11-5##Haplotype and mutation analysis in Greek patients with Wilson disease.##In this study, we report the results of haplotype and mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Greek origin. We have analysed 25 WD families and two single patients and characterised 94% of the WD chromosomes investigated. We have found 12 different molecular defects (three frameshifts, two splice site, two nonsense, five missense mutations), four of which are novel. Five of the mutations are widely prevalent accounting for 74% of the WD chromosomes analysed. These results may enable preclinical diagnosis in the large majority of WD patients of Greek descent, thereby improving genetic counselling and disease management.
9891702##1999-1-19##Wilson's disease. Update of a systemic disorder with protean manifestations.##In Wilson's disease, a genetic defect in a copper transporter causes defective incorporation of copper into apo-ceruloplasmin and the failure to excrete copper into bile. Copper accumulated in hepatocytes generates damage via reactive oxygen species. Release of copper from necrotic hepatocytes leads to damage of other tissues, including the brain, urinary tract, red blood cells, heart, endocrine glands, skin, pancreas, bones, and joints. Treatment is designed to chelate the excess copper for urinary excretion, prevent copper absorption, and render tissue copper nontoxic. Liver transplantation, with replacement of the defective hepatic gene, may be necessary in some cases.
9840146##1998-12-5##Idiopathic thrombocytopenia associated with Wilson's disease.##We present the case of a 53 year-old patient with idiopathic thrombocytopenia associated with Wilson's disease. Idiopathic thrombocytopenia was diagnosed in August of 1994, and as the response to corticosteroid therapy was poor, the patient underwent a splenectomy in October of the same year. A liver biopsy, which was performed during the operation, showed Wilson's disease in the form of mild, chronic, active hepatitis. The serum ceruloplasmin was low, and the Kayser Fleischer's ring was positive. MRI of the brain showed cortical reductive changes with areas of copper accumulation in the white brain matter. An unusual presentation of Wilson's disease associated with idiopathic thrombocytopenia has not been published as of yet. The diagnosis of Wilson's disease was made at an advanced, adult age, which may implicate a heterozygous genetic configuration.
9765000##1998-10-9##Wilson's disease before and after 5 years of treatment with D-penicillamine.##
9748041##1998-9-25##Cerebral manifestation of Wilson's disease successfully treated with liver transplantation.##The main indication for orthotopic liver transplantation (OLTx) in Wilson's disease (WD) is severe hepatic decompensation. Our 15-year-old patient is the second case to date in whom OLTx was performed because of neurologic manifestations resulting from WD. His initial condition involving recurrent headaches, tremor, and athetoid hand movements progressively deteriorated during therapy with D-penicillamine, zinc sulfate, and trientine until he was severely dysarthric, unable to walk, and bedridden. After OLTx, his neurologic condition became almost normal.
9724794##1998-9-2##Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation.##Wilson disease is an autosomal recessive disorder of hepatic copper metabolism caused by mutations in a gene encoding a copper-transporting P-type ATPase. To elucidate the function of the Wilson protein, wild-type and mutant Wilson cDNAs were expressed in a Menkes copper transporter-deficient mottled fibroblast cell line defective in copper export. Expression of the wild-type cDNA demonstrated trans-Golgi network localization and copper-dependent trafficking of the Wilson protein identical to previous observations for the endogenously expressed protein in hepatocytes. Furthermore, expression of the Wilson cDNA rescued the mottled phenotype as evidenced by a reduction in copper accumulation and restoration of cell viability. In contrast, expression of an H1069Q mutant Wilson cDNA did not rescue the mottled phenotype, and immunofluorescence studies showed that this mutant Wilson protein was localized in the endoplasmic reticulum. Consistent with these findings, pulse-chase analysis demonstrated a 5-fold decrease in the half-life of the H1069Q mutant as compared with the wild-type protein. Maintenance of these transfected cell lines at 28 degreesC resulted in localization of the H1069Q protein in the trans-Golgi network, suggesting that a temperature-sensitive defect in protein folding followed by degradation constitutes the molecular basis of Wilson disease in patients harboring the H1069Q mutation. Taken together, these studies describe a tractable expression system for elucidating the function and localization of the copper-transporting ATPases in mammalian cells and provide compelling evidence that the Wilson protein can functionally substitute for the Menkes protein, supporting the concept that these proteins use common biochemical mechanisms to effect cellular copper homeostasis.
9874280##1999-1-5##Fetal copper uptake and a homolog (Atp7b) of the Wilson's disease gene in rats.##LEC rats are defective at the p-type copper transport ATPase gene (Atp7b) and exhibit excessive hepatic copper accumulation. However, copper concentration in fetal liver of LEC rats is lower than that of F344 normal rats. In this study, we made fetal backcrosses between LEC and F344 normal rats. At 19 days of gestation, hepatic copper concentrations of (LECXF344)F1XLEC and LECX(LECXF344)F1 fetuses were equivalent to those of F344 and LEC fetuses, respectively, irrespective of their Atp7b genotype. Furthermore, Atp7b expression was identified in the uterus and the maternal portion of placenta, but not in the fetal portion of placenta, in pregnant F344 rats. From these results, we speculate that the Atp7b product might contribute to a copper transport system from mother to fetus in the maternal portion, but not in the fetal portion of placenta.
9796400##1998-10-31##[Severe hemolytic anemia with tear drop red cells as initial manifestation of Wilson's disease].##A 16-year-old girl was admitted for a detailed examination of hemolytic anemia in November 1995. Initial laboratory findings included a total bilirubin concentration of 1.46 mg/dl, hemoglobin of 9.1 g/dl, and a reticulocyte count of 89/1000 percent. The plasma haptoglobin concentration was below 10 mg/dl. A blood smear showed many dacryocytes and a few echinocytes and codocytes. GOT was 71 IU/l; GPT, 44 IU/l; and LDH, 812 IU/l; the results of a hepaplastin test were 45% of normal. On further investigation, the level of serum ceruloplasmin was found to be 4 mg/dl, and of serum copper, 43 micrograms/dl. Urinary copper excretion was markedly increased, at 345 micrograms per day. Slit-lamp examination of both corneas revealed obvious Kayser-Fleischer rings. A liver biopsy sample showed fibrosis histologically and an elevated copper concentration of 535 micrograms/g dry weight and 183 micrograms/g wet weight. In family studies, the patient's asymptomatic 5-year-old sister was observed to have metabolic abnormalities consistent with Wilson's disease. These findings suggested that the patient's hemolytic anemia with red cell deformities was due to abnormal copper metabolism associated with Wilson's disease.
9863403##1998-12-24##[Treatment of chronic Wilson's disease in 2 patients using plasmapheresis--clinico-biochemical observations].##
9761160##1998-10-7##Five successful deliveries following 9 consecutive spontaneous abortions in a patient with Wilson disease.##
9728340##1998-9-5##Menkes disease: underlying genetic defect and new diagnostic possibilities.##Cloning of the gene defective in the X-linked neurodegenerative disorder Menkes disease led to a cascade of new findings. Besides giving a better understanding of the intracellular copper homeostasis, these findings had important consequences from a clinical point of view. Today the underlying genetic defect has been described in several patients affected by one of the three hereditary disorders of copper metabolism: Menkes disease, occipital horn syndrome and wilson disease. In this review we discuss mainly Menkes disease and the impact of the recent findings on the diagnosis of this disorder.
9757472##1998-10-3##[A case of neurologic type of Wilson's disease with increased aluminum in liver: comparative study with histological findings to metal contents in the liver].##Histological findings and metal contents in the liver were studied in a patient with neurologic type of Wilson's disease. Copper and aluminum contents in the biopsied liver of the patient with Wilson's disease were measured simultaneously by neutron activation analysis at Research Reactor Institute, Kyoto University. Four cases of adult cirrhosis were selected as the control for cirrhosis and five cases of adult liver as the control for neurologically normal. The biopsied liver showed markedly increase in the copper content (814.4 micrograms/g: dry weight) and extremely high content of aluminum (479.4 micrograms/g: dry weight), compared to those of the controls. On the other hand, macroscopically no cirrhosis was observed and the characteristic appearances of macronodular cirrhosis failed to detect histologically. Interestingly the fibrosis or inflammation of the liver was seen faintly. It is likely that toxic metals in the liver such as aluminum, copper and manganese might be implicated in the pathogenesis of neurologic type of Wilson's disease.
11819316##2002-1-31##Copper-chelating therapeutic effect in Wilson disease with different clinical phenotypes and polymorphisms of ATP7B gene.##AIM:To investigate the copper-chelating therapeutic effect in Wilson disease (WD) with different clinical phenotypes and polymorphisms of ATP7B gene.METHODS:One hundred and twenty-two WD patients with different clinicalphenotypes were given DMPS intravenously and Gandou copper-chelating tablet orally for one month. The therapeutic effect was judged by modified Goldstein mothod. Exon 18 of ATP7B gene extracted from the DNA of patients and 20 healthy volunteers was amplified with PCR mutation and polymorphism were screened with SSCP technique.RESULTS:Four kinds of abnormal migration bands in PCR-SSCP were observed in 37 WD patients, mutation frequencies of three different disease phenotypes, and curative effect between mutation group and non-mutation group showed no statistically significant difference (P > 0.05), but the total effectiveness rates in patients with Wilson type or pseudosclerosis type were significantly higher than those of patients with hepatic type (X(2) = 6.17, P < 0.05).CONCLUSION:Most WD patients are compound heterozygotes, the patients with different clinical phenotypes have different response to copper-chelating therapy. Specific mutation, at least in part, plays a role in influencing the disease phenotypes and therapeutic effect.
9691136##1998-8-6##[Detection of presymptomatic patients and heterozygotes with Wilson's disease by using haplotypes of microsatellites].##
9672279##1998-7-22##Effect of treatment of Wilson's disease on natural history of haemochromatosis.##
9726045##1998-9-3##Value of histochemical stains for copper in the diagnosis of Wilson's disease.##
12152840##2002-8-3##Wilson's disease: clinical and radiological features.##
9667562##1998-7-17##Dopamine transporter imaging with [123I]-beta-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson's disease.##
12687097##2003-4-11##Logical and Statistical Approach for the Analysis of Immunological Parameters in Patients with Wilson's Disease.##The immunological tests were performed for blood samples from 30 patients with Wilson's disease and 37 healthy patients. The processed data included conventional statistical analysis and computer programs, consisting of new pattern recognition methods - method of statistically weighted syndromes and that of detecting the informative conjunctions. In Wilson's disease group the significant alterations of parameters were determined: the decrease of T lymphocytes amount and CD4/CD8 ratio; the increase of circulating immune complexes and IgM levels; and B lymphocytes and NK amount. The methods of pattern recognition allowed to generate the rule to discriminate the cases from Wilson's disease and control groups with 87% effectiveness. The most frequently observed combinations of the altered parameters' values were revealed, and then the subgroups of Wilson's disease cases were considered. They were characterised by activation of the humoral immunity and/or depression of the cellular one. The heterogeneity of the immunity modifications may be the reflection of both genetic polymorphism and stages of the immunity violation. Some essential features of the immune status of patients with Wilson's disease are discussed.
9890078##1999-1-16##Other hereditary diseases and the liver.##In this chapter, an abbreviated account is presented on the subject of hereditary diseases and the liver. However, it is incomplete because Alagille syndrome, storage disorders, alpha-1-antitrypsin deficiency and Wilson disease are not included as they appear in other chapters of this volume. Biliary atresia is omitted because all available evidence does not support any significant genetic association. Molecular biological techniques have enabled linkage of several liver cholestatic disorders to chromosomal loci, and further characterization of the canalicular bile salt transporter (cBST) will advance our understanding of pathogenetic mechanisms involved in benign and progressive cholestatic syndromes. Disorders that have been treated as separate entities may have common 'roots', exemplified by the concept of the ductal plate malformation in fibropolycystic disease. Whereas the majority of disorders referred to in this chapter present early in life, there are several that are associated with liver failure in the neonatal period, which makes early recognition particularly important. Liver transplantation offers a cure for many hereditary disorders affecting the liver but it is not applicable to all.
9890071##1999-1-16##Wilson disease.##Wilson disease is a recessively inherited disorder of copper transport. Clinical features are highly variable, with any combination of neurological, hepatic or psychiatric illness. The age of onset varies from 3 to 50 years of age. Diagnosis is challenging because no specific combination of clinical or biochemical features is necessarily definitive. The genetic defect is due to a variety of abnormalities in a copper-transporting membrane ATPase. Most of the more than 80 mutations are present at a low frequency, and mutations differ between ethnic groups. At least two mutations are sufficiently common to aid in rapid diagnosis, in European and Asian populations respectively. Molecular analysis can provide a definitive diagnosis for asymptomatic sibs. Treatment, using chelating agents or zinc, is most effective when started before permanent tissue damage occurs.
9649217##1998-7-2##Autoantibody prevalence in children with liver disease due to chronic hepatitis C virus (HCV) infection.##HCV infection and interferon-alpha (IFN-alpha) therapy have been associated with autoimmunity. To assess whether chronic liver disease (CLD) due to HCV infection or its treatment with IFN-alpha cause autoimmune manifestations, the prevalence of tissue autoantibodies in 51 children with chronic HCV infection and 84 with other CLD was analysed by standard techniques. Sixty-five percent of patients with chronic HCV infection, 66% with chronic hepatitis B infection and 60% with Wilson's disease were positive for at least one autoantibody. In the 51 subjects with chronic HCV infection (29 treated with IFN-alpha, 22 untreated), tested on 165 occasions over a median of 9 months (range 5-42 months), autoantibodies to nuclei (ANA), smooth muscle (SMA), gastric parietal cell (GPC) and/or liver kidney microsomal type 1 (LKM-1) were similarly prevalent in treated and untreated patients (90% versus 68%, P = 0.12). Positivity for SMA was present in 67%, GPC in 32%, ANA in 10%, LKM-1 in 8% of cases. Treatment with IFN-alpha had to be suspended due to transaminase elevation in one SMA-positive, one ANA-positive but in three of four LKM-1-positive patients. Our results show that: (i) autoantibodies are common in viral-induced hepatitis and Wilson's disease; (ii) positivity for SMA, GPC, ANA is part of the natural course of chronic HCV infection, their prevalence being unaffected by IFN-alpha; and (iii) IFN-alpha should be used cautiously in the treatment of LKM-1/HCV-positive patients.
9642515##1998-6-27##Orthotopic liver transplantation for hepatic associated metabolic disorders.##Hepatic associated metabolic disorders represent 5% of the indications for orthotopic liver transplantation (OLTX) according to the European Liver Transplant Registry. We studied the outcome of this group at our institution after OLTX and combined liver/kidney transplantation. Between September 1988 and January 1997, 837 OLTXs were performed in 735 patients. Patient survival and graft function at 1 yr were 91.3 and 86%, respectively. Thirty-nine OLTXs were performed in 38 patients (15 female/23 male, median age +/- SD: 35 +/- 14 yr, range 4-60 yr) due to liver associated metabolic disorders (4.7%). Indications included Wilson's disease (n = 14), alpha-1-anti-trypsin-deficiency (n = 7), hemochromatosis (n = 4), erythropoetic protoporphyria (n = 4), cystic fibrosis (n = 2), Crigler-Najjar syndrome type I (n = 1), glycogenosis type I (n = 1), ornithine-transcarbomylase-deficiency (n = 1). In addition 4 patients suffering from primary hyperoxaluria type I received combined liver/kidney grafts. Survival rate the 1 yr after OLTX and combined OLTX/NTX was 91.8%. Twenty patients received cyclosporin A (55%) and 17 patients tacrolimus (45%) as primary immunosuppression. The mean follow-up was 28.6 months (range 4-73 months). Two patients with hemochromatosis died 1 and 3 months after OLTX, respectively, from Aspergillus sepsis followed by multiorgan-failure. One patient died of malignant lymphoma 5 months after transplantation. One patient required retransplantation 2 months after OLTX following arterial thrombosis and ischemic type biliary lesion. One year after OLTX, all patients demonstrated good graft function, liver grafts (ALT 17.9 +/- 13.6 IU/L, bilirubin 0.8 +/- 0.3.mg/dl, thromboplastin time 94 +/- 15%), and combined liver/kidney grafts (creatinine 2.4 +/- 1.4 mg/dl). OLTX, respectively combined OLTX/NTX, represent a successful therapy for hepatic associated metabolic disorders. Survival rates and graft function are similar to those in liver graft recipients for established indications at our institution. OLTX seems to be an excellent treatment for hepatic based therapy resistant neurological disorders.
9635624##1998-7-4##Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate analysis.##Viral hepatitis is the commonest cause of fulminant hepatic failure (FHF) in developing countries. We evaluated the early indicators of prognosis in these patients by multivariate analysis. The records of 204 consecutive patients with acute liver failure admitted with hepatic encephalopathy over five years were studied. The etiology of these patients included virus related in 186 (91.1%), drug induced in 15 (7.4%), Wilson's disease in one (0.5%), acute Budd-Chiari syndrome in one (0.5%), and malignant infiltration in one (0.5%). Patients with FHF complicating viral hepatitis were analyzed by univariate and multivariate analysis. These patients were further subclassified depending upon the interval between the onset of jaundice and the onset of encephalopathy into hyperacute (HALF; interval 0-7 days), acute (ALF; interval 8-28 days) and subacute liver failure (SALF; interval 4-12 weeks). Sixty (32.3%) patients with viral hepatitis survived. Univariate analysis showed that the interval between onset of encephalopathy and onset of jaundice, grade of encephalopathy, raised intracranial pressure, prothrombin time, and serum bilirubin levels on admission were related to outcome in these patients. Multivariate logistic regression analysis showed that the presence of raised intracranial pressure at the time of admission, prothrombin time >100 sec on admission, age (>50 yr), and onset of encephalopathy seven days after onset of jaundice were associated with poor prognosis. Forty seven (37.0%) of 129 patients with HALF survived compared with 9 (22.5%) of 40 with ALF and 4 (21.1%) of 19 with SALF (P = NS). Raised intracranial pressure was more frequent in patients with HALF (48.8%) than in patients with ALF (32.5%) and SALF (15.8%; P = 0.01), while clinically detectable ascites was more frequent in patients with SALF (78.9%) compared with HALF (19.7%) and ALF (37.5%; P < 0.0001). The factors adversely affecting the outcome in our patients with FHF complicating viral hepatitis include presence of overt clinical features of raised ICP at the time of hospitalization, prothrombin time (>100 sec) on admission, age (>50 yr), and onset of encephalopathy seven days after onset of jaundice.
9759594##1998-10-6##Use of the stable isotope 65Cu test for the screening of Wilson's disease in a family with two affected members.##
9686357##1998-8-1##Copper and ceruloplasmin metabolism in the LEC rat, an animal model for Wilson disease.##
9654149##1998-7-8##Analysis of functional domains of Wilson disease protein (ATP7B) in Saccharomyces cerevisiae.##Wilson disease is a genetic disorder of copper metabolism characterized by the toxic accumulation of copper in the liver. The ATP7B gene, which encodes a copper transporting P-type ATPase, is defective in patients with Wilson disease. To investigate the function of ATP7B, wild type or mutated ATP7B cDNA was introduced into a yeast strain lacking the CCC2 gene (delta ccc2), the yeast homologue of ATP7B. Wild type and the H1069Q mutant could rescue delta ccc2, however, the N1270S mutant could not, reflecting phenotypic variability of Wilson disease. In addition, the mutant containing only the sixth copper binding domain could rescue delta ccc2, indicating its functional importance.
9600907##1998-5-30##Localization of the Wilson's disease protein product to mitochondria.##Wilson's disease (WND) is an inherited disorder of copper homeostasis characterized by abnormal accumulation of copper in several tissues, particularly in the liver, brain, and kidney. The disease-associated gene encodes a copper-transporting P-type ATPase, the WND protein, the subcellular location of which could be regulated by copper. We demonstrate that the WND protein is present in cells in two forms, the 160-kDa and the 140-kDa products. The 160-kDa product was earlier shown to be targeted to trans-Golgi network. The 140-kDa product identified herein is located in mitochondria as evidenced by the immunofluorescent staining of HepG2 cells with specific mitochondria markers and polyclonal antibody directed against the C terminus of the WND molecule. The mitochondrial location for the 140-kDa WND product was confirmed by membrane fractionation and by analysis of purified human mitochondria. The antibody raised against a repetitive sequence in the N-terminal portion of the WND molecule detects an additional 16-kDa protein, suggesting that the 140-kDa product was formed after proteolytic cleavage of the full-length WND protein at the N terminus. Thus, the WND protein is a P-type ATPase with an unusual subcellular localization. The mitochondria targeting of the WND protein suggests its important role for copper-dependent processes taking place in this organelle.
9767885##1998-10-13##[Pregnancy in a patient treated with trientine dihydrochloride for Wilson's disease].##
9587157##1998-5-20##Wilson disease and canine copper toxicosis.##In this article we review the current clinical and research status of Wilson disease and canine copper toxicosis. One of the main clinical challenges in Wilson disease is for clinicians to recognize the possibility of Wilson disease when young patients present with liver disease, psychiatric disease, or a movement-disorder type of neurologic disease. Once the possibility of the disease is recognized, many copper-related tests are available that are quite accurate in making the diagnosis or ruling it out. It is important to remember that this is an inherited disease and that family members at risk should be screened, particularly siblings. The cloning of the Wilson disease gene opened up the possibility that a direct DNA test could be developed, allowing convenient screening of certain patients and family members. However, the large number of mutations already found, with no small set of mutations dominating the picture, have thwarted this approach. Once the diagnosis has been made, a variety of treatments are available. For maintenance therapy, therapy of presymptomatic patients, and therapy of pregnant patients, we use zinc. For initial therapy of patients with liver disease, we use a combination of zinc and trientine. For initial therapy of patients with neurologic disease we use tetrathiomolybdate. Canine copper toxicosis in Bedlington terriers is due to a gene different from the gene for Wilson disease. However, the disease is treatable with the same array of anticopper therapies that work in humans. Recently, we established linkage of the copper toxicosis gene to a microsatellite marker, which has made available a linkage test to breeders of Bedlington terriers.
9587151##1998-5-20##Copper absorption and bioavailability.##The human gastrointestinal system can absorb 30-40% of ingested copper from the typical diets consumed in industrialized countries. Experimental data support the existence of a carrier-mediated transport mechanism with an affinity constant in the micromolar range. Aging probably decreases the efficiency of copper homeostasis, resulting in higher plasma copper concentrations in the elderly. Physiologic differences may account for the higher cupremia of females. Supplements of minerals with similar chemical characteristics could reduce copper absorption. This property has pharmacologic applications in Wilson disease. Manipulation of the fiber content of the diet may have an indirect effect on copper bioavailability by altering the bioavailability of mineral antagonists. Proteins and soluble carbohydrates tend to improve copper absorption and bioavailability by enhancing its solubility and intestinal bulk flow. Organic acids, other than ascorbic acid, or agents that form low-molecular-weight chelates, are likely to have a positive effect on overall copper absorption. Conditions associated with malabsorption of macronutrients and gastrointestinal disease can impair copper uptake and contribute to suboptimal copper status.
9587141##1998-5-20##Functional analysis of copper homeostasis in cell culture models: a new perspective on internal copper transport.##The movement of copper ions across membrane barriers of vital organs and tissues is a priority topic in nutrition and one for which there continues to be little understanding of the mechanism. Reports of membrane-bound, copper-transporting adenosine triphosphatases (Cu-ATPases) selective for copper ions have brought new focus to the problem and prompted fresh ideas. Using a cell culture model approach, we attempted to learn whether transport into and out of cells depends on a Cu-ATPase. Measurement of transport kinetics in fibroblasts, brain glial cells, neuroblastoma cells, and placental cells showed differences in the rates of copper uptake and response to sulfhydryl reagents. BeWo cells, a human choriocarcinoma placental cell line, behaved as did Menkes fibroblasts by avidly absorbing copper but not releasing copper to the immediate environment. Further tests showed that BeWo cells did not express the transcript for the membrane-bound Cu-ATPase that has been identified with Menkes syndrome. Transcript induction, however, was achieved by growing BeWo cells on porous filters that allowed apical and basolateral surfaces to form. With transcript expression, the cells showed a capacity to release copper into the medium. BeWo cells also synthesized a form of ceruloplasmin whose structure differed from that of the plasma protein and hence may be a product of a different gene. BeWo cells may also express the gene for Wilson disease, thus linking Menkes and Wilson proteins to maternal delivery of copper. We constructed a model in which both ATPases work in concert in a vesicle-based transport mechanism. The vesicle model may help us understand the transport of copper across the placenta and all cells in general.
9587140##1998-5-20##Physiologic function of the Wilson disease gene product, ATP7B.##The genes responsible for Wilson disease and Menkes syndrome have been cloned and identified as copper ATPases. These enzymes form part of a large family of transporters, the P-type ATPases. Although copper ATPases share strong structural similarities with these other pumps, comparatively little is known about their physiologic function. In this review, we examine data relating to the Wilson disease protein, ATP7B, in the liver. We present evidence suggesting that ATP7B is located intracellularly, together with data suggesting that, at least in part, ATP7B may also be found on the canalicular membrane. We also examine the form of copper that the transporter recognizes. We then review data on the Long-Evans Cinnamon rat, a model for Wilson disease, and discuss what effect the Wilson disease mutation has on copper transport. Finally, we conclude that, although we have made major advances in our understanding of copper metabolism in the liver, there are still many questions awaiting answers.
9610794##1998-6-4##Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson's disease and primary hemochromatosis.##To assess DNA damage caused by lipid peroxidation due to copper and iron storage disorders in the human liver, the formation of the etheno adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytine (epsilon dC) was measured in liver DNA from normal subjects and from patients with Wilson's disease (WD) and primary hemochromatosis. The mean epsilon dA and epsilon dC levels per 10(9) parent nucleotides in normal liver were 19.3 +/- 4.9 and 27.5 +/- 10.0, respectively. The mean epsilon dA and epsilon dC levels per 10(9) parent nucleotides in WD were 61.03 +/- 7.95 and 91.50 +/- 36.02, and in primary hemochromatosis, they were 46.62 +/- 32.83 and 64.32 +/- 11.55, respectively, two to three times higher than those in the normal liver. The etheno adduct levels were highly correlated with the copper content of the liver in the normal and WD samples. This study demonstrates for the first time the formation of promutagenic etheno adducts in humans in association with copper and iron storage-induced lipid peroxidation. Thus, the etheno adducts are implicated as initiating DNA damage in copper/iron-induced carcinogenesis in humans and should also be explored as biomarkers in disease progression and prevention trials.
9702524##1998-8-14##A marked increase in free copper levels in the plasma and liver of LEC rats: an animal model for Wilson disease and liver cancer.##Most of copper present in rat plasma and liver binds to caeruloplasmin and metallothionein, respectively, and is not redox active. However, free forms of copper including loosely bound forms to other molecules are redox active. We assessed the free copper in Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease and liver cancer. Compared to those of control rats, the liver and plasma of LEC rats showed a marked elevation of free copper, especially at the stage of acute hepatitis, in parallel with an increase of total copper levels in the livers and a decrease of plasma caeruloplasmin (ferroxidase I) activity. At the onset of jaundice, the total copper levels, however, decreased in liver, but increased in plasma, while free copper levels in both liver and plasma remained higher. Free iron levels in both liver and plasma were also determined and did not change significantly, except for the case of plasma in jaundiced rats. The data are consistent with a proposal in which increased levels of redox active free copper in the liver of LEC rats catalyze Fenton-type reactions, producing a large flux of hydroxyl radicals that would play an important role in the observed liver dysfunction, leading to acute hepatitis, and finally, hepatocarcinoma. This is the first demonstration that the free copper may participate in the pathophysiology of the LEC rats and Wilson disease.
9852306##1998-12-16##Abnormal cortical development; towards elucidation of the LIS1 gene product function (review).##Lissencephaly is a relatively common brain malformation. Lissencephaly type 1 is characterized by the smooth appearance of the cortex and the presence of four abnormally positioned layers instead of the normal six. Lissencephaly is considered to be an abnormality in neuronal migration. The gene mutated in type 1 lissencephaly was cloned by us and designated LIS1. Recently, several genes involved in cortical development have been cloned in the mouse. In human an additional X-linked lissencephaly gene has been identified. We summarize here our current knowledge on the LIS1 gene and its function. It has been identified as a non-catalytic subunit of PAF-acetylhydrolase, a heterotrimeric enzyme which inactivates the platelet-activating factor (PAF). In addition, we have demonstrated that LIS1 interacts with tubulin, and affects the dynamics properties of microtubles. LIS1 contains seven WD repeats and may structurally resemble the beta-subunit of heterotrimeric G proteins. Interestingly, the catalytic subunit of PAF-acetylhydrolase was found to resemble the alpha subunit of heterotrimeric G proteins. We raise the possibility that LIS1 is part of an intracellular signaling pathway involved in neuronal migration.
9585233##1998-5-19##Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.##Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD95 system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease.
9638674##1998-6-25##1H MR spectroscopy of the basal ganglia in childhood: a semiquantitative analysis.##Proton MR spectra of the basal ganglia were obtained from 28 patients, 24 male and 14 female, median age 16.3 months (5 weeks to 31 years). They included 17 patients with normal MRI of the basal ganglia without metabolic disturbance (control group) and 11 patients with various metabolic diseases: one case each of high serum sodium and high serum osmolarity, cobalamin C deficiency, Leigh disease, Galloway-Mowat syndrome, Pelizaeus-Merzbacher disease, hemolytic-uremic syndrome and Wilson disease and two cases of Alagille syndrome and methylmalonic acidemia with abnormal MRI of the basal ganglia or blood or urine analysis (abnormal group). The MR spectrum was measured by using STEAM. The MR-visible water content of the region of interest was obtained. Levels of myoinositol, choline, creatine and N-acetylaspartate were measured using a semiquantitative approach, with absolute reference calibration. In the control group, there was a gradual drop of water content over the first year of life; N-acetylaspartate, creatine and myoinositol levels showed no significant change with age, in contrast to the occipital, parietal and cerebellar regions. Choline showed a gradual decrease for the first 2 years of life and then remained fairly constant. In the abnormal group the water content was not significantly different. N-Acetylaspartate was decreased in patients with high serum sodium and high serum osmolarity, cobalamin C deficiency, Leigh disease and one case of methylmalonic acidemia. Decreased creatine was also found in Leigh disease, and decreased choline in Galloway-Mowat syndrome and Wilson disease. Myoinositol was elevated in the patient with abnormally high serum sodium, and decreased in the hemolytic-uremic syndrome.
9621702##1998-6-11##[A case of Wilson's disease associated with hypoparathyroidism and amenorrhea].##
9615694##1998-6-6##[Progress of acute liver failure and indications for liver transplantation].##
9845729##1998-12-10##A simple and rapid stain for copper in liver tissue.##We report a modified copper stain that can be completed in 2 hours, rather than overnight, which is required for other stains. This is useful in the diagnosis of chronic cholestatic syndromes, Wilson's disease, Indian childhood cirrhosis, and other conditions associated with copper retention.
9612534##1998-6-5##Cytopenias secondary to copper depletion complicating ammonium tetrathiomolybdate therapy for Wilson's disease.##
9624223##1998-6-13##Metal (molybdenum, copper) accumulation and retention in brain, pituitary and other organs of ammonium tetrathiomolybdate-treated sheep.##Ammonium tetrathiomolybdate (TTM) is the treatment of choice for chronic Cu poisoning in sheep and is recommended in Wilson's disease. However, the long-term effects have not been fully evaluated and some evidence questions the long-term safety of the drug. The aim of the present study was to investigate the systemic distribution and retention of Cu and Mo in TTM-treated sheep of different breeds and Cu status. Low-Cu Cambridge sheep were divided into a TTM trial group (3.4 mg/kg, subcutaneously, on three alternate days per month, for 5 months) and a control group, and were killed at the end of the course or 7 months later. High-Cu sheep consisting of a Cu-supplemented (150 mg/kg) Cambridge group and a North Ronaldsay group were administered TTM as before and compared with untreated controls. Brain, liver, kidney, heart, skeletal muscle, pituitary, adrenals, tests and ovaries were retained for metal analysis. Mo accumulated in all organs including brain and pituitary (P < 0.02) in all TTM trial groups and was retained after cessation of treatment, except in liver, kidney and skeletal muscle. Cu was increased (P < 0.02) and retained in the cerebellum and medulla oblongata in the TTM-treated high-Cu Cambridge groups. Brain Cu v. Mo concentrations showed a strongly positive correlation (r. 0.7) in the high-Cu Ronaldsay group 7 months after TTM treatment. It is concluded that TTM is not all excreted but (Mo) is widely distributed and retained in many organs including brain and pituitary. In addition TTM may redistribute some displaced excess liver Cu (Cu-TTM) to the brain. The consequences of these disturbances await clarification.
9615909##1998-6-6##Association of copper to metallothionein in hepatic lysosomes of Long-Evans cinnamon (LEC) rats during the development of hepatitis [se e comments].##
9566847##1998-5-5##Wilson's disease: the scourge of copper.##
9661287##1998-7-14##Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats.##The uptake of tetrathiomolybdate (TTM) by the liver and the removal of copper (Cu) accumulating in the liver in a form bound to metallothionein (MT) by TTM were studied in Long-Evans cinnamon (LEC) rats, an animal model of Wilson disease, in order to develop better treatments for the disease and Cu toxicity. Although molybdenum (Mo) was incorporated in a dose-dependent manner into the livers of both LEC and Long-Evans agouti (LEA) rats, the original strain of LEC rats used as a reference animal, the uptake into the liver of LEC rats was 13 times higher than that in LEA rats. The concentration of Mo in the soluble fraction plateaued and it was distributed more in the insoluble fraction with a higher dose in LEC rats. The concentration of Cu in the whole livers of LEC rats was decreased by TTM in a dose-dependent manner only at lower doses. However, the concentration of Cu in the soluble fraction continued to decrease with the dose of TTM. The results can be explained in terms of complex formation. Namely, TTM forms a complex with Cu, tentatively referred to a Cu/TTM complex, that can be effluxed into the bloodstream, and then binds selectively to albumin when the dose of TTM is low. On the other hand, TTM forms an insoluble complex, named as a Cu/TTM polymer that is precipitated in the liver when the dose is high. The results further indicate that TTM taken up by a cell is immobilized in the cell through the dose-dependent formation of a complex containing Cu, Mo and sulfur (S), which causes further uptake of TTM. TTM injected into rats or incubated in vitro with serum does not remove Cu from ceruloplasmin. TTM is, thus, suggested to target a cell accumulating excess Cu as Cu-MT, and to remove Cu selectively without interacting with Cu in Cu-enzymes. The results indicate that TTM is taken up by the liver depending on the amount of Cu accumulating in the form of MT, and then Cu is effluxed together with Mo in the form of Cu/TTM complex into the bloodstream.
10090006##1999-3-25##Spontaneous cholangiofibrosis in Long-Evans Cinnamon rats: a rodent model for Wilson's disease.##The Long-Evans Cinnamon (LEC) rat is a rodent model of Wilson's disease characterized by ceruloplasmin deficiency, hepatic copper accumulation, and hepatocellular injury. So far, the LEC rat appears to be the only strain in which cholangiofibrosis develops spontaneously. The aim of the study reported here was to characterize the time course of development and investigate the structural and ultrastructural features of cholangiofibrosis and their possible relationship to hepatic copper and iron content. The livers of 54 rats (22 males), ages 5 to 113 weeks, were examined by light microscopy and graded for statistical analysis, with respect to extent of replacement of liver tissue by cholangiofibrosis. The study was complemented by electron microscopy, and by measurements of copper and iron contents by atomic absorption spectroscopy. Cholangiofibrosis was present in LEC rats by 20 weeks of age. The hyperplastic biliary epithelial cells varied markedly in size and shape, ranging from flat to cuboidal or elongated. Epithelial cells did not exhibit characteristics of intestinal cells. Some basement membranes had splits, duplications, or multiplications. Cytoplasmic organelles within hyperplastic biliary cells appeared unremarkable in contrast to the characteristic mitochondrial abnormalities present in neighboring hepatocytes. There was a positive correlation between histologic grades of cholangiofibrosis and ages of the animals (r = 0.68, P < 0.001), but no significant correlation between histologic grade and hepatic copper or iron content. We conclude that cholangiofibrosis is the predominant pathologic response to chronic liver injury induced by excess copper in LEC rats. The pathogenic role of copper in the development of cholangiofibrosis requires clearer definition.
9595013##1998-5-22##Effective removal of copper by plasma exchange in fulminant Wilson's disease.##
9521204##1998-4-1##Living-related liver transplantation and neurological outcome in children with fulminant hepatic failure.##
9529450##1998-4-8##The prognostic value of a rare sonographic pattern in Wilson's disease. A case report.##
11717929##2001-11-23##Cloning and characterization of a metal responsive element-containing fragment from the Wilson disease gene locus by junction trapping.##All mammalian metallothionein genes studied to date have several metal responsive elements (MRE) with consensus sequences of TGCRCNC (R, purine) in their regulatory region. MRE-like sequences were also found in many other metal-related genes. To see whether there is also such a sequence at the genetic locus (13q14.3) of Wilson disease, which is a genetic disorder of copper metabolism, junction-trapping method based on the MRE sequence was used. A fragment containing MRE and MRE-like sequences from YAC 27D8 at the WND locus was successfully cloned and mapped back to the YAC by PCR. Presence of such a sequence in the copper transporter gene at the WD locus might imply that it has a possible interesting role in the regulation of WD gene expression.
9500710##1998-3-21##Intracellular distribution of the Wilson's disease gene product (ATPase7B) after in vitro and in vivo exogenous expression in hepatocytes from the LEC rat, an animal model of Wilson's disease.##In patients with Wilson's disease, both copper incorporation into ceruloplasmin and excretion of this metal into bile are impaired. These conditions are caused by a genetic defect in the Wilson's disease gene (ATP7B). To investigate the Wilson's disease gene protein (ATPase7B) in hepatocytes, we constructed an expression plasmid carrying full-length complementary DNA for human Wilson's disease gene and attempted to express the gene in hepatocytes of LEC rats, an animal model of Wilson's disease. Transfection of hepatocytes, either in vitro or in vivo, was done using a newly developed cationic liposome containing 1,4-bis(3-(N-hexadecyl) aminopropyl) piperazine. Immunological analyses of human ATPase7B with specific monoclonal antibodies showed human ATPase7B to be a membrane protein with a molecular mass of 155 kd. Analysis of human ATPase7B expressed in hepatocytes from LEC rats suggested that this protein is present in the trans-Golgi network and at the plasma membrane, a distribution pattern similar to that of Menkes' disease protein (ATPase7A). These findings suggest that these two putative copper-transporting P-type ATPases function similarly at the cellular level. Cotransfection and coexpression of the human Wilson's disease gene and ceruloplasmin gene in cultured hepatocytes indicate that the distribution of ceruloplasmin is always accompanied by ATPase7B at the perinuclear region, but that part of ATPase7B localizes irrespective of the distribution of ceruloplasmin. Based on these investigations, we propose that ATPase7B exists in the trans-Golgi network and transports copper into this compartment. This seems to ensure an appropriate delivery of copper to the apoceruloplasmin. On the other hand, part of ATPase7B that is not accompanied by ceruloplasmin in the perinuclear region and at the plasma membrane seems to contribute to efflux of this metal from the hepatocytes. Thus the distribution patterns of ATPase7B in hepatocytes may explain the dual roles of this P-type ATPase in hepatocytes.
9563918##1998-5-1##Subacute hepatic failure: diagnosis of exclusion?##Subacute hepatic failure has been a controversial diagnosis ever since it was first identified more than 15 years ago. The Working Committee on Subacute Hepatic Failure has attempted to redefine this entity in which exclusion of preexisting cirrhosis on liver biopsy has been emphasized. Acute viral hepatitis in a patient with asymptomatic chronic liver disease (e.g., hepatitis B or C, Wilson's disease) can be misdiagnosed as subacute hepatic failure in the absence of a liver biopsy. This situation is common in developing countries where the prevalence of feco-orally transmitted (hepatitis A [<20 years] and hepatitis E [>20 years]) and parenterally transmitted (hepatitis B) viruses is high. To obtain and interpret liver biopsy specimens in such a situation is difficult and hazardous, and hence rarely performed. Acute viral hepatitis in a patient with asymptomatic chronic liver disease should be carefully looked for and excluded, especially in developing countries, before a diagnosis of subacute hepatic failure is confirmed.
9732096##1998-9-10##Liver problems in pregnancy: part 2--managing pre-existing and pregnancy-induced liver disease.##In distinguishing normal from abnormal hepatic changes, the author described the expected changes in liver tests that occur during complicated pregnancy. This article reviews the forms of pre-existing liver disease that may affect or be affected by pregnancy, as well as liver diseases that tend to arise during pregnancy. Among the pre-existing liver diseases are autoimmune chronic active hepatitis, which may be activated by pregnancy and tends to be associated with an increased risk of still and premature births. Worsening of chronic hepatitis B and C has occasionally been observed. While some women with cirrhosis can sustain a normal pregnancy without any worsening of hepatic function, others develop liver failure; plus, women with cirrhosis are less fertile and have higher rates of both stillbirths and premature infants. Other liver disorders that may or may not be affected by pregnancy include Dubin-Johnson syndrome, Gilbert syndrome, benign recurrent intrahepatic cholestasis, Wilson's disease, hepatic adenomas, and focal nodular hyperplasia. Among the hepatic disorders that occur during pregnancy in normally healthy women and then resolve after delivery is intrahepatic cholestasis of pregnancy (also known as pruritus gravidarum, recurrent intrahepatic cholestasis of pregnancy, and obstetric hepatosis). Others include acute fatty liver of pregnancy and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which may be part of the spectrum of disorders associated with pre-eclampsia/eclampsia. Pregnancy may also trigger the dissemination of herpes infection to the liver.
9539354##1998-4-16##Arm tremor secondary to Wilson's disease.##
9565982##1998-5-5##[Schizophrenia-like symptoms in the Westphal-Strümpell variation of Wilson disease].##Wilson's disease is a rare, autosomal recessive disorder of copper metabolism due to low serum ceruloplasm, resulting in increased copper deposition, especially in the liver and basal ganglia in the brain. The pseudosclerotic type of Wilson's disease, also known as the Westphal-Strümpell form, is distinguished by positional tremor, ataxia and dysarthria as the main symptoms. We use the example of a 23-year-old patient whose neurological symptoms were preceded by a long history of a schizophrenic-like disorder. Clinical symptoms are presented. MRI, SPECT and PET images are illustrated. Therapy and outcome are discussed.
9760555##1998-10-7##[Modern views on the pathogenesis of Wilson's disease].##Wilson's disease is a rare, multiorganic genetically coded disorder, induced by impaired copper transport. The recent identification of the disease gene and the discovery of gene product--copper transporting P-type ATPase that is integrate membranous protein has contributed greatly to better understanding of the pathogenesis. This protein is probably essential for incorporation of copper into ceruloplasmin and for its biliary excretion. Multiple mutations of Wilson's disease gene are responsible for the excess of so called "free" copper which is toxic to tissues. Copper toxicity involves first of all, functional disorders of many enzymatic systems, particularly those of respiratory chain enzymes. In the central nervous system, a special kind of copper toxicity is medicated by astroglia, so that a direct, harmful effect of both copper and ammonia on the brain is observed. The authors present a current review on biochemical mechanisms of copper toxicity and physiopathological significance of the CNS astroglia in Wilson's disease.
9591324##1998-5-20##Increased polyploidy, delayed mitosis and reduced protein phosphatase-1 activity associated with excess copper in the Long Evans Cinnamon rat.##Until now, it is not known whether copper hepatotoxicity impairs mitosis. Enlarged hepatocytes with huge nuclei considered as polyploids are frequently observed in the Long Evans Cinnamon (LEC) rat which exhibits an abnormal accumulation of hepatic copper due to a defect in the gene homologous to human Wilson's disease gene responsible for intracellular copper delivery. This defect may lead to a abnormal mitotic progression in increased polyploidization and is associated with excessive hepatic copper. This study was designed to examine whether excess copper impairs mitotic progression and results in increased polyploidization using a model of LEC rat liver. Polyploidy was analyzed by flow cytometry. The rate of mitotic progression was investigated using the fraction of mitotic hepatocytes or a mitosis-specific phosphoprotein retained in regeneration. Nuclear protein phosphatase-1 (PP-1) activity essential to mitotic progression was measured. The effect of excess copper on incidence of polyploidy, the rate of mitotic progression and nuclear PP-1 activity was investigated using age- or copper overload-dependent changes in them in LEC rat, or genetic profile-dependent changes of them in backcrosses. LEC rat liver showed an increase of polyploidy, a delay of mitotic progression, and a reduction of nuclear PP-1 activity. These abnormal features concurred with increase of copper concentration accompanied by changes of age in LEC rats from 2 to 4 months of age, induced by dietary copper overload in LEC rat, or caused by single genetic defect in backcrosses. Excess copper impairs mitotic progression, resulting in increased polyploidization. Nuclear PP-1 activity is likely to be at least one of targets of copper hepatotoxicity leading to impairment of mitotic progression.
9654718##1998-7-9##[Wilson disease and pregnancy. Review of the literature and case report].##Wilson's disease is an autosomal recessive disorder of copper metabolism. Since the introduction of penicillamine treatment successful pregnancies have been reported. However little is known about the risks of breast feeding in patients on this medication. We describe the case of a patient suffering from Wilson's disease, who had two uncomplicated pregnancies and breast fed both children for a period of three months each. In the 22 year old gravida I para I the diagnosis of Wilson's disease had been previously made by liver biopsy and penicillamine therapy had been begun. At the time of her first presentation at our department she was 8 week pregnant. Her renal and liver function were normal. Neurologic or psychiatric symptoms were not observed. At 18 weeks the dosage of penicillamine was reduced from 900 mg/d to 750 mg/d. The course of the pregnancy remained uneventful. At 38 + 1 weeks a healthy boy of 3100 gm was delivered. 19 months later the patient presented again in the 16th week of her second pregnancy. Concerning Wilson's disease no major changes were observed, especially liver and renal function were not impaired. The dosage of penicillamin was reduced from 900 mg/d to 750 mg/d during the 21st week. The pregnancy again was uncomplicated and at 38 + 2 weeks resulted in the spontaneous deliver of a healthy boy, weighting 3940 gm. Both children were breast fed over a period of three months and with the exception of an icterus prolongatus no adverse effects were noted.
9465110##1998-3-21##A pineal regulatory element (PIRE) mediates transactivation by the pineal/retina-specific transcription factor CRX.##The circadian hormone melatonin is synthesized predominantly in the pineal gland by the actions of two pineal-specific enzymes: serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). Pineal night-specific ATPase (PINA), another pineal- and night-specific protein we recently identified, is produced as a truncated form of the Wilson disease gene (Atp7b) product. To identify the regulatory elements required for pineal-specific gene expression, we isolated sequences upstream of the rat PINA gene and discovered a cis-acting element that is recognized by a novel pineal/retina-specific nuclear factor. This pineal regulatory element (PIRE) has a consensus of TAATC/T and is present in six copies in the 5' regulatory region of the PINA gene, at least three copies in the rat NAT promoter, and at least one copy in each of the putative HIOMT promoters A and B. A recently identified retina-specific protein, cone rod homeobox (CRX), binds to PIRE in vitro and transactivates PIRE-reporter constructs. These data suggest that Crx may play a crucial role in regulating pineal gene expression through interactions with PIRE.
9452509##1998-3-7##Functional expression of the menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases.##Menkes disease is a fatal neurodegenerative disorder of childhood caused by the absence or dysfunction of a putative P-type ATPase encoded on the X chromosome. To elucidate the function of the Menkes disease protein, a plasmid containing the open reading frame of the human Menkes disease gene was constructed and used to transform a strain of Saccharomyces cerevisiae deficient in CCC2, the yeast Menkes/Wilson disease gene homologue. ccc2Delta yeast are deficient in copper transport into the secretory pathway, and expression of a wild type human Menkes cDNA complemented this defect, as evidenced by the restoration of copper incorporation into the multicopper oxidase Fet3p. Site-directed mutagenesis demonstrated the essential role of four specific amino acids in this process, including a conserved histidine, which is the site of the most common disease mutation in the homologous Wilson disease protein. The expression of Menkes cDNAs with successive mutations of the conserved cysteine residues in the six amino-terminal MXCXXC metal binding domains confirmed the essential role of these cysteine residues in copper transport but revealed that each of these domains is not functionally equivalent. These data demonstrate that the Menkes disease protein functions to deliver copper into the secretory pathway of the cell and that this process involves biochemical mechanisms common to previously characterized members of this P-type ATPase family.
9583209##1998-5-16##Severely decompensated abdominal Wilson disease treated with peritoneal dialysis: a case report.##A 12-year-old girl with severely decompensated abdominal Wilson disease was treated with abdominal dialysis in order to accelerate the excretion of chelated copper. Dialysate without human serum albumin or D-penicillamine was used and was able to accelerate the excretion of chelated copper, with an increment of 5.5-19.7% compared with urinary excretion only.
9463339##1998-4-16##The -75A-->C substitution in the 5' UTR of the Wilson disease gene is a sequence polymorphism in the Mediterranean population.##
15560044##2004-11-25##Wilson's disease.##Wilson's disease is an autosomal, recessive-inherited disorder of impaired biliary copper excretion that results in the accumulation of copper in various organs including the liver, the cornea and the brain. The Wilson's disease gene on chromosome 13 codes for a copper transporting P-type ATPase-ATP7B. More than 60 mutations of this gene have been described. The diagnosis of Wilson's disease is based on clinical findings and laboratory abnormalities and can be made if two of the following symptoms are present: Kayser-Fleischer rings; topical neurologic symptoms; and low serum ceruloplasmin levels. In less typical cases diagnosis requires various other tests of copper metabolism. Effective medical treatment with copper chelators (D-penicillamine, trientine) or zinc results in symptomatic improvement and normal life expectancy. Orthotopic liver transplantation is indicated in advanced cases with hepatic decompensation or in patients with fulminant Wilson's disease.
9749714##1998-9-28##High-affinity copper block of GABA(A) receptor-mediated currents in acutely isolated cerebellar Purkinje cells of the rat.##The actions of Cu2+ ions on GABAA receptor-mediated currents in acutely isolated Purkinje cells from rat cerebellum were studied using the whole-cell patch-clamp technique and a rapid perfusion system. Bath application of Cu2+ reduced currents induced by 2 microM gamma-aminobutyric acid (GABA) in a concentration-dependent manner with an IC50 of 35 nM. The Cu2+-induced block of GABA responses was not voltage-dependent. Increasing the GABA concentration (from 2 to 50 microM) decreased the blocking effect of Cu2+. Dose-response analysis for activation of GABAA receptors revealed a twofold decrease in apparent affinity for GABA in the presence of 0.1 microM Cu2+. Recovery from the block required several minutes after removal of Cu2+ from the medium. The block was removed by histidine, which preferentially forms complexes with Cu2+, or by other chelating substances. Application of 10 microM histidine immediately before application of 2 microM GABA completely relieved the block of GABA responses produced by 0.1 microM Cu2+. The effect of histidine was concentration-dependent with an EC50 of 0.75 microM. The results demonstrate that Cu2+ is a potent inhibitor of GABA-evoked responses in rat Purkinje cells. Copper may be an endogenous synaptic modulating factor. Cu2+ toxicity, notably in Wilson's disease, could result to some extent from chronic GABAA receptor blockade.
9504786##1998-3-21##Early and severe neurological features in a Wilson disease patient compound heterozygous for two frameshift mutations.##
9602696##1998-5-29##A case of systemic pseudo-pseudoxanthoma elasticum with diverse symptomatology caused by long-term penicillamine use.##A 47 year old man presented with a two year history of increasing cervical dysphagia, dyspnoea, and cutaneous signs. He had been diagnosed 27 years previously with Wilson's disease and was treated with penicillamine (1.5 g daily). Systemic abnormality of elastic fibres was confirmed by light and electron microscopy following biopsy of skin, lung, oesophageal muscle, gum, pharyngeal tissue, and cervical connective tissue. Dysphagia was relieved by cricopharyngeal myotomy. Substitution of trientene dihydrochloride for penicillamine relieved cutaneous and systemic manifestations. This is possibly the first case demonstrating an association between prolonged penicillamine use and biopsy proved systemic pseudo-pseudoxanthoma elasticum. The presenting symptoms may have resulted from the abnormal numbers and properties of elastic fibres, and the changes were caused by penicillamine use, rather than by idiopathic, inherited pseudoxanthoma elasticum.
9489523##1998-3-7##Atypical MR findings in Wilson's disease: pronounced lesions in the dentate nucleus causing tremor.##
9484715##1998-3-4##Metallothionein and apoptosis in the toxic milk mutant mouse.##Toxic milk mutant (tx) mice accumulate excess copper (Cu) in liver with age and develop symptoms similar to those seen in human Wilson disease. Because metallothionein (MT) is the major Cu-binding protein in tx mouse liver and Cu-MT can enhance lipid peroxidation initiated by an organic hydroperoxide, the potential genotoxicity of Cu-MT in tx mice was assessed in male tx mice (11 to 12 months old) and in age- and sex-matched control wild-type (DL) mice. Toxic milk mutant mice, but not control DL mice, developed regenerative liver nodules (tx-N) with normal histologic appearance. Residual, non-nodular tx mouse liver (tx-R) was microscopically abnormal with large, atypical hepatocytes. The levels of Cu, zinc (Zn), and MT, and the numbers of apoptotic cells (APC) in tx-N, tx-R, and DL livers were measured by atomic absorption spectrophotometry, 109cadmium-heme assay, and the TUNEL method, respectively. Significantly higher levels of MT, Cu, and Zn, as well as increased numbers of APC were found in both tx-N and tx-R compared with DL mouse livers. Intense nuclear and cytoplasmic immunohistochemical staining for MT was observed in both normal and atypical hepatocytes of the tx mouse, whereas only cytoplasmic staining for MT was detected in DL mouse liver tissue. Accumulated Cu could be detected in tx-R and tx-N liver by rhodanine staining but was not detected in other tx mouse organs, or in mouse liver or other organs of DL. The number of APC and level of MT were significantly higher in tx-R liver compared with both tx-N and DL liver. These results suggest that: (a) aged tx mouse accumulate excess Cu in liver accompanied by striking morphologic changes, and (b) although MT binds to Cu in tx mouse liver, the presence of high Cu-MT and Cu in the nucleus can be genotoxic and may lead to enhanced apoptosis.
9773037##1998-10-17##[Cerebral hemosiderosis related to hereditary ceruloplasmin deficiency. Clinical familial case study].##A 59-year-old patient progressively developed dementia, hallucinations and facial dyskinesia. Brain T and T2-weighted MRI images showed low signal intensity on basal ganglia specially striatum, posterior thalamic and dentate nuclei. He had no evidence of ceruloplasmin and a high level of ferritin in the serum. Liver biopsy confirmed accumulation of iron in the cytoplasm of many hepatocytes. Similar clinical and biological signs were also observed in two brothers. All the three siblings were homozygous for a hereditary ceruloplasmin deficiency. This new clinico-pathological entity, first described in 1987, is different from Wilson's disease, Hallervorden-Spatz's disease and idiopathic hemochromatosis and linked to a mutation of the ceruloplasmin gene located on chromosome 3.
9430732##1998-1-27##Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA.##Wilson's disease, an autosomal recessive disorder, is characterized by the excessive accumulation of copper in the liver. WND (ATP7B) gene, which encodes a putative copper transporting P-type ATPase, is defective in the patients. To investigate the in vivo function of WND protein as well as its intracellular localization, WND cDNA was introduced to the Long-Evans Cinnamon rat, known as a rodent model for Wilson's disease, by recombinant adenovirus-mediated gene delivery. An immunofluorescent study and a subcellular fractionation study revealed the transgene expression in liver and its localization to the Golgi apparatus. Moreover, since the synthesis of holoceruloplasmin is disturbed in the Long-Evans Cinnamon rat, the plasma level of holoceruloplasmin, oxidase-active and copper-bound form, was examined to evaluate the function of WND protein with respect to the copper transport. Consequently, the appearance of holoceruloplasmin in plasma was confirmed by Western blot analysis and plasma measurements for the oxidase activity and the copper content. These findings indicate that introduced WND protein may function in the copper transport coupled with the synthesis of ceruloplasmin and that the Golgi apparatus is the likely site for WND protein to manifest its function.
9439629##1998-1-24##Abnormal accumulation of porphyrin derivatives in the kidneys of Long-Evans Cinnamon rats, as evidenced by microspectrophotometry.##In the study described here we have revealed an abnormal accumulation of porphyrin derivatives in the kidneys of Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. In addition, we have confirmed that the derivatives emitted red-orange light in renal sections under UV excitation. This renal red-orange emission has previously been identified as luminescence from cuprous metallothioneins [Cu(I)-MTs], which also accumulate in both the kidneys and liver of LEC rats. In this study, we measured the emission spectra of the luminescence in the kidneys using microspectrophotometry. The spectra of the renal red-orange emission resembled those of porphyrin derivatives rather than those of Cu(I)-MTs. We then extracted these derivatives from the kidneys. An abundance of porphyrin derivatives was established. A significant increase in the levels of the derivatives in the liver and urine of the LEC rats was also confirmed. These results provide evidence of a heme-metabolism abnormality in LEC rats.
9437064##1998-3-28##Unusual liver MR findings of Wilson's disease in an asymptomatic 2-year-old girl.##We describe the unusual magnetic resonance (MR) findings of a case of Wilson's disease (WD) in an asymptomatic 2-year-old girl. Preenhanced computed tomography revealed multiple hyperdense areas in the liver. These lesions were hyperintense on T1-weighted and hypointense on T2-weighted MR images, results that might be ascribed to the paramagnetism of copper deposited in liver at a relatively early stage of the disease before severe liver cirrhosis had evolved.
9752500##1998-9-30##[Epidemiology and diagnosis of hepatocellular carcinomas in cirrhosis].##Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and the most frequent tumour in males, worldwide. The annual incidence of HCC is maximum in Asian and African countries, lower in western countries where it is close to 4/100,000 inhabitants. In 90% of the cases, HCC complicates course of liver cirrhosis, with an annual incidence in cirrhoties of 2 to 6%. Risk factors for HCC in cirrhotics are male gender (sex-ratio: 4/1), age (above 50 years old), macronodular cirrhosis and large cell dysplasia. HCC can complicate the course of cirrhosis of any cause, but might be less frequent in primary biliary cirrhosis, Wilson's disease and auto-immune hepatitis. Currently, the diagnosis of HCC is usually considered in the presence of a focal nodular lesion, during systematic ultrasonographic examination of the liver. In high incidence areas, HCC can still be diagnosed because of HCC-related symptoms. In the case of a focal lesion discovered on a cirrhotic liver, the diagnosis of HCC can be confirmed by studying the behaviour of the lesion of helical CT scan of the liver (enhancement of the tumour during the arterial phase) or MRI (hyperintensity of the tumour on T2 relaxation time); study of peritumour vessels can also be helpful. Serum alpha-foeto-protein level, when higher than 300 to 500 micrograms/L is very specific of HCC. When aggressive treatment of HCC is considered and when the diagnosis of HCC remains uncertain, HCC can be assessed by means of cytological or histological study of the tumour on samples taken by fineneedle aspiration (80% sensitivity) or liver biopsy during laparoscopic laparotomy. Forthcoming improvements in imaging technology might eliminate the need for such invasive diagnostic techniques in the future.
9475826##1998-2-26##Zinc acetate treatment in Wilson's disease.##
9711308##1998-8-26##[Wilson's disease ("hepatic form") in a region endemic for schistosomiasis mansoni: clinical presentation of 25 patients].##Brazil has a young population and areas of endemic mansoni schistosomiasis where Wilson's disease might be easily misdiagnosed in patients erroneously classified as having either the hepatosplenic or the hepatointestinal form of the helminthiasis. Twenty five patients with the "hepatic form" of Wilson's disease (14 males and 11 females) were investigated in Belo Horizonte, MG; the mean age was 13.7 years (3 to 22). Nineteen had hepatomegaly (76%) and nine splenomegaly (36%). Twenty two (88%) had cirrhosis. The Kaiser-Fleisher ring was detected in fifteen (60%). Four (16%) had clear neurological abnormalities. Eleven (44%) had ascitis and/or jaundice. Ninety one point three per cent and 92% had low ceruloplasmin and copper serum levels respectively. Eighty four point two per cent showed an increased 24 hours urinary copper excretion; seven patients in whom hepatic copper was determined had increased values. Six out of nine had at least a ten fold increase in 24 hours urinary copper excretion following penicillamine use ("penicillamine test"). Three out of 19 patients (15.8%) had mansoni schistosoma ova in stools examination, a common prevalence in our population. Their biopsies showed inactive cirrhosis without schistosomiasis-associated alterations. At least fourteen patients (56%) could be misdiagnosed as having hepatointestinal or hepatosplenic schistosomisis when in fact they suffered from Wilson's disease with or without asymptomatic intestinal schistosomiasis, losing the chance of an early treatment. The follow-up time of 22 patients was 52 months (1 to 96); eight (36.3%) died, four from bleeding esphageal varices, three from terminal hepatic failure and one from fulminant liver failure. The majority of the patients, including those who died, had abandomned the use of penicillamine or had taken it irregularly, due mainly to its highly expensive cost. A 17 year old patient underwent a successful liver transplant in 1989.
9544415##1998-4-17##Liver transplantation for neuropsychiatric Wilson disease.##Although neuropsychiatric manifestations are prominent in some patients with Wilson disease, there is little published information regarding the efficacy of liver transplantation for these patients. A 22-year-old male with advanced neurological impairment and prominent psychiatric manifestations due to Wilson disease who underwent liver transplantation is presented. After transplantation, the ceruloplasmin and copper studies normalized and eventually the Kayser-Fleischer rings disappeared. Neurological recovery was very slow and incomplete, and his behavioural and personality disorder was entirely unaffected. He committed suicide 43 months post-transplantation. A review of the small number of related published cases in the English language literature shows variable neurological recovery post-transplantation, but the course of psychiatric manifestations is virtually never described. This case suggests that one must be cautious regarding liver transplantation for Wilson disease in patients with prior psychiatric manifestations. Aggressive medical management is likely to be preferable in most cases.
9694062##1998-8-7##Pseudogout in a young patient.##Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is conventionally classified into cases that are hereditary, idiopathic (sporadic) or associated with other disorders. In the idiopathic form, the disease usually occurs in middle-aged or elderly patients. An earlier age of disease onset is observed in the hereditary form and the form associated with other disorders. Therefore, the occurrence of CPPD crystal deposition disease in a young patient merits thorough investigation for an underlying cause such as haemochromatosis, hyperparathyroidism, Wilson's disease, hypophosphatasia or hypomagnesaemia and requires a family study to investigate a possible hereditary cause. We report a case of a young female patient who presented with pseudogout at the age of 24 years; no associated diseases or familial occurrence were found despite a follow-up of more than 12 years.
9745943##1998-9-24##Lesions affecting the claustrum.##MR imaging examinations of seven patients with a variety of claustral disorders are included in this study. The ages of the patients ranged from 4 to 65 years, and all of them were males. The lesions involving the claustrum comprised cases with asphyxia, Wilson's disease, ischemic white matter disease, thalamic arteriovenous malformation, MELAS syndrome, viral encephalitis and Parkinson's disease.
9476721##1998-2-26##Acute dystonia with thalamic and brainstem lesions after initial penicillamine treatment in Wilson's disease.##Dystonia is a common manifestation in Wilson's disease (WD). The striatum, especially the putamen, has been considered to be responsible for dystonia. We reported 3 patients who developed acute generalized dystonia and akinetic rigid syndrome following an initial therapy with d-penicillamine 125-500 mg daily. Brain MRI revealed lesions in the thalamus and the brainstem, particularly the tegmentum, and the basis pontis in addition to the basal ganglion lesions. After the episode, 1 patient continued to receive d-penicillamine therapy and 2 changed to zinc sulfate treatment. The generalized dystonia improved in the following 3 months and 3 years respectively in 2 patients. Follow-up brain MRI of these 2 patients revealed that the lesions in the thalamus and brainstem disappeared or resolved almost completely. From these data, acute generalized dystonia with brainstem and thalamic lesions may occur in WD patients after an initial d-penicillamine therapy. Furthermore, the dystonia may resolve following the disappearance of the brainstem and thalamic lesions.
9428241##1998-1-15##PET scanning as a diagnostic tool in Wilson's disease.##
9829905##1998-11-26##Mutation analysis of Wilson disease in Taiwan and description of six new mutations.##Wilson disease is an autosomal recessive disorder of copper metabolism. Mutation screening in Wilson disease has led to the detection of at least 89 disease-specific mutations. Some mutations appear to be population specific, while others are common to many populations. In this study, 38 Taiwanese patients with Wilson disease were screened using single-strand conformation polymorphism analysis, followed by direct DNA sequencing. We found 12 different mutations, six of which were novel. All our detected mutations were found to be in eight exons. Four mutations in three loci (Arg778Gln, Arg778Leu, Gly943Asp, and Pro992Leu) accounted for about 58% of the mutant alleles we detected. Using an RNA transcriptional assay, we confirmed that both of our detected splice-site mutations resulted in exon skipping.
9671269##1998-7-22##Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.##This study presents the update results of an ongoing project on the delineation of the spectrum of mutations at the Wilson disease (WD) gene in WD patients of Mediterranean origin. In studying 59 patients, of whom were 26 Continental Italians, 22 Sardinians, 9 Turkish, and 2 Albanians, we have found 31 novel and three known mutations. Of the novel mutations, 3 are deletions, two nonsense, 2 splice or consensus splice site, and 24 missense. The large majority of the missense mutations lie in evolutionary conserved regions of the WD gene of documented functional importance. Most of our patients were compound heterozygotes, and only a few were homozygotes. In addition, three polymorphisms were detected. By adding the new data to those previously reported by our group, we have to date detected 85% of mutations in the WD chromosomes from Continental Italians, 30% from Sardinians, 81.7% from Turkish and 66.7% from Albanians. Most of the mutations characterized are rare, and only a limited number are common. Of the common mutations 5 were found in Continental Italians, two in Sardinians and a single one in Turkish. Because there are so many causative mutations of the disease, the preclinical and prenatal diagnosis of WD should be carried out by a combination of mutation and linkage analysis.
9554743##1998-4-29##Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease.##Four mutations--R778L, A874V, L1083F, and 2304delC--in the copper-transporting enzyme, P-type ATPase (ATP7B), were identified in Korean Patients with Wilson disease. Arg778Leu, the most frequently reported mutation of this enzyme, was found in six of eight unrelated patients studied, an allele frequency of 37.5%, which is considerably higher than those in other Asian populations. The novel single nucleotide deletion, 2304delC, was found in one patient. Since a mutation at cDNA nucleotide 2302 (2302insC) had been previously described, this region of the ATP7B gene may be susceptible to gene rearrangements causing Wilson disease.
9482578##1998-3-3##Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups.##We characterized microsatellite marker haplotypes and identified mutations in members of 19 ethnically diverse Israeli families affected by Wilson disease (WD). Eighteen unique haplotypes were derived from allelic combinations for four marker loci spanning the WD gene, ATP7B, at chromosome 13q14.3: D13S133, D13S296, D13S301 and D13S295. Most of these haplotypes are population specific and vary among and even within different ethnic groups. Intrafamilial variability of WD haplotypes was observed in two large consanguineous families in which a single origin of WD was expected. In contrast, some WD haplotypes were identified in more than one group. Five novel and four previously described mutations were detected in our sample. The novel mutations include two deletions (845delT and 1639delC) and three missense mutations (E1064A, M645R, and G1213V). Mutations were identified for 11 of the 18 WD haplotypes, suggesting that other mutations may reside in noncoding regions of the ATP7B gene. Identification of all WD mutations will undoubtedly increase our understanding of the normal function of ATP7B as well as lead to more accurate prognosis and genetic counseling.
9452121##1998-2-6##Mutations of ATP7B gene in Wilson disease in Japan: identification of nine mutations and lack of clear founder effect in a Japanese population.##
9575447##1998-5-12##Wilson disease in 1998: genetic, diagnostic and therapeutic aspects.##
9523453##1998-4-2##Genes for all metals--a bacterial view of the periodic table. The 1996 Thom Award Lecture.##Bacterial chromosomes have genes for transport proteins for inorganic nutrient cations and oxyanions, such as NH4+, K+, Mg2+, Co2+, Fe3+, Mn2+, Zn2+ and other trace cations, and PO4(3-), SO4(2-) and less abundant oxyanions. Together these account for perhaps a few hundred genes in many bacteria. Bacterial plasmids encode resistance systems for toxic metal and metalloid ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, TeO3(2-), Tl+ and Zn2+. Most resistance systems function by energy-dependent efflux of toxic ions. A few involve enzymatic (mostly redox) transformations. Some of the efflux resistance systems are ATPases and others are chemiosmotic ion/proton exchangers. The Cd(2+)-resistance cation pump of Gram-positive bacteria is membrane P-type ATPase, which has been labeled with 32P from [gamma-32P]ATP and drives ATP-dependent Cd2+ (and Zn2+) transport by membrane vesicles. The genes defective in the human hereditary diseases of copper metabolism, Menkes syndrome and Wilson's disease, encode P-type ATPases that are similar to bacterial cadmium ATPases. The arsenic resistance system transports arsenite [As(III)], alternatively with the ArsB polypeptide functioning as a chemiosmotic efflux transporter or with two polypeptides, ArsB and ArsA, functioning as an ATPase. The third protein of the arsenic resistance system is an enzyme that reduces intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. In Gram-negative cells, a three polypeptide complex functions as a chemiosmotic cation/protein exchanger to efflux Cd2+, Zn2+ and Co2+. This pump consists of an inner membrane (CzcA), an outer membrane (CzcC) and a membrane-spanning (CzcB) protein that function together.
9452344##1998-2-6##Pretreatment and posttreatment positron emission tomographic scan imaging in a 20-year-old patient with Wilson's disease.##Wilson's disease is an autosomal-recessive inherited disorder that results in predominantly hepatic and neurologic manifestations. Neurologic abnormalities include tremor, ataxia, bradykinesia, rigidity, chorea, and dystonia. We report the clinical, radiologic, and serial FDG PET findings in a 20-year-old woman who presented with an asymmetric upper limb tremor caused by Wilson's disease. Reduced striatal and cerebral cortical glucose metabolism was demonstrated on a FDG PET study performed before the commencement of D-penicillamine therapy. After 6 months of treatment, the patient had shown only minimal clinical improvement, despite an increase in striatal and cerebral cortical glucose metabolism on a repeat FDG PET study. After 14 months of treatment, however, a moderate clinical improvement was noted and there was further increase in glucose metabolism on FDG PET.
9629758##1998-6-18##[Neuroradiological findings in 2 cases of Wilson disease with neurological involvement].##Wilson disease is an inborn error of copper metabolism that has neurological and hepatic manifestations. We report a 13 years old girl and a 12 years old boy with Wilson disease. In both patient, brain computed tomography and magnetic resonance imaging showed marked involvement of basal ganglia and other deep gray nuclei. Considering that this is a treatable disease, it should be included in the differential diagnosis of the so called "striatal necrosis of childhood".
9645034##1998-6-30##[Wilson disease].##
9511434##1998-3-25##[Molecular genetic and biochemical studies of human inherited diseases].##The paper gives the results of complex studies of human inherited diseases, which involved reverse genetics for the analysis of mutant genes, biochemical and immunological studies of anomalous proteins, the products of these genes. It describes the main results of the studies which used this complex approach to examining the etiology and pathogenesis of Wilson's disease, alpha 1-antitrypsin deficiency, familial hypercholesterolemia and cystic fibrosis.
9407118##1998-1-31##Expression, purification, and metal binding properties of the N-terminal domain from the wilson disease putative copper-transporting ATPase (ATP7B).##The putative copper binding domain from the copper-transporting ATPase implicated in Wilson disease (ATP7B) has been expressed and purified as a fusion to glutathione S-transferase. Immobilized metal ion affinity chromatography revealed that the fusion protein is able to bind to columns charged with different transition metals with varying affinities as follows: Cu(II)>Zn(II)>Ni(II)>Co(II). The fusion protein did not bind to columns charged with Fe(II) or Fe(III). 65Zinc(II) blotting analysis showed that the domain is able to bind Zn(II) over a range of pH values from 6.5 to 9.0. Competition 65Zn(II) blotting showed that Cd(II), Hg(II), Au(III), and Fe(III) can successfully compete with Zn(II), at comparable concentrations, for binding to the domain. In contrast, the domain had little or no affinity for Ca(II), Mg(II), Mn(II), and Ni(II) relative to copper. Neutron activation analysis of the copper bound to the domain showed a copper:protein ratio of 6.5-7.3:1. Both Cu(II) and Cu(I) were found to have a higher affinity for the domain relative to Zn(II). In addition, a sharp, reproducible transition was only observed in competition experiments with copper, which may suggest that copper binding has some degree of cooperativity.
9483264##1998-3-4##Depression in hepatolenticular degeneration (Wilson's disease).##
9437572##1998-1-23##Wilson's disease, psychosis, and ECT.##
9496454##1998-3-13##Etheno-DNA base adducts as tools in human cancer aetiology and chemoprevention.##Etheno adducts in DNA are formed from the carcinogens vinyl chloride and urethane, and also from products of lipid peroxidation (LPO), such as trans-4-hydroxy-2-nonenal. Using an ultrasensitive detection method, the formation of etheno-DNA adducts in the liver was demonstrated in LEC rats (a strain with hereditary abnormal copper metabolism) that develop hepatitis and hepatocellular carcinoma. Wilson's disease and primary haemochromatosis are human genetic disorders that cause copper or iron accumulation resulting in a high risk for primary liver cancers. Levels of etheno adducts were also significantly elevated in the liver of these patients. In a group of male and female volunteers kept on a controlled diet, the effect of dietary fatty acid composition on the endogenous formation of lipid peroxidation-derived DNA adducts was determined in DNA from white blood cells. Dietary omega-6-polyunsaturated fatty acids greatly increased LPO-derived etheno-DNA adducts in vivo, in females. Thus, exocyclic DNA adducts are promising biomarkers for elucidating the effect of dietary fat intake, oxidative stress and protective dietary antioxidants on endogenous DNA damage and thus may provide a possible mechanistic link with elevated risk for diet-related cancers.
9508488##1998-3-21##[Diagnosis of Wilson's disease].##
9415675##1998-2-7##Arthropathy of Wilson's disease presenting as noninflammatory polyarthritis.##
9640083##1998-6-26##[Liver failure in the course of Wilson's disease--report of two cases].##Wilson's disease is an autosomal recessive disorder characterized by inability to excrete copper, and manifests by hepatic, neurologic or/and psychiatric symptoms. The therapy is available if diagnosis is made in time. The hepatic form of the disease is rarely recognized in Poland. The authors describe two patients with Wilson's disease who developed acute hepatic failure leading to death, in the first case within few months, in the second within few weeks. The diagnosis was established in the terminal stage of the disease and attempts of treatment were uneffective.
9485527##1998-3-5##Copper in plasma reflects its status and subsequent toxicity in the liver of LEC rats.##The possible relation of the increase in the concentration of copper (Cu) in the bloodstream with the increased supply of Cu to ceruloplasmin in the liver was examined in relation to the onset of jaundice in Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease. The Cu concentration in serum and that in liver, and then that in kidneys of LEC rats were correlated, and then the relationship between the Cu concentration in serum and the malondialdehyde (MDA) concentration in the liver, a marker for lipid peroxidation, and also the activities of alanine aminotransferase and lactate dehydrogenase, marker enzymes for liver damage, were examined. An increase in the Cu concentration in liver induced significant increases in the Cu concentrations in serum and kidneys, and their relationship was different before and after the onset of jaundice, as reflected by the concentration of Cu in serum (lower than 1.5 and higher than 2.7 micrograms/ml, respectively). The relationship between the MDA concentration in liver and the Cu concentration in serum showed a characteristic change between before and after the onset of jaundice. The marker enzymes for liver damage increased significantly with age, and showed distinct responses at the Cu concentration of 1.5-2.7 micrograms/ml in serum. The results suggest that the Cu concentration in plasma reflects the on-going biological and toxicological actions of non-MT-bound Cu in the livers of LEC rats.
9476382##1998-2-26##[Copper and the human body].##Copper is one of the essential trace elements. It is part of a number of enzymes. Deficiency of the element is manifested by impaired haematopoesis, bone metabolism, disorders of the digestive, cardiovascular and nervous system. Deficiency occurs in particular in patients suffering from malnutrition, malabsorption, great copper losses during administration of penicillamine. Sporadically copper intoxications are described (suicidal intentions or accidental ingestion of beverages with a high copper content). Acute exposure to copper containing dust is manifested by metal fume fever. Copper salts can produce local inflammations. Wilson's disease is associated with inborn impaired copper metabolism. In dialyzed patients possible contaminations of the dialyzate with copper must be foreseen as well as the possible release of copper from some dialyzation membranes. With the increasing amount of copper in the environment it is essential to monitor the contamination of the environment.
9359859##1998-1-10##Expression of Menkes disease gene in mammary carcinoma cells.##Two P-type ATPases, MNK and WND were recently shown to be defective in the human disorders of copper transport, Menkes disease and Wilson disease respectively. These proteins are important in copper homeostasis but their full physiological function has not been established. This study uses the human breast carcinoma line, PMC42, to investigate copper transport in the mammary gland. Northern blot analysis indicated that both MNK and WND mRNA are expressed in these cells. Western blot analysis with an MNK-specific antibody demonstrated a band of approx. 178 kDa, close to the expected size of 163 kDa. Treatment of PMC42 cells with lactational hormones (oestrogen and progesterone for 3 days followed by dexamethasone, insulin and prolactin for a further 3 days) did not produce an obvious increase in MNK expression as measured by Northern and Western blots. By using indirect immunofluorescence with the MNK antibody, the intracellular distribution of MNK was found to be predominantly perinuclear, consistent with Golgi localization. Punctate staining was also seen in a smaller proportion of cells, suggesting that some MNK is associated with endosomes. Treatment of PMC42 cells with lactational hormones increased the intensity of the perinuclear and punctate fluorescence. Exposure of cells to 100 mM copper resulted in the dispersion of the fluorescence towards the periphery of the cell. The results suggest a role for MNK in the secretion of copper into milk and that PMC42 cells are a valuable model for investigating the detailed cellular function of MNK and WND.
9570363##1998-5-7##Activation of serum response factor in the liver of Long-Evans Cinnamon (LEC) rat.##We have studied the DNA binding activities of transcription factors in the liver of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. Owing to a genetic defect, this strain of rats accumulates excessive copper in the liver and develops severe hepatitis and hepatocellular carcinoma. We found that the DNA binding activity of the serum response factor (SRF) was higher in the liver of LEC rats (approximately 2-fold) than in that of Wistar rats. There was a close correlation between the intensity of the activity and the concentrations of copper in the nuclear protein. The DNA binding activity of Sp1, on the other hand, showed similar levels in both LEC and Wistar rats. SRF may play an important role in the development of hepatocellular carcinoma in LEC rats by mediating the proto-oncogene c-fos induction. We suggest that the copper in nuclear protein may be involved in the activation of SRF.
9490214##1998-3-7##[Copper--biochemistry, metabolism and physiologic function].##The submitted paper presents contemporary knowledge of the biochemistry, metabolism and biological function of copper, an essential trace element. The causes of copper deficiency, its clinical and laboratory manifestations and its diagnosis. Pathophysiology, clinical and laboratory manifestations and diagnosis of Wilson's disease.
9405849##1997-12-24##Copper-stimulated adenosine triphosphatase from rat liver. Isolation and kinetic characterization.##
9405803##1997-12-24##Heterologous expression of the metal-binding domains of human copper-transporting ATPases (P1-ATPases).##
9772425##1998-10-17##Identification of a novel missense mutation in Wilson's disease gene.##
9451822##1998-2-6##Copper deficiency and heart disease: molecular basis, recent advances and current concepts.##Copper is an essential trace element and has profound influence on cardiac myopathy and heart metabolism. Dietary Cu restriction in rats results in cardiomyopathy, and affects the integrity of the basal lamina of cardiac myocytes and capillaries. Decreased levels of delta subunits of ATP synthetase and nuclear encoded subunits of cytochrome oxidase system have been observed. Alteration in expression of glutathione peroxidase and catalase in heart and liver in Cu deficiency (Cu-) has been noted involving both transcriptional and post transcriptional mechanisms. A short description of two genetically inherited disorders of Cu metabolism, i.e. Wilson's disease and Menkes' disease, and Indian childhood cirrhosis (environmental and/or genetic) have been included to illustrate that advances in the knowledge of Cu cellular transport gives a better understanding of the molecular basis of the pathophysiology of these diseases. Menkes' disease, a human model of defective Cu transport and Cu- has shown many pathological changes, similar to those of heart disease in Cu-. The recent cloning of four genes of putative Cu pumping ATPases (Cu-ATPases) from widely different sources, i.e. two from Enterococcus hirae and one each from Wilson's and Menkes disease patients (which are defective in Cu transport and metabolism), has opened a new chapter in the study of Cu cellular transport and metabolism. The encoded gene products, i.e. Cu-ATPases, show extensive homology and are members of a new class of ATP-driven Cu pumps involved in regulation of cellular Cu. Further, Cu transport by Cop B-ATPase (E. hirae) in membrane vesicles and in isolated rat liver plasma membrane has provided biochemical evidence of its role in ATP-driven Cu transport. In this short review I have critically examined the current evidence of the molecular basis of the pathophysiology of cardiomyopathy in Cu- and, have indicated the possible role of P-type Cu ATPase which may be one of the obligatory factors contributing to cardiomyopathy in experimental animals and probably humans. Experimental verification of this hypothesis will be the aim of future studies.
9430043##1998-1-16##Hepatitis C virus (HCV) genotypes and chronic liver disease in Pakistan.##
9358851##1997-11-14##Copper-metallothionein in the kidney of macular mice: a model for Menkes disease.##Menkes disease is an X-linked disorder of copper metabolism. Excess amounts of copper in the kidney of Macular mice, a model for this disease, were found as copper-metallothionein (Cu-MT) from kidney of the mice. Histochemical studies of Cu-MT based on its autofluorescent emission properties showed that the protein was predominant in the proximal convoluted tubule (PCT) cells of the cortex. PCT cells are known to be the primary site of the nephrotoxicity caused by heavy metals. MT mRNA was also observed in the cortex, indicating that the protein was biosynthesized in this region. On the basis of these results, we suggest that biosynthesis and degradation of Cu-MT occur repeatedly in the PCT cells of the cortex. We also compared the histochemical localization of Cu-MT in Macular mice and Long-Evans cinnamon rats, a model for Wilson's disease. The significance of this comparison is discussed.
9509311##1998-3-24##Clinical evaluation of posterior embryotoxon in one institution.##To elucidate the pathogenesis of posterior embryotoxon, we estimated its incidence in our clinic and evaluated its associated ocular and systemic anomalies. Slit-lamp and gonioscopic examinations were performed on 440 randomly selected patients at Nagoya City University Hospital over a 10-month period. Posterior embryotoxon was detected in 107, 50 bilateral and 57 unilateral, cases (24.3%). Twelve (11.2%) of the 107 cases had open-angle glaucoma. Accompanying ocular anomalies included six cases of sclerocornea, two each of persistent pupillary membrane and familial exudative vitreoretinopathy, and 1 each of melanocytoma of the optic nervehead, choroidal nevus and subconjunctival dermoid cyst. Associated systemic anomalies included three cases of Alagille syndrome, two of congenital biliary atresia, and one each of congenital facial palsy with microtia, congenital adrenal hyperplasia, empty sella syndrome, Hirschsprung disease and Wilson disease. Many of these ocular and systemic anomalies were caused by the maldevelopment of neural crest cells. Patients with posterior embryotoxon should be examined for the possible presence of open-angle glucoma and for ocular and systemic anomalies related to maldevelopment of neural crest cells.
9404965##1997-12-24##Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases.##This report summarizes a recent meeting cosponsored by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases to formulate minimal criteria by which patients with severe liver disease will be placed on the waiting list for liver transplantation. The participants agreed that only patients in immediate need of liver transplantation should be placed on the waiting list. Patients should not be placed in anticipation of some future need for such therapy. It was agreed that minimal criteria could assist but not replace the clinical judgment of the transplant professionals at individual centers. The criteria will be summarized below for adult patients with acute or chronic liver disease. The most important non-disease-specific criterion for placement on the transplant waiting list was an estimated 90% chance of surviving 1 year. This translated into a Child-Pugh score of > or = 7 for patients with cirrhosis which places the patient in Child-Pugh class B or C. Cirrhotic patients who have experienced gastrointestinal bleeding caused by portal hypertension or a single episode of spontaneous bacterial peritonitis would meet the minimal criteria irrespective of their Child-Pugh score. There were disease-specific criteria also. These include a sole minimal criterion for patients with fulminant hepatic failure regardless of etiology of the onset of stage 2 hepatic encephalopathy. A requirement for 6 months abstinence from alcohol before placement on the transplant waiting list was considered appropriate for most patients with alcoholic liver disease. Exceptional cases could get access to the waiting list through a regional review process. Chronic cholestatic diseases present difficulties because of a different natural history than that of chronic hepatocellular diseases. The use of specific risk scores for primary biliary cirrhosis and primary sclerosing cholangitis will likely replace Childs-Pugh classification as the scoring systems become refined. Minimal criteria for any patient with a primary hepatocellular cancer would admit any patient with a tumor confined to the liver irrespective of size or number of tumors, after careful investigation had failed to show spread to lymph nodes, the portal vein, or distant organs. Unusual or rare indications for liver transplantation, including Budd-Chiari syndrome, Wilson's disease, and other hereditary disorders, were also discussed. Finally, it was agreed that there should be no absolute contraindications to placement of patients on the liver transplant waiting list. These criteria should be open to regular review to accommodate advances in the field.
9465719##1998-2-18##[Ocular manifestations of Wilson disease].##
9523486##1998-4-2##[Etiology of Wilson's disease].##
9346482##1997-11-5##Metal ion chaperone function of the soluble Cu(I) receptor Atx1.##Reactive and potentially toxic cofactors such as copper ions are imported into eukaryotic cells and incorporated into target proteins by unknown mechanisms. Atx1, a prototypical copper chaperone protein from yeast, has now been shown to act as a soluble cytoplasmic copper(I) receptor that can adopt either a two- or three-coordinate metal center in the active site. Atx1 also associated directly with the Atx1-like cytosolic domains of Ccc2, a vesicular protein defined in genetic studies as a member of the copper-trafficking pathway. The unusual structure and dynamics of Atx1 suggest a copper exchange function for this protein and related domains in the Menkes and Wilson disease proteins.
9325307##1997-11-5##Restriction of copper export in Saccharomyces cerevisiae to a late Golgi or post-Golgi compartment in the secretory pathway.##The CCC2 gene in the yeast Saccharomyces cerevisiae encodes a P-type ATPase (Ccc2p) required for the export of cytosolic copper to the extracytosolic domain of a copper-dependent oxidase, Fet3p. Ccc2p appears to be both a structural and functional homolog of ATPases impaired in two human disorders of intracellular copper transport, Menkes disease and Wilson disease. In the present work, three approaches were used to determine the locus of Ccc2p-dependent copper export within the secretory pathway. First, like ccc2 mutants, sec mutants blocked in the secretory pathway at steps prior to and including the Golgi complex failed to deliver radioactive copper to Fet3p. Second, also like ccc2 mutants, vps33 and certain other mutants with defects in post-Golgi sorting exhibited phenotypes traceable to deficient copper delivery to Fet3p. These findings were sufficient to explain the respiratory deficiency of these mutants. Third, immunofluorescence microscopy revealed that Ccc2p was distributed among several punctate foci within wild-type cells, consistent with late Golgi or post-Golgi localization. Thus, copper export by Ccc2p appears to be restricted to a late or post-Golgi compartment in the secretory pathway.
9408705##1997-12-31##The contraceptive choice for a Wilson's disease patient with chronic liver disease.##Preserved fertility status is frequently encountered in patients with Wilson's disease, and contraceptive counseling may, therefore, be a relevant issue. Yet, several contraceptive methods can adversely influence the hepatic function, and the efficacy of others may be affected by the liver disease. We describe a patient with Wilson's disease manifested by cirrhosis, portal hypertension, and bleeding esophageal varices who underwent termination of pregnancy at 9 weeks' gestation. Following the procedure, contraceptive advice was sought in order to postpone conception until portal hypertension was controlled and hepatic function improved. Intramuscular depot medroxyprogesterone acetate was administered and tolerated well by the patient. A detailed discussion of the contraceptive options for patients with chronic liver disease, in general, and Wilson's disease, in particular, follows the case report.</AbstractText>            </Abstract>            <AuthorList CompleteYN="Y">                <Author ValidYN="Y">                    <LastName>Haimov-Kochman</LastName>                    <ForeName>R</ForeName>                    <Initials>R</Initials>                    <Affiliation>Department of Obstetrics and Gynecology, Hadassah University Hospital-Mount Scopus, Jerusalem, Israel.</Affiliation>                </Author>                <Author ValidYN="Y">                    <LastName>Ackerman</LastName>                    <ForeName>Z</ForeName>                    <Initials>Z</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Anteby</LastName>                    <ForeName>E Y</ForeName>                    <Initials>EY</Initials>                </Author>            </AuthorList>            <Language>eng</Language>            <PublicationTypeList>                <PublicationType>Case Reports</PublicationType>                <PublicationType>Journal Article</PublicationType>                <PublicationType>Review</PublicationType>            </PublicationTypeList>        </Article>        <MedlineJournalInfo>            <Country>UNITED STATES</Country>            <MedlineTA>Contraception</MedlineTA>            <NlmUniqueID>0234361</NlmUniqueID>            <ISSNLinking>0010-7824</ISSNLinking>        </MedlineJournalInfo>        <ChemicalList>            <Chemical>                <RegistryNumber>0</RegistryNumber>                <NameOfSubstance>Contraceptive Agents, Female</NameOfSubstance>            </Chemical>            <Chemical>                <RegistryNumber>C2QI4IOI2G</RegistryNumber>                <NameOfSubstance>Medroxyprogesterone Acetate</NameOfSubstance>            </Chemical>        </ChemicalList>        <CitationSubset>IM</CitationSubset>        <CitationSubset>J</CitationSubset>        <MeshHeadingList>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Abortion, Induced</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Adult</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Chronic Disease</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Contraceptive Agents, Female</DescriptorName>                <QualifierName MajorTopicYN="Y">administration &amp; dosage</QualifierName>                <QualifierName MajorTopicYN="N">adverse effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Female</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Follow-Up Studies</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Hepatolenticular Degeneration</DescriptorName>                <QualifierName MajorTopicYN="Y">complications</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Humans</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Injections, Intramuscular</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Medroxyprogesterone Acetate</DescriptorName>                <QualifierName MajorTopicYN="Y">administration &amp; dosage</QualifierName>                <QualifierName MajorTopicYN="N">adverse effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Pregnancy</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Pregnancy Complications</DescriptorName>                <QualifierName MajorTopicYN="N">surgery</QualifierName>                <QualifierName MajorTopicYN="Y">therapy</QualifierName>            </MeshHeading>        </MeshHeadingList>        <NumberOfReferences>15</NumberOfReferences>        <OtherID Source="PIP">129682</OtherID>        <OtherID Source="POP">00271913</OtherID>        <OtherAbstract Type="PIP" Language="eng">            <AbstractText>Although the fertility status of women with Wilson's disease may be preserved, contraceptive method choice is complicated by the tendency for some methods to have an adverse effect on hepatic function and, conversely, for liver disease to compromise the efficacy of some contraceptives. This paper presents the case of a 28-year-old woman diagnosed with Wilson's disease at 13 years of age. She presented to an Israeli hospital at 9 weeks' gestational age with bleeding esophageal varices, cirrhosis, and portal hypertension. Although the patient had been oligomenorrheic, with menses every 2-3 months, she had experienced 3 spontaneous first-trimester abortions. Due to the urgent need for a portal decompression shunt procedure and the risk of further bleeding, the patient opted to terminate the current pregnancy. To prevent conception until the patient's liver condition stabilized, she was injected with Depo-Provera and penicillamine treatment was resumed. Although IUDs and estrogen-containing oral contraceptives are relatively contraindicated in women with liver dysfunction, spermicide and barrier contraceptives are highly recommended and progesterone-only preparations can be safely prescribed.
9567550##1998-5-6##Current spectrum of hepatobiliary disorders in northern India.##
9407349##1998-1-4##Evoked potentials in liver diseases.##Evoked potentials are objective and quantitative methods capable of evaluating functions of both peripheral and central nervous systems (PNS and CNS). During the past 8 years, we have been using somatosensory, brainstem auditory, and pattern-reversal visual evoked potentials (SEP, BAEP, VEP) to study hepatic encephalopathy (HE) as well as functional status of the PNS and CNS in various liver diseases including viral hepatitis B, alcoholic liver disease and Wilson's disease (WD). In HE irrespective of its etiologies, there is a sequential prolongation and eventual disappearance of cortical components of the median nerve evoked SEP while there is no change in BAEP, suggesting that HE is primarily due to a disturbance in cerebral cortical function and that median SEP may be used for early detection of HE and for monitoring its clinical course. In addition, absence of the N20-P25 component, or presence of only the N20 component of the wave complex in fulminant hepatic failure is associated with high mortality, whereas presence of late cortical components in HE is usually associated with reversibility of clinical course. Central conduction time (CCT) of the BAEP is prolonged in patients with WD, alcoholic liver disease and liver cirrhosis due to hepatitis B. Furthermore, BAEP abnormality is most severe in WD, followed by alcoholic liver disease, and finally hepatitis B. Peripheral nerve conduction as determined by the N9 latency of SEP is slowed in alcoholic liver disease and liver cirrhosis of chronic hepatitis B, but normal in WD. Our studies, therefore, suggest that evoked potentials may be useful in the evaluation of both CNS and PNS functions in various liver diseases and also in the diagnosis and monitoring of HE.
9407345##1998-1-4##Review: molecular approaches to inherited liver disease. Focus on Wilson disease.##Although infectious agents account for a large proportion of liver disease, inherited forms of liver disease, often treatable, must not be overlooked. New approaches to the cloning of disease genes are allowing an increased understanding of the basic defect of human diseases. Identification of disease genes can have practical applications for diagnosis, can provide information on prognosis and can lead to new therapies. This review focuses on selected inherited liver diseases and the knowledge to be gained from molecular studies. Three genetic diseases affecting the liver, Wilson disease, haemochromatosis and alpha 1-antitrypsin deficiency, are selected as examples of current approaches to the study of genetic liver disease.
9307043##1997-10-23##Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments.##Copper is an essential trace element in prokaryotes and eukaryotes and is strictly regulated by biological mechanisms. Menkes and Wilson diseases are human disorders that arise from disruption of the normal process of copper export from the cytosol to the extracellular environment. Recently a gene for Wilson disease (WD)(also named the ATP7B gene) was cloned. This gene encodes a copper transporter of the P-type ATPase. We prepared monoclonal and polyclonal anti-(WD protein) antibodies and characterized the full-length WD protein as well as a shorter form that is produced by alternative splicing in the human brain. We found that the WD protein is localized mainly in the Golgi apparatus, whereas the shorter form is present in the cytosol. These results suggest that the alternative WD proteins act as key regulators of copper metabolism, perhaps by performing distinct roles in the intracellular transport and export of copper.
9311362##1997-10-6##Penicillamine-related neurologic syndrome in a child affected by Wilson disease with hepatic presentation.##
9352458##1997-11-14##Very high frequency of the His1069Gln mutation in Polish Wilson disease patients.##
9261163##1997-8-22##Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae.##Wilson disease is a disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration due to inherited mutations in a gene encoding a putative copper-transporting P-type ATPase. Polyclonal antisera generated against the amino terminus of the Wilson protein detected a specific 165-kDa protein in HepG2 and CaCo cell lysates. Further analysis revealed that this protein is synthesized as a single-chain polypeptide and localized to the trans-Golgi network under steady state conditions. An increase in the copper concentration resulted in the rapid movement of this protein to a cytoplasmic vesicular compartment. This copper-specific cellular redistribution of the Wilson protein is a reversible process that occurs independent of a new protein synthesis. Expression of the wild-type but not mutant Wilson protein in the ccc2Delta strain of Saccharomyces cerevisiae restored copper incorporation into the multicopper oxidase Fet3p, providing direct evidence of copper transport by the Wilson protein. Taken together these data reveal a remarkable evolutionary conservation in the cellular mechanisms of copper metabolism and provide a unique model for the regulation of copper transport into the secretory pathway of eucaryotic cells.
9311736##1997-8-1##Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses.##Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.
9265898##1997-8-1##Molecular biological methods in diagnosis and treatment of liver diseases.##Molecular biology is making a tremendous impact on the diagnosis and treatment of liver diseases. Methods such as the polymerase chain reaction are changing the way physicians diagnose and monitor patients with viral hepatitis. Assays based on recombinant protein antigens allow for detection of specific autoantibodies in diseases such as primary biliary cirrhosis. The diagnosis of inherited metabolic diseases, such as hemochromatosis and Wilson disease, is being revolutionized by discovery of the defective genes involved and the development of methods to rapidly sequence DNA and identify mutations. Treatments and preventive measures are now possible with use of drugs and vaccines produced by recombinant DNA technology. Gene therapy and nucleic acid-based therapeutics are also realistic future treatment options for individuals with liver diseases.
15562573##1997-8-1##Liver transplantation for hemochromatosis, Wilson's disease, and other metabolic disorders.##Liver transplantation provides an effective means for replacing a failing liver, in addition to correcting the underlying abnormality in many metabolic disorders. Results of liver transplantation for metabolic diseases have been generally encouraging, with the exception of hereditary hemochromatosis, in which infectious and cardiac complications appear to increase post-transplant mortality. Better pretransplant diagnosis of hemochromatosis, utilizing the recently identified putative gene, may help reduce post-transplant complications. In metabolic diseases, improved understanding of the underlying genetic and molecular defects will lead to advances in medical therapy and perhaps a decreased need for liver transplantation. NTBC therapy for hereditary tyrosinemia and purified glucocerebroside therapy for Gaucher disease are two such examples. The prospects of gene therapy are being actively pursued for many metabolic diseases, such as CF, hemophilia, and familial hypercholesterolemia. Until such investigation leads directly to clinical practice, however, liver transplantation remains an effective option for therapy for a wide range of metabolic diseases.
9247482##1997-8-1##Premature oxidative aging of hepatic mitochondrial DNA in Wilson's disease.##
9288611##1997-8-1##Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin.##
9285454##1997-8-1##Wilson's disease.##
9171319##1997-8-1##Autonomic involvement in Wilson's disease: a study of sympathetic skin response and RR interval variation.##Autonomic nervous system involvement in Wilson's disease (WD) was studied in 25 patients by sympathetic skin response (SSR) and RR interval variation (RRIV). The control group consisted of age-matched healthy subjects. Palmar SSRs were obtained by central activation from median nerve stimulation and by activation of sympathetic trunk from magnetic stimulation of the neck. Electric SSRs were prolonged in 11 patients and absent in 2; magnetic SSRs were delayed in 4 and absent in 1; and the sympathetic central conduction time was prolonged in 3. The mean latencies and mean central conduction of the SSRs were all significantly prolonged in WD when compared to the control group. On the other hand, parasympathetic function was abnormal in 3 patients only during forced deep breathing, and as a group only mean D% was significantly reduced. The present findings suggest that autonomic dysfunction may occur in WD, and that sympathetic function is predominantly affected, mainly due to central involvement.
9380528##1997-8-1##[Striatal uptake of I-123-beta-CIT and I-123-IBZM in patients with extrapyramidal symptoms].##
9251169##1997-8-1##Influence of 3,4-dihydroxybenzoic acid on metal ion concentrations in guinea pig tissues after copper intoxication.##3,4-Dihydroxybenzoic acid (3,4-dhbH3 or protocatechuic acid) is a copper chelator which has potential as an agent for the treatment of copper-overload disease (Wilson's disease). The present investigation describes the fluctuation in copper, magnesium, zinc and calcium (Cu, Mg, Zn, Ca) concentrations in tissues of guinea pigs intoxicated with Cu after the administration of 3,4-dhbH3. We investigated the efficacy of 3,4-dhbH3 to eliminate Cu from poisoned guinea pigs, as well as to assess the changes in concentrations of Zn, Ca and Mg which normally occur in the tissues of experimental animals. The results are in agreement with other experimental data when we administered drugs capable of forming complexes with metal ions. Although 3,4-dhbH3 is capable of forming in vitro complexes with Cu, it can not be used successfully for chelation therapy of Cu intoxication, but its effectiveness as a ligand for Ca, Zn and Mg mobilization is discussed.
9228074##1997-7-25##N-terminal domains of human copper-transporting adenosine triphosphatases (the Wilson's and Menkes disease proteins) bind copper selectively in vivo and in vitro with stoichiometry of one copper per metal-binding repeat.##N-terminal domains of the Wilson's and Menkes disease proteins (N-WND and N-MNK) were overexpressed in a soluble form in Escherichia coli as fusions with maltose-binding protein, purified, and their metal-binding properties were characterized. Both N-MNK and N-WND bind copper specifically as indicated by the results of metal-chelate chromatography, direct copper-binding measurements, and chemical modification of Cys residues in the presence of different heavy metals. When E. coli cells are grown in the presence of copper, N-MNK and N-WND bind copper in vivo with stoichiometry of 5-6 nmol of copper/nmol of protein. Copper released from the copper-N-MNK and copper-N-WND complexes reacts with the Cu(I)-selective chelator bicinchoninic acid in the absence of reducing agents. This suggests that in proteins, it is bound in reduced Cu(I) form, in agreement with the spectroscopic properties of the copper-bound domains. Copper bound to the domains in vivo or in vitro specifically protects the N-MNK and N-WND against labeling with the cysteine-directed probe; this indicates that Cys residues in the repetitive motifs GMTCXXCXXXIE are involved in coordination of copper. Direct involvement of the N-terminal domains in the binding of copper suggests their important role in copper-dependent functions of human copper-transporting adenosine triphosphatases (Wilson's and Menkes disease proteins).
9214255##1997-7-1##Genetic heterogeneity in Wilson disease: lessons from rare alleles.##
9214248##1997-7-1##Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction.##
9207299##1997-7-1##Overcoming obstacles to the diagnosis of Wilson's disease.##
9207298##1997-7-1##Muddying the water: Wilson's disease challenges will not soon disappear.##
9207280##1997-7-1##Wilson's disease in patients presenting with liver disease: a diagnostic challenge.##
9214462##1997-7-1##In situ detection of lipid peroxidation by-products in chronic liver diseases.##Lipid peroxidation is an autocatalytic mechanism leading to oxidative destruction of cellular membranes. The deleterious consequences of this mechanism are related in part to the formation of reactive aldehydic products that bind to intra- or extracellular molecules to form adducts. Specific antibodies directed against malondialdehyde (MDA) and 4-hydroxynonenal (HNE) adducts, major aldehydic metabolites of lipid peroxidation, allowed us to investigate in situ, with an immunohistochemical procedure, the occurrence of lipid peroxidation in a panel of different chronic liver diseases. Intracellular HNE and MDA adducts were detected respectively in 24 of 39 cases (62%) and in 12 of 34 cases investigated (35%). They were localized mainly in the cytoplasm of hepatocytes, with the strongest staining observed in hemochromatosis, Wilson's disease, and in areas of acute alcoholic hepatitis in cases of alcoholic liver diseases. A peculiar pattern of immunostaining was observed in primary biliary cirrhosis where biliary cells of destroyed but also intact bile ducts strongly expressed HNE adducts. The liver extracellular matrix also displayed MDA adducts (30 of 34 cases, 88%) and HNE adducts (23 of 39 cases, 59%). While HNE adducts were specifically localized on large bundles of collagen fibers, MDA adducts were detected in a thin reticular network and in sinusoidal cells around portal tracts or fibrous septa. In conclusion, lipid peroxidation by-products are detectable in chronic liver diseases. Immunohistochemical results suggest that this mechanism is implicated very early in the pathogenesis of some of these diseases.
9215673##1997-7-1##Developmental expression of the mouse mottled and toxic milk genes suggests distinct functions for the Menkes and Wilson disease copper transporters.##Menkes disease and Wilson disease are human disorders of copper transport caused by mutations in distinct genes encoding similar copper-transporting P-type ATPases. These genes are expressed in different adult tissues in patterns reflecting disease manifestations. The mouse homologues for the Menkes (MNK) and Wilson (WND) disease genes are the mottled (Atp7a) and toxic milk (Atp7b) genes, respectively. Using RNA in situ hybridization we describe the distribution of mottled and toxic milk transcripts during mouse embryonic development. The mottled gene is expressed in all tissues throughout embryogenesis and is particularly strong in the choroid plexuses of the brain. Mottled expression in the liver is in contrast to the prior observation of absent or very low expression in the adult liver. Expression of the toxic milk gene is significantly more delimited, with early expression in the central nervous system, heart and liver. Later in gestation, toxic milk transcript is clearly seen in the liver, intestine, thymus and respiratory epithelium including nasopharynx, trachea and bronchi. In lung, toxic milk expression is restricted to bronchi, while mottled expression is diffuse. Hepatic expression of both toxic milk and mottled is in the parenchyma, as opposed to blood cells. These results suggest that the mottled gene product functions primarily in the homeostatic maintenance of cell copper levels, while the toxic milk gene product may be specifically involved in the biosynthesis of distinct cuproproteins in different tissues.
9251089##1997-7-1##Stereotypies in Wilson's disease.##
9269219##1997-6-21##Molecular diagnosis of Wilson's disease.##
9199563##1997-6-1##Haplotype and mutation analysis in Japanese patients with Wilson disease.##Wilson disease (WD), an autosomal recessive disorder of copper transport, is characterized by impaired biliary excretion and by impaired incorporation of copper into ceruloplasmin. Toxic accumulation of copper causes tissue damage, primarily in the liver, brain, and kidneys. The gene for WD (ATP7B) has been cloned, and the protein product is predicted to be a copper-transporting P-type ATPase with high amino acid identity with that for Menkes disease, an X-linked disorder of copper transport. Mutation screening in WD patients has led to the identification of at least 40 mutations. In addition, haplotype analysis using three dinucleotide-repeat markers, D13S314, D13S301, and D13S316, has been a useful indicator of specific mutations. We have determined haplotypes for the patients and their parents and sibs, in 21 unrelated WD families from Japan. Twenty-eight different haplotypes were observed on 42 WD chromosomes. In all the patients, the ATP7B coding sequence, including the intron-exon boundaries, was screened for mutations, by SSCP, followed by direct-sequence analysis of the shifted fragments. We identified 13 mutations, of which 11 mutations are novel, including 7 mutations-1 insertion, 4 deletions, and 2 missense mutations-in the coding region. The mutations reported in previous studies are 2299insC and Arg778Leu. Two patients were shown to have the 2299insC mutation, which has occurred in many different haplotypes in several populations, indicating a mutation hot spot. Primer-extension analysis of ATP7B mRNA has revealed multiple transcription start sites. Four of the novel mutations (three 1-bp changes and one 5-bp deletion) occur in the 5' UTR and may result in altered expression of the WD gene.
9471969##1997-6-1##[Copper levels in the tissues of patients with Wilson's disease].##The evaluation of tissue copper concentration is essential for the diagnosis of Wilson's disease. It is characterized by symptoms of the damages to parenchymatous organs, primarily liver and brain, due to chronic copper intoxication. The paper presents the autopsy tissue analysis of a 39-year-old patient diagnosed to suffer from the Wilson's disease while still alive. The patient died from sepsis due to burns caused by direct flame exposure. The standard histochemical staining of tissue samples failed to demonstrate the presence of copper but it was qualitatively proved by line spectrum-based mass spectrography. The copper concentrations in the liver, brain, and kidney (240, 73.8, and 30 micrograms/g wet tissue weight, respectively), measured by flame-atomic absorption spectrometry, were significantly elevated. In this study, the Wilson's disease was verified by a postmortem determination of increased copper concentration in the tissues. The results obtained contribute to the understanding of this rare disease.
9193846##1997-6-1##Liver transplantation: treatment of choice for hepatic and neurological manifestation of Wilson's disease.##Liver transplantation (LTX) is an approved method to treat patients with end-stage liver cirrhosis and acute liver failure due to Wilson's disease. Initially, there was some consideration about the indication for LTX in the case of Wilson's disease with severe neurological impairment but normal liver function. From 1988 until 1995, 13 out of 700 LTX (1.9%) were performed for Wilson's disease. Indications for LTX were (I) intractable neurological impairment with normal liver function (n = 4; including one patient with Child A cirrhosis), (II) fulminant hepatic failure (n = 3), and (III) end-stage liver cirrhosis (n = 6) (Child B, n = 1; Child C, n = 5). There were 8 females and 5 males with a mean age of 27 yr (range 15-34 yr). All patients of group I required continuous nursing care before LTX, in spite of pretreatment with d-penicillamine and zinc. The most frequent symptoms in these patients were dysphagia (n = 4), dysarthria (n = 4), tremor (n = 4), sialorrhea (n = 3), ataxia (n = 3), dystonia (n = 3) and handwriting difficulties (n = 3). All patients of group II presented with hemolytic anemia. The survival rate was 100%, and all patients were doing well after a mean follow-up period of 32.8 months (range 8-68 months). The postoperative course was without severe infectious and other complications. All patients of group I revealed the first signs of improvement for all types of neurological symptoms 4-6 wk after LTX. One patient has been without any symptoms from 18 months until 5.5 yr after LTX. Two patients with short-term follow-up also had noticeable improvement of neurological impairment, but residual symptoms are still present. One patient showed only slight improvement. We conclude that Wilson's disease may be a good indication for LTX for both neurological manifestation with stable liver function and hepatic manifestation with cirrhosis or acute liver failure.
9354393##1997-6-1##Caenorhabditis elegans cDNA for a Menkes/Wilson disease gene homologue and its function in a yeast CCC2 gene deletion mutant.##The full-length cDNA coding for a putative copper transporting P-type ATPase (Cu2+-ATPase) was cloned from Caenorhabditis elegans. The putative Cu2+-ATPase is a 1,238-amino acid protein, and highly homologous to the Menkes and Wilson disease gene products mutations of which are responsible for human defects of copper metabolism. The Saccharomyces cerevisiae mutant with a disrupted CCC2 gene (yeast Menkes/Wilson disease gene homologue) was rescued by the cDNA for the C. elegans Cu2+-ATPase but not by the cDNA with an Asp-786 (an invariant phosphorylation site) to Asn mutation, suggesting that the C. elegans Cu2+-ATPase functions as a copper transporter in yeast. The expressed C. elegans protein was detected in yeast vacuolar membranes by immunofluorescence microscopy. The yeast expression system may facilitate further studies on copper transporting P-type ATPases.
9241968##1997-6-1##Acanthosis nigricans associated with hepatolenticular degeneration.##Acanthosis nigricans and hepatolenticular degeneration (Wilson's disease) developed simultaneously in a 16-year-old boy. The diagnosis of Wilson's disease was based on the clinical presentation, including Kayser-Fleischer ring, hypoceruloplasminemia, hypocupremia, and hypercupriuria. His skin lesions were characterized by thick, dark brown, verrucous plaques on the dorsa of both feet, the neck, axillae, and groin. The histological findings were compatible with acanthosis nigricans. Six months after treatment with D-penicillamine, two grams per day, his skin lesions and neurological symptoms were much improved and no complications were observed.
9178732##1997-6-1##Treatment of Wilson's disease with zinc: XIV. Studies of the effect of zinc on lymphocyte function.##Although administration of zinc to human subjects has been reported to interfere with lymphocyte function, this single report has never been confirmed or refuted. We have developed zinc as a lifelong therapy for patients with Wilson's disease. Interference with lymphocyte function occurring as a side effect of zinc therapy could produce serious problems in our patients. We evaluated lymphocyte mitogenic response and natural killer cell activity in patients with Wilson's disease treated for 5 years or longer with zinc, in comparison with normal controls, and found no differences. In a second study, we evaluated these same parameters in patients with Wilson's disease before and after 1 year of zinc therapy, and again found no significant differences. We have seen no indications of immune suppression or increased susceptibility to infections in our patients, who have now been treated with zinc for up to 15 years. We conclude that any side effects from compromised lymphocyte function caused by administration of zinc are not of concern to patients with Wilson's disease.
9249618##1997-6-1##Advances in the genetics of movement disorders: implications for molecular diagnosis.##Recent developments in molecular genetics have had a profound influence on the diagnosis and classification of inherited movement disorders. Huntington's disease is caused by the expansion of an unstable trinucleotide repeat sequence. Molecular diagnosis can now be performed by a simple PCR-based assay, and the study of the effects of the repeat expansion on the function of the encoded protein will allow to elucidate the molecular pathogenesis of the disease. Wilson's disease is caused by a large number of different mutations, which complicates molecular diagnosis. Genes for a number of inherited dystonic syndromes have been mapped, one of them, the gene for dopa-responsive dystonia, has already been identified. The genetic basis of several other prevalent movement disorders, such as essential tremor and the restless-legs syndrome however, is still obscure. Current research is also directed at the identification of inherited risk-factors in genetically complex movement disorders, such as Parkinson's disease.
9228244##1997-6-1##Wilson's disease: presymptomatic patients and Kayser-Fleischer rings.##
9203178##1997-6-1##Proteinuria and other renal functions in Wilson's disease.##Renal lesions have repeatedly been described in Wilson's disease (WD). We investigated the excretion of total protein, albumin, low (LMW) and high molecular weight (HMW) proteins, N-acetyl-beta-D-glucosaminidase (NAG), and calcium, as well as creatinine clearance, in 24-h urine samples of 41 patients with WD aged 6-37 (mean 17) years who had been treated for a period of 0-15 (mean 4.5) years with D-penicillamine (900 mg/day). The amount of all protein excreted was significantly increased compared with controls, 39% of patients presenting with total proteinuria more than two standard deviations from the mean of controls. The changes in protein excretion depended on the duration of treatment. LMW proteinuria was elevated almost exclusively in the first 2 years after the start of treatment, indicating early tubular damage. This is supported by an initially high excretion of beta 2-microglobulin, NAG, and calcium. Increased excretion of HMW proteins, including albumin, persisted over longer periods, which suggests glomerular injury in some patients, possibly related to the use of D-penicillamine. Creatinine clearance remained roughly within normal limits. We propose that renal function should regularly be checked in patients with WD.
9258597##1997-5-1##MR imaging of Wilson's disease: contrast enhancement of the cerebral cortex, and corticomedullary junction.##A patient with Wilson's disease is reported whose brain MR imaging study disclosed enhancement of the cerebral cortex, and corticomedullary junction after administration of contrast medium, in the absence of a clinically detectable ischemic condition. It is difficult to explain such contrast enhancement. However, we would suggest that a &quot;vasculitis&quot; secondary to accumulation of copper in the walls of the small vessels may be the causative factor. Further studies are required to investigate the clinical and radiological significance of contrast enhancement of the cerebral cortex and corticomedullary junction on MR images in patients with Wilson's disease.
9114118##1997-5-1##Differentiation between portal-systemic encephalopathy and neurodegenerative disorders in patients with Wilson disease: H-1 MR spectroscopy.##
9160075##1997-5-1##Wilson's disease.##We describe a patient who had severe neurologic symptoms, psychiatric abnormalities, and secondary amenorrhea superimposed on a history of hemolytic anemia and micronodular cirrhosis attributed to hemochromatosis. The correct diagnosis of Wilson's disease was delayed until the appearance of Kayser-Fleischer rings and a low serum ceruloplasmin level. Appropriate treatment ameliorated symptoms, and maintenance therapy has been effective in retarding progression. It is essential to consider Wilson's disease in patients with unexplained hepatic, neurologic, and psychiatric dysfunction, because appropriate early medical treatment can prevent further organ damage and reduce the risk of permanent damage to the liver and brain.
9772488##1997-5-1##[Identification of a novel missense mutation in Wilson disease gene].##
9248126##1997-5-1##Fulminant hepatic failure as the first manifestation of Wilson disease: a report of two cases.##Two cases of fulminant hepatic failure as a first manifestation of Wilson disease are reported. They were diagnosed as acute hemolytic anemia initially, and took a fatal course despite intensive medical therapy. The main object of this report is to emphasize that Wilson disease must be included in the differential diagnosis of fulminant hepatic failure in children. Liver transplantation is the only effective means of treatment in patients presenting with fulminant hepatic failure, but this procedure is difficult to perform because of insufficient organ donation in Taiwan. The best treatment for Wilson disease is prevention through diagnosis at a presymptomatic stage, and institution of life-long therapy with D. penicillamine.
9083014##1997-4-4##CopY is a copper-inducible repressor of the Enterococcus hirae copper ATPases.##The cop operon of Enterococcus hirae effects copper homeostasis in this organism. It encodes a repressor, CopY, an activator, CopZ, and two P-type copper ATPases, CopA and CopB. Expression of all four genes is regulated by the ambient copper. In this regulation, CopY apparently acts as a copper-inducible repressor. By DNase I footprinting, it was shown that purified CopY protected two discrete sites in the region encompassing nucleotides -71 to -11 relative to the translational start site and containing hyphenated inverted repeats. Transcription is initiated between these repeats at nucleotide -42, in a domain that remained accessible to DNase I in the DNA-repressor complex. Chemical cross-linking revealed that CopY exists as a dimer in solution. In DNA band-shift assays, it was apparent that the CopY-DNA interaction occurred in two discrete steps. Half-maximal binding of repressor to the two operator sites was observed at 2 x 10(-9) M and 5 x 10(-9) M CopY, respectively. Copper ions released CopY from the promoter/operator with an apparent half-binding constant for Cu(I) of 20 microM. The site-directed mutations A-61T and A-30T essentially abolished the binding of CopY to the respective binding sites, and the double mutation A-61T/A-30T inactivated both binding sites. Thus, CopY is a copper-inducible repressor of the cop operon of E. hirae, exhibiting highly specific DNA-protein interactions with two sites on the cop promoter/operator and playing a key role in copper homeostasis in E. hirae.
9096611##1997-4-1##Posttransplantation chronic hepatitis in fulminant hepatic failure.##Non-A, non-B or seronegative hepatitis is the leading indication for liver transplantation in patients with fulminant hepatic failure (FHF). We examined protocol annual review liver allograft biopsy specimens in consecutive adult patients transplanted for FHF in an attempt to determine the extent of the histological changes. One hundred eleven biopsy specimens from 41 patients transplanted for fulminant seronegative hepatitis and 34 from a comparison group of 16 patients transplanted for other causes of FHF (11 paracetamol overdose, 2 idiosyncratic drug reaction, 3 Wilson's disease) were available. Specimens were analyzed using standard proforma without knowledge of the original diagnosis. Chronic hepatitis was present in 29 patients (71%) transplanted for fulminant seronegative hepatitis (23 mild, 3 moderate, and 3 severe) compared with 5 patients (31%, all mild) transplanted for other causes of FHF. Twenty-five patients (61%) grafted for seronegative FHF had fibrosis (13 mild, 9 moderate, and 3 severe) in contrast to 4 fibrosis (25%) (all mild) in the comparison group. Excluding early allograft failure because of primary graft nonfunction or vascular complications, six patients with seronegative FHF required retransplantation (2 = chronic rejection; 1 = severe hepatitis with panacinar necrosis, resembling original liver; and 3 = chronic hepatitis with precirrhotic fibrosis and prominent cholestasis of unknown cause). One patient in the comparison group had a second graft (chronic rejection). Posttransplantation chronic hepatitis is more frequent and severe in patients transplanted for seronegative hepatitis. Graft survival may be adversely influenced by the development of chronic hepatitis, which may represent persistent or recurrent disease.
9646197##1997-4-1##Syndromic variability of Wilson's disease in children. Clinical study of 44 cases.##
9138147##1997-4-1##Menkes disease: recent advances and new aspects.##
9232542##1997-4-1##The mechanism of excretion of trientine from the rat kidney: trientine is not recognized by the H+/organic cation transporter.##Trientine dihydrochloride is used to treat Wilson's disease by chelating copper and increasing its urinary excretion. The mechanism of renal excretion of trientine has been investigated in-vivo and in-vitro. Trientine clearance in the rat-was significantly faster than creatinine clearance. When trientine and the same number of moles of copper ions were administered simultaneously to the rat, however, trientine clearance decreased to almost the same level as the creatinine clearance. To clarify this active excretion system for trientine, the uptake of trientine and a physiological polyamine compound, spermine, was investigated using rat renal brush-border membrane vesicles. Although, because trientine and spermine are organic cations, the H+/organic cation transporter is expected to recognize these compounds, neither an outwardly directed H+ gradient nor an inward Na+ gradient stimulated trientine uptake. [14C]Spermine uptake was, nevertheless, trans-stimulated by both unlabelled spermine and trientine and the trans-stimulating effect of spermine on trientine uptake was, furthermore, completely abolished by addition of copper ions to the incubation medium. These results suggest that there is a specific transport system for spermine and trientine on the renal brushborder membrane. This transport system contributes to the secretion of trientine in the kidney proximal tubule but does not recognize the trientine-copper complex.
9197144##1997-4-1##A woman physician-patient: her view of Wilson's disease.##
9460294##1997-4-1##[Pregnancy and Wilson's disease: safety of penicillamine use].##
9093161##1997-3-1##Cranial MR findings in Wilson's disease.##
9077636##1997-3-1##Successful pregnancy in a neurologically impaired woman with Wilson's disease.##Patients with treated Wilson's disease and no residual impairments should have successful pregnancies. We report a case of a neurologically impaired patient with Wilson's disease who had a successful pregnancy with no complications. This is the first case to document that compliance with penicillamine therapy as low as 500 mg/day avoids placental and fetal copper accumulation.
9147644##1997-3-1##Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network.##We have generated polyclonal antibodies against the amino-terminal third of the Menkes protein (ATP7A; MNK) by immunizing rabbits with a histidine-tagged MNK fusion construct containing metal-binding domains 1-4. The purified antibodies were used in Western analysis of cell lysates and in indirect immunofluorescence experiments on cultured cells. On Western blots, the antibodies recognized the approximately 165 kDa MNK protein in CHO cells and human fibroblasts. No MNK signal could be detected in fibroblasts from a patient with Menkes disease or in Hep3B hepatocellular carcinoma cells, confirming the specificity of the antibodies. Immunocytochemical analysis of CHO cells and human fibroblasts showed a distinct perinuclear signal corresponding to the pattern of the Golgi complex. This staining pattern was similar to that of alpha-mannosidase II which is a known resident enzyme of the Golgi complex. Using brefeldin A, a fungal inhibitor of protein secretion, we further demonstrated that the MNK protein is localized to the trans-Golgi network. This data provides direct evidence for a subcellular localization of the MNK protein which is similar to the proposed vacuolar localization of Ccc2p, the yeast homolog of MNK and WND (ATP7B), the Wilson disease gene product. In light of the proposed role of MNK both in subcellular copper trafficking and in copper efflux, these data suggest a model for how these two processes are linked and represent an important step in the functional analysis of the MNK protein.
9072557##1997-3-1##(D)-penicillamine increases hepatic oxalate production resulting in hyperoxaluria.##
9101534##1996-3-1##Neuroimaging in Wilson disease.##
9106287##1997-3-1##Atypical MRI features of Wilson's disease: high signal in globus pallidus on T1-weighted images.##Most reports of MRI in Wilson's disease have been of abnormal low-signal lesions on T1-weighted images and high signal intensity on T2-weighted images. In contrast, we report three patients who had high-signal lesions in the globus pallidus on T1-weighted images, a finding seen in patients with portal-systemic encephalopathy. The possible causes include the paramagnetic effect of copper or iron and accumulation of Alzheimer type II glial cells.
9131675##1997-3-1##Nutritional considerations and management of the child with liver disease.##Nutritional management of the infant and child with liver disease is highly dependent upon the type of liver disease. Acute liver disease, such as that secondary to viral hepatitis, requires no specific nutritional therapy with the exception that branched-chain amino acid supplements may be indicated in the management of hepatic encephalopathy. Nutritional management of the child with chronic liver disease depends upon whether or not cholestasis is present, since in that condition, large amounts of fat-soluble vitamin supplements and medium-chain triglycerides are usually required for optimum growth. However, anicteric cirrhotic liver disease also presents nutritional challenges because of hypermetabolism, enteropathy, and increased protein oxidation. Certain inborn errors of metabolism that result in liver disease (including galactosemia, hepatorenal tyrosinemia, hereditary fructose intolerance, and Wilson's disease) have specific nutritional requirements. And, finally, the advent of pediatric liver transplantation has placed new emphasis on the importance of optimum nutritional management of the child with chronic liver disease, since improvement of nutritional status in the pretransplant period maximizes success of the transplant. This review will focus on the pathogenesis of malnutrition in childhood liver disease and will provide recommendations for nutritional assessment and monitoring as well as nutritional management of cholestatic liver disease, anicteric cirrhotic liver disease, and the inborn errors of metabolism enumerated above. Specific recommendations for nutritional management of the child awaiting liver transplantation will be provided.
9093597##1997-3-1##Western blot analysis in patients with hypocaeruloplasminaemia.##Inherited copper toxic disease, Wilson's disease, is an autosomal recessive disorder arising from a defect in biliary copper excretion. Although there are several pathognomonic clinical features, such a multisystem disease can be difficult to diagnose, particularly in the early stages of copper toxicity. Even measurements of serum copper and caeruloplasmin, the major copper-transporting protein typically reduced in Wilson's disease, may mimic other metabolic conditions such as Menke's disease and chronic active hepatitis. We have previously shown that the major biliary isoform of copper-transporting protein is 125 kDa caeruloplasmin, and this is always absent in the bile of Wilson's disease patients. In this paper we describe Western blot analysis of molecular species of caeruloplasmin in hypocaeruloplasminaemia, which can distinguish between the overlap which occurs in Wilson's disease homozygotes, heterozygotes and other conditions mimicking Wilson's disease. This may be useful for identifying patients with low plasma caeruloplasmin concentrations, and hepatic or neurological clinical features which may also be found in Wilson's disease.
9296124##1997-3-1##[Late form with psychiatric presentation of Wilson's disease, with pseudo-compulsive stereotyped movements. Neuro-radiological correlations].##Wilson's disease rarely starts after the third decade and may present with misleading psychiatric signs. We observed a 39-year-old white male who developed hysterical behaviour followed by frank delusional psychosis. Secondary neurological symptoms like astasia and dyarthria were misinterpreted as drug-induced. Despite a treatment with D-penicillamine and zinc sulfate there was further deterioration with anarthria and pseudo-compulsive stereotypies. These latter signs cleared after five months, whereas astasia and abasia remained the same and MRI imaging showed further deterioration characterized by marked bilateral putaminal cavitation. SPECT imaging could not predict the clinical evolution. Our case emphasizes that Wilson's disease can have variable initial presentations, and confirms the relationship between pseudo-compulsive stereotypies and bilateral lenticular lesions, as already described in other diseases of the basal ganglia.
9138412##1997-3-1##[Etiological treatment of cirrhosis in adults].##Etiological treatment is based upon: abstinence in case of alcoholic cirrhosis; alpha-interferon in case of B or C viral cirrhosis; corticosteroids in case of autoimmune cirrhosis; ursodeoxycholic acid in case of primary biliary cirrhosis; stopping the drug in case of drug-induced cirrhosis; surgery in case of secondary biliary cirrhosis; venesections in case of genetic haemochromatosis; liver transplantation in cases of Wilson's disease and alpha 1-anti-trypsin deficiency. Overall, these treatment are more effective when undertaken early in the course of the liver disease.
9173689##1997-3-1##[Acute hemolytic crisis as the initial manifestation of Wilson disease].##A 25-year-old woman who had delivered a normal child after a normal pregnancy four months ago, was suffering from a common cold. The latter was treated by tetracyclines. A few days later she developed an acute severe hemolysis. Moreover she had signs of hepatic failure which was characterized by a considerably reduced synthetic capacity of the liver but low serum aminotransferase levels and a proximal renal tubular disorder. With a negative Coombs test an autoimmune hemolytic anemia was unlikely. Therefore diagnostic procedures were directed at the cause of the liver injury. An increased urinary excretion of copper, strongly elevated levels of liver tissue copper and the detection of a Kayser-Fleischer ring by slit-lamp examination proved the diagnosis of Wilson's disease-presenting clinically only as severe hemolysis. Ceruloplasmin concentration in serum was in low normal range and not diagnostic.
9151461##1997-3-1##Pediatric Wilson's disease: presentation and management.##Eleven patients (4 males, 7 females) with Wilson's disease who presented before 18 years of age are described. The mean age onset of symptoms was 11.2 +/- 3.9 (SD) years. The mean age at diagnosis was 13.3 +/- 3.4 (SD) years. All patients had hepatic manifestations of the disease when diagnosed: cirrhosis (6 patients), chronic hepatitis (2) and fulminant hepatic failure (3). Three patients were asymptomatic at diagnosis. Two of the symptomatic patients presented with new undescribed manifestations: one with blurred vision and the other with acalculous cholecystitis. At diagnosis, 6 patients had Kayser Fleischer rings and 5 had hemolytic anemia. The three patients with fulminant hepatic failure had hemolysis with relatively low serum aminotransferase and alkaline phosphatase levels, possibly helpful findings for rapid diagnosis of Wilson's disease in such presentation. Ten patients were treated with penicillamine. Liver transplantation was performed in 4 patients, 2 of which presented with fulminant hepatic failure. One patient died while waiting for liver transplantation, the remainder of the patients live free of symptoms. It is important to be aware of the different manifestations of Wilson's disease in the pediatric population, in order to make appropriate evaluations in a timely manner to facilitate early diagnosis and appropriate treatment.
9024302##1997-2-1##Alcohol dehydrogenase: a target of humoral autoimmune response in liver disease.##
9123101##1997-2-1##Neurological improvement of Wilson's disease after liver transplantation.##
9245074##1997-2-1##[Occurrence of copper metabolism abnormalities in the families of four individuals with newly diagnosed Wilson's disease].##The author describes the incidence of abnormalities of copper metabolism in families of four patients with recently diagnosed Wilson's disease. The patients were three men ad one girl, age 17-22 years where Wilson's disease was diagnosed on the basis of liver symptomatology and a typical laboratory finding. The period which elapsed between detection of the first clinical and laboratory symptoms and the establishment of the diagnosis of Wilson's disease varied between 1 months to eight years. Clinical and laboratory examination of all relatives of the affected subjects (parents and siblings) revealed an increased incidence of biochemical abnormalities as regards copper and ceruloplazmin levels in siblings. In the parents of the affected patients there were no marked biochemical abnormalities in the laboratory results in the examined families. Among seven siblings of the affected subjects in three Wilson's disease was diagnosed and in one instance a reduced serum copper and ceruloplazmin level without signs of increased copper retention in the organism. In one family Wilson's disease was detected in three siblings. The assembled findings confirm the urgency of systematic and careful laboratory and clinical examination of siblings of subject with diagnosed Wilson's disease.
9020864##1997-1-15##Decreased carbonic anhydrase III levels in the liver of the mouse mutant 'toxic milk' (tx) due to copper accumulation.##The mouse mutant 'toxic milk' (tx) is characterized by marked hepatic accumulation of copper, similar to that found in patients with the genetic disorder of copper transport, Wilson disease. In addition, lactating tx females produce copper-deficient milk. To characterize further the biochemical basis of this defect, Western blots of tissue extracts from normal and tx mice were probed with various heavy-metal radioisotopes (63Ni. 65Zn and 64Cu). A 30 kDa Ni/Zn-binding polypeptide was found to be markedly decreased in the livers of the tx mice. This protein was isolated from normal adult mice using a procedure based on Ni-chelation chromatography. The amino acid sequences of two CNBr peptides were identical with portions of the mouse skeletal muscle carbonic anhydrase III (CAIII) sequence. Two other peptides sequenced had closely related sequences to that of CAIII, but with two differences in 45 amino acids. These two peptides may be derived from a novel CAIII isoform, which we term CAIIIB to distinguish it from the published form, CAIIIA. We isolated a cDNA clone corresponding to CAIIIA and used this to show that CAIIIA mRNA was also decreased in the mutant liver, but not in muscle. Copper loading of normal mice also decreased hepatic CAIIIA mRNA, suggesting that the decrease in CAIII mRNA in the tx mouse liver is a secondary consequence of the high copper levels in the liver.
9000360##1997-1-1##Portal hypertension in children and young adults: sonographic and color Doppler findings.##Portal hypertension is a relatively uncommon pathologic condition in children and young adults in contrast with older adults. The aim of this study is to evaluate the utility of sonography and color Doppler sonography in the diagnosis of portal hypertension in children and young patients and to evaluate the sonographic pattern of each disease. We reviewed 25 such patients who were younger than 30 years old and obtained the following sonographic findings: (1) liver cirrhosis: (a) multiple intrahepatic venovenous shunts in patients with primary Budd-Chiari syndrome and (b) intrahepatic vascular narrowing and nodular coarse parenchymal texture, with multiple very-high-echo spots along the portal vein in patients with Wilson disease; (2) congenital hepatic fibrosis: marked and developed collaterals, wide periportal echogenic band, and a heterogeneous parenchymal texture comprised of multiple high echoes but without portal thrombus; and (3) extrahepatic portal thrombosis: invisible portal lumen except as an echogenic band. Sonography and color Doppler sonography are very useful in diagnosing these portal hypertensive diseases. However, there are no specific sonographic findings, and the role of sonography is limited to follow-up observation of associated secondary hepatobiliary changes in patients with congenital biliary atresia.
9233407##1997-1-1##Posteroventral pallidotomy in movement disorders.##Since 1992 there has been renewed interest in pallidotomy now that the limitations and adverse effects of long-term dopaminergic therapy have become more apparent and more difficult to control in patients with advanced Parkinson's disease. The authors describe the effect of pallidotomy in 19 patients, sixteen of whom had advanced Parkinson's disease with painful dystonia and/or response fluctuations with severe akinesia while in &quot;off&quot; and dyskinesias while in &quot;on&quot;. One patient had cortico-basal degeneration with rigidity, one patient had secondary dystonia and one had dystonic posturing due to Wilson's disease. Fifteen patients underwent unilateral pallidotomy, four patients had a staged bilateral procedure. Follow-up ranged from 3 to 42 months (mean 18 months). All patients with peak-dose dyskinesias and/or dystonia had marked reduction of symptoms, including the cases of Wilson's disease and secondary dystonia. The akinesia and rigidity scores of Parkinson-patients in &quot;off&quot; were greatly reduced, mainly but not only on the contralateral side. Evaluation by the patients showed remarkable improvement of symptoms in 79%, leading to substantially improved functional abilities in 68%. In this series the decrease in dopamine-response fluctuations, dystonia, hypokinesia and rigidity with functional improvement as judged by examiners and patients reflect a significant regain of independence.
9079209##1997-1-1##Physiological factors predisposing to neurotoxicity.##Many factors determine individual susceptibility to toxic agents in addition to their primary interaction with the target site. Absorption, delivery to target tissues, bio-activation, bio-inactivation, elimination, and adaptive or protective responses all play important parts in determining the overall response of the individual. In addition changes in the physiological significance of the function which is disrupted may be crucially important. Pulmonary absorption can be limited by ventilation or perfusion, both of which increase with work rate. Tissue uptake can be limited by local blood flow, which is strongly influenced by local functional activity. In areas with a blood-tissue barrier, such as brain and testis, tissue uptake can be strongly influenced by developmental state, protein binding or vascular damage. Metabolic transformation can show marked inter-individual variations at both hepatic and extra-hepatic sites, due to genetic or nutritional influences. The capacity for adaptation to toxicological insult can also vary markedly, depending on functional reserve capacity as well as on inherent plasticity. Examples used to illustrate these factors include: the influence of motor activity on the toxicity of carbon monoxide; of noise on the ototoxicity of aminoglycoside antibiotics; of brain activity on the neurotoxicity of dinitrobenzene; of acid-base balance on the toxicity of nicotine; and of developmental stage on the neurotoxicity of haloperidol. In addition disease states can influence sensitivity. Thus anaemia sensitises to manganese; calcium deficiency to lead; nerve trauma to hexane; and Wilson's disease to copper overload.
9458954##1997-1-1##[Intestinal parasitosis and hepatic cirrhosis].##The authors describe their experience, in a prospective survey, with the prevalence rates of intestinal parasites in patients with hepatic cirrhosis admitted to the Gastroenterology Unit of University Hospital of Federal University in Juiz de Fora, Brazil, whose fresh stools were examined by Hoffman-Pons-Janner, Baermann-Moraes and Willis methods. They compare the results of stool exams with two control groups and look for a relation with cirrhosis' etiology. A higher prevalence of some parasites was observed in cirrhosis than in people with other digestive diseases (group I). mainly for the Strongyloides stercoralis, found in 40.2%, chiefly in alcoholic cirrhosis. Oddly no one of the group I admitted in the same period had strongyloidiasis. Another group including all the people who had stool samples examined in the same period at the hospital had 1.91% of that helmintic infection (group II). A comparison is also made with the prevalence in schoolchildren between the ages of 7 and 14 studies eight years before (13.16%). Other parasites were also observed in different incidence between those with cirrhosis and the other groups and the results are presented. They conclude that hepatic cirrhosis must be included in the list of conditions which increases the risk of Strongyloides stercoralis infection.</AbstractText>            </Abstract>            <AuthorList CompleteYN="Y">                <Author ValidYN="Y">                    <LastName>Gaburri</LastName>                    <ForeName>D</ForeName>                    <Initials>D</Initials>                    <Affiliation>Serviço de Gastroenterologia, Hospital Universitário, Faculdade de Medicina, Universidade Federal de Juiz de Fora-UFJF.</Affiliation>                </Author>                <Author ValidYN="Y">                    <LastName>Gaburri</LastName>                    <ForeName>A K</ForeName>                    <Initials>AK</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Hubner</LastName>                    <ForeName>E</ForeName>                    <Initials>E</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Lopes</LastName>                    <ForeName>M H</ForeName>                    <Initials>MH</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Ribeiro</LastName>                    <ForeName>A M</ForeName>                    <Initials>AM</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>de Paulo</LastName>                    <ForeName>G A</ForeName>                    <Initials>GA</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Pace</LastName>                    <ForeName>F H</ForeName>                    <Initials>FH</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Gaburri</LastName>                    <ForeName>P D</ForeName>                    <Initials>PD</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Ornellas</LastName>                    <ForeName>A T</ForeName>                    <Initials>AT</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Ferreira</LastName>                    <ForeName>J O</ForeName>                    <Initials>JO</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Chebli</LastName>                    <ForeName>J M</ForeName>                    <Initials>JM</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Ferreira</LastName>                    <ForeName>L E</ForeName>                    <Initials>LE</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>de Souza</LastName>                    <ForeName>A F</ForeName>                    <Initials>AF</Initials>                </Author>            </AuthorList>            <Language>por</Language>            <PublicationTypeList>                <PublicationType>Comparative Study</PublicationType>                <PublicationType>English Abstract</PublicationType>                <PublicationType>Journal Article</PublicationType>            </PublicationTypeList>            <VernacularTitle>Parasitoses intestinais e cirrose hepática.</VernacularTitle>        </Article>        <MedlineJournalInfo>            <Country>BRAZIL</Country>            <MedlineTA>Arq Gastroenterol</MedlineTA>            <NlmUniqueID>15310600R</NlmUniqueID>            <ISSNLinking>0004-2803</ISSNLinking>        </MedlineJournalInfo>        <CitationSubset>IM</CitationSubset>        <CitationSubset>J</CitationSubset>        <MeshHeadingList>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Adolescent</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Adult</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Aged</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Child</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Female</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Humans</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Intestinal Diseases, Parasitic</DescriptorName>                <QualifierName MajorTopicYN="N">complications</QualifierName>                <QualifierName MajorTopicYN="Y">epidemiology</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Liver Cirrhosis</DescriptorName>                <QualifierName MajorTopicYN="N">complications</QualifierName>                <QualifierName MajorTopicYN="Y">parasitology</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Male</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Middle Aged</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Prevalence</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Prospective Studies</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Strongyloidiasis</DescriptorName>                <QualifierName MajorTopicYN="N">epidemiology</QualifierName>            </MeshHeading>        </MeshHeadingList>        <OtherID Source="PIP">131454</OtherID>        <OtherID Source="POP">00276702</OtherID>        <OtherAbstract Type="PIP" Language="eng">            <AbstractText>In a prospective study conducted between July 1995 and June 1996 the prevalence of intestinal parasites is described in 35 (32 male, 3 female) patients with hepatic cirrhosis, aged 13-77 years, who had been admitted to the gastroenterology unit of the Federal University in Juiz de Fora, Brazil. The causes of cirrhosis were: alcohol (19 cases), hepatitis B virus (HBV) (3 cases), hepatitis C virus (HCV) (5 cases), HBV and HCV (2 cases), cryptogenetics (3 cases), Wilson's disease (1 case), biliary cirrhosis (1 case), and Gaucher's disease (1 case). Another 45 patients who were hospitalized during this period served as controls (Group I). Group II was comprised of 1411 persons who underwent parasitological tests during December 1995 and May 1996. Comparison was also made with 7371 tests performed in children aged 7-14 years who had been studied in 1988. Stools were examined by the Hoffman-Pons-Janner, Baermann-Moraes, and Willis methods. The results of stool exams were compared with those of the two control groups. A higher prevalence of some parasites was observed in cirrhosis patients than in patients with other digestive diseases (Group I). Of the 35 cirrhosis patients, 19 presented with positive parasite tests. Strongyloides stercoralis was found in 40.2%, chiefly in alcoholic cirrhosis patients, which was significant when compared to the other two control groups, but not significant when compared to the patients with nonalcoholic cirrhosis (4 cases of strongyloidiasis out of 16 patients). None of the 45 patients in Group I had strongyloidiasis. Group II (including all the people who had stool samples examined during the same period in the hospital) had a 1.91% rate of helminthic infection. A rate of 13.16% was found in the children's group.
9833399##1997-1-1##Quantitative study of pathological forms of astroglia in Wilson's disease.##The number and distribution of Alzheimer type I and II cells (Alz I and II) as well as Opalski cells (Opl) were estimated in chosen brain regions of seven autopsied cases with Wilson's disease (WD). The authors of this study focused especially on the question whether the kind and intensity of astrocytes is linked to the clinical form of the disease and to the intensity of brain damage. Alz I and II cells were counted by the use of the HE method, whereas the number of Opl cells was calculated using the PAS method. The study revealed that among the three types of cells the number of Alz II cells was the highest and that of Alz I cells was the lowest. The distributional patterns of these three types of cells were different. Alz I cells were found mainly in the putamen. Alz II cells were observed diffusely, although they occurred in different numbers in the whole brain. The highest number of Opl cells was found in the putamen. Alz I cells were found only in the neurological type of the disease. The highest number of Alz II cells was seen in the hepatic type of the disease, whereas the highest number of Opl cells was observed in the neurological &quot;mixed&quot; forms. Moreover, intensity of tissue damage with presence of necroses was greatest in neurological WD. In the hepatic type dispersed areas of status spongiosus were observed, without presence of necroses. Our study revealed that the type and amount of the pathological astroglia may correlate both with the clinical form of WD and intensity of tissue damage. Alz II cells seem to be a characteristic feature of the early stage of astroglial response to the pathogenic factor whereas Alz I and Opl cells occur in WD only in the advanced stage of tissue damage.
9443062##1997-1-1##Suppression of long-term potentiation in hippocampal slices by copper.##Cu(2+)-ions are known to interfere with gamma-aminobutyric acid (GABA)- and glutamate-operated ion channels from experiments with isolated neurons. Such actions are likely involved in the pathophysiology of Wilson's disease. We have now studied the effects of Cu2+ in the CA1 region of hippocampal slices. Field excitatory postsynaptic potential (EPSP) slopes in the CA1 region were unaffected by 1 microM Cu2+ but were depressed by 10 microM (to 85%) and 100 microM (to 50%). A paired-pulse test revealed no difference in facilitation in the presence or absence of Cu2+, indicating a postsynaptic action. A late component of intracellularly registered EPSPs in Mg(2+)-free solution was also reduced by Cu2+. The N-methyl-D-aspartate (NMDA) component of the field EPSP, isolated by adding CNQX and bicuculline in Mg(2+)-free solution, was reduced to 69% of control by 1 microM and to 50% of control by 10 microM Cu2+. Long-term potentiation, evoked by 3 x 50 pulses at 100 Hz, 20 s interval amounted to 132 +/- 11% 90 min after tetanization under control conditions but was absent in the presence of 1 microM Cu2+ in the bath. Thus low concentrations of copper can selectively reduce NMDA-mediated potentials and synaptic plasticity.
9222767##1997-1-1##24 bp deletion and Ala1278 to Val mutation of the ATP7B gene in a Sardinian family with Wilson disease.##
9148016##1997-1-1##Presence of ATP-dependent copper transport in the hepatocyte canalicular membrane of the Long-Evans cinnamon rat, an animal model of Wilson disease.##
8980283##1997-1-1##A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts.##Wilson disease is a rare autosomal recessive disease of copper metabolism. The gene for Wilson disease was characterized recently and has been predicted to encode a copper-transporting ATPase highly homologous to the protein encoded by the gene of Menkes disease. In this study, the genetic mutations of two Finnish patients with Wilson disease were investigated. One patient was homozygous for a novel nonsense mutation in exon 4, while the other was a compound heterozygote. Lysyl oxidase (EC 1.4.3.13) is an extracellular copper enzyme with deficient activity in Menkes disease. The levels of lysyl oxidase activity in cultured skin fibroblasts from these Wilson disease patients were also measured.
9284083##1997-1-1##Metabolism of administered triethylene tetramine dihydrochloride in humans.##Triethylene tetramine dihydrochloride (trien 2HCl) has been used for the treatment of Wilson's disease, which is characterized by the accumulation of copper in various organs. We previously developed an HPLC system for analyzing trien, and found a trien metabolite in the urine when trien was orally given to humans. In this study, the metabolite was identified as 1-N-acetyltriethylene tetramine (acetyltrien) by FAB-MS and 1H-NMR spectroscopy. Trien and acetyltrien were capable of combining with copper, iron and zinc. However, the chelating activity of acetyltrien was significantly lower than that of trien. When trien was given to healthy adults, the amount of trien excreted in the urine was about 1% of the administered trien, whereas that of acetyltrien was about 8%. Most of the trien was excreted within the first 6 hours after the administration, while acetyltrien was excreted for over 26 hours. The urinary copper, iron and zinc levels all increased in parallel with the trien excretion.
9102715##1997-1-1##[Wilson's disease].##Wilson's disease is a rare inherited metabolic disorder usually characterized by liver and/or neurological degeneration. Unlike most genetically transmitted diseases, it rapidly responds to pharmacological treatment in case of early diagnosis and treatment. Often, however, as this disease presents with aspecific symptoms, patients are wrongly diagnosed as psychiatric cases or as having generic chronic liver disease and the true cause of symptoms is only discovered at a much later stage. The authors give a detailed review of the literature with the aim of presenting the most recent research on the main aspects of this disease and offering a practical and simple approach to early diagnosis.
9277909##1997-1-1##[Wilson's disease].##
9002153##1997-1-1##Liver transplantation for fulminant hepatic failure: importance of renal failure.##One hundred eighty-one consecutive patients with fulminant hepatic failure (FHF) presenting in a 2-year period were reviewed. In this cohort we examined the impact of pretransplant renal failure on mortality and morbidity following orthotopic liver transplantation (OLTx). Twenty-seven patients (18 female, 9 male) with a median age of 43.5 years (range 19-65 years) underwent OLTx. FHF was due to idiosyncratic drug reaction (n = 4), paracetamol overdose (n = 3), seronegative hepatitis (n = 17), hepatitis B (n = 1), veno-occlusive disease (n = 1), and Wilson's disease (n = 1). Renal failure was present in 14 patients, 7 of whom died (whereas there was 100% survival in patients without renal failure). Pretransplant renal failure was associated with prolonged mechanical ventilation (13 days vs 6 days, P = 0.05), prolonged intensive care stay (17 days vs 8 days, P = 0.01) and prolonged hospital stay (27 vs 21 days, P = NS). Pretransplant renal failure did not predict renal dysfunction at 1 year after OLTx. We conclude that the survival of patients transplanted for FHF is inferior to that of patients transplanted for chronic liver disease (67% vs 88% 1-year survival in Birmingham). For patients with FHF undergoing transplantation, pretransplant renal failure strongly predicts poor outcome with significantly greater consumption of resources.
9017032##1996-12-1##Wilson disease: asymptomatic or late-onset type?##
8956601##1996-12-1##Cranial MR imaging in Wilson's disease.##
8957098##1996-12-1##Inherited liver diseases affecting the adult.##A variety of different inherited disorders may cause liver disease in adults. Recent advances in molecular genetics have improved our understanding of these diseases, such as the isolation and characterization of the genes responsible for Wilson disease, alpha1-antitrypsin deficiency, and cystic fibrosis. A candidate gene responsible for hereditary hemochromatosis has also recently been cloned. These scientific advances have important implications in the diagnosis, treatment, and screening of patients with genetic diseases and their families. We review the most common inherited liver diseases affecting adults, with emphasis on the clinical implications of recent molecular advances.
8942746##1996-12-1##Intrahepatic transplantation of normal hepatocytes prevents Wilson's disease in Long-Evans cinnamon rats.##
8931691##1996-12-1##Wilson disease mutations associated with uncommon haplotypes in Mediterranean patients.##This study reports 12 novel mutations of the Wilson disease (WD) gene which have been detected by the molecular analysis of 29 patients of Mediterranean descent carrying uncommon chromosomal haplotypes at the WD locus. These mutations include two nonsense, one splice site and nine missense. The missense mutations lie in regions of the WD gene critical for its function, such as the transmembrane region, the transduction domain and the ATP loop and ATP-binding domain, indicating that they are disease-causing mutations. These new findings improve our knowledge for the role played by functional domains on the ATP7B function.
9104075##1996-12-1##Wilson's disease presenting as haemolytic anaemia and its successful treatment with penicillamine and zinc.##Haemolysis is an uncommon first manifestation of Wilson's disease. We describe a young woman who presented with episodic haemolysis and abnormal liver functions; the diagnosis of Wilson's disease was not made until nine months later. She responded well to a combination of penicillamine and zinc. This report underscores the importance of considering Wilson's disease as a cause in a patient with haemolysis of uncertain aetiology, since the disease can be successfully treated in the early stages. the mechanism of oxidative damage to erythrocytes by the excessive copper and the present role of zinc therapy are also discussed.
8962200##1996-12-1##Neurologic symptoms improve in patients with Wilson's disease despite immunosuppression.##
8984578##1996-11-19##[Current diagnosis: hereditary metabolic diseases of the liver (primary hemochromatosis, Wilson disease)].##Primary hemochromatosis is characterized by a specific pattern of clinical manifestations. It includes liver disease with hepatomegaly, glucose intolerance, e.g. diabetes, hyperpigmentation oft the skin, impotence/ amenorrhea, arthropathy, cardiomyopathy and fatigue. Laboratory investigation reveals significantly elevated serum ferritin and transferrin saturation with iron. The diagnosis is confirmed by liver biopsy and quantitative determination of elevated liver iron content. Wilson's disease represents a copper storage disease. Prominent clinical features are hepatomegaly and splenomegaly. Neurological alterations and detection of Kayser-Fleischer corneal rings are typical. In the acute initial phase the often young patients present with Coombs-negative hemolysis. Psychiatric alterations, cardiomyopathy, arthropathy, nephropathy, as well as thrombocytopenia and leucopenia are other clinical features. Laboratory parameters of Wilson's disease include low serum ceruloplasmin and serum copper. There is an elevated urinary copper excretion and elevated serum free copper concentration. The diagnosis is confirmed by liver biopsy with quantitative determination of an elevated liver copper content.
8991852##1996-11-7##Bacterial resistances to toxic metal ions--a review.##Bacterial plasmids encode resistance systems for toxic metal ions, including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+ and Zn2+. The function of most resistance systems is based on the energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The Cd(2+)-resistance ATPase of Gram-positive bacteria (CadA) is membrane cation pump homologous with other bacterial, animal and plant P-type ATPases. CadA has been labeled with 32P from [alpha-32P] ATP and drives ATP-dependent Cd2+ (and Zn2+) uptake by inside-out membrane vesicles (equivalent to efflux from whole cells). Recently, isolated genes defective in the human hereditary diseases of copper metabolism, namely Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to bacterial CadA than to other ATPases from eukaryotes. The arsenic resistance efflux system transports arsenite [As(III)], alternatively using either a double-polypeptide (ArsA and ArsB) ATPase or a single-polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. The triple-polypeptide Czc (Cd2+, Zn2+ and Co2+) chemiosmotic efflux pump consists of inner membrane (CzcA), outer membrane (CzcC) and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell.
8944686##1996-11-1##ATP-dependent copper transporter, in the Golgi apparatus of rat hepatocytes, transports Cu(II) not Cu(I).##The Wilson disease adenosinetriphosphatase (ATPase; ATP7B) is believed to bind copper as Cu(I). We provide evidence to suggest that the ATPase actually transports Cu as Cu(II). When the copper is presented to rat liver microsomes as Cu(I), virtually all uptake is ATP independent. If the copper is presented as copper oxalate [Cu(II)], total uptake is reduced to approximately 10% of Cu(I) levels, but ATP-dependent uptake rises, both as a proportion of total uptake and in absolute terms. The reducing agent vitamin C and the Cu(I) chelator bathocuproine both override the effect of oxalate. The data indicate that there are two transporters in the microsomes, an ATP-independent Cu(I) transporter and an ATP-dependent Cu(II) pump. The activity of the Cu(I) transporter correlates most strongly with alkaline phosphatase, suggesting that it is derived from plasma membrane contamination. Cu(II) ATP-dependent transport correlates only with beta-1, 4-galactosyltransferase, which indicates that it is located in the Golgi apparatus.
8899270##1996-11-1##Regression of Kayser-Fleischer rings during oral zinc therapy: correlation with systemic manifestations of Wilson's disease.##Fourteen patients presenting with neuropsychiatric manifestations of Wilson's disease were treated with oral tetrathiomolybdate (TM) for 8 weeks followed by oral zinc (Zn) maintenance therapy. The patients were evaluated prospectively at baseline and at yearly intervals for up to 5 years by slit-lamp biomicroscopy and photography, quantitative neurologic and speech pathology examinations, 24-h urine copper collection, and a quantitative scoring of magnetic resonance imaging (MRI) of the brain. Kayser-Fleischer (KF) ring size decreased significantly during the 5-year study period (p &lt; 0.0001). Although results of neurologic examination, speech pathology examination, and 24-h urine copper level analysis in symptomatic Wilson's disease patients improved during the study period, KF ring regression did not correlate with the improvement in these clinical parameters (p &gt; 0.05). However, there was a correlation between MRI scores and KF ring regression (p = 0.02). Anticopper therapy with TM followed by zinc maintenance therapy is a safe and effective treatment for patients with neurologically symptomatic Wilson's disease. This treatment leads to reduction in KF ring size; however, KF ring reduction is not a good predictor of clinical improvement for patients with neuropsychiatric manifestations of Wilson's disease.
8938442##1996-11-1##Efficient detection of mutations in Wilson disease by manifold sequencing.##We have applied a solid support for parallel handling and direct loading of sequencing reactions--manifold sequencing--to analyze the coding sequence for the deficient copper transporting P-type ATPase in 24 families with Wilson disease. At least 100 different amplification reactions could be handled in parallel, with a minimal turnaround time of 12 h from isolated genomic DNA to identification of the mutations. Sixteen different mutations were found, accounting for 92% of the mutant genes. Ten of these mutations have not been previously described. Eleven were observed only in single families. Mutation His1069Gln, previously identified as the most prevalent mutation in Northern Europe, was found in one-third of the Northern European chromosomes in our material. Four patients were homozygous for this mutation, and three were homozygous for Thr977Met. The method allowed us to establish the diagnosis of Wilson disease in 24 h in a patient with acute hepatic failure.
8937346##1996-11-1##Hereditary caeruloplasmin deficiency: clinicopathological study of a patient.##A 58 year old patient with dementia, oral dyskinesia, and diabetes mellitus is described. He had an undetectable concentration of serum caeruloplasmin, as an autosomal recessive trait. Brain MRI disclosed a pronounced hypointensity in the bilateral putamina, caudate, and dentate nuclei on both T1 and T2 weighted images. Pathological findings were mainly in those regions of the brain and consisted of neuronal cell loss with gliosis, heavy iron deposition, and spheroids. Visceral organs also had iron deposition, especially severe in the liver and pancreas. The present patient and other recorded cases constitute a clinicopathological entity of hereditary caeruloplasmin deficiency, different from Wilson's disease.
8897491##1996-10-4##Neurochemical and histochemical evidence for an abnormal catecholamine metabolism in the cerebral cortex of the Long-Evans Cinnamon rat before excessive copper accumulation in the brain.##Distributions of norepinephrine (NE), dopamine (DA) and its metabolites in the cerebral cortex in Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease, aged 4, 10 (in the early stage of the disease) and 20 weeks (in the advanced stage of the disease) were determined to elucidate the effect of the abnormal copper (Cu) metabolism observed in the LEC rat on the brain catecholamine metabolism. NE depression as well as excessive accumulations of DA and facilitation of the DA catabolic pathway to its acidic metabolites were observed in the cerebral cortex of the LEC rat at 4 and 10 weeks of age. Furthermore, immunohistochemical analysis of the cuproenzyme dopamine-beta-hydroxylase (DBH) showed lower antigenicity of DBH in the cortical neurons in the cerebral cortex of LEC rats aged 4 weeks than in control rats. These results suggest that neurochemical disturbances involved in an abnormal catecholamine metabolism may occur in the cerebral cortex of the LEC rat before excessive Cu accumulation.
8859064##1996-10-1##Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy.##
8930453##1996-10-1##Cardiac evaluation of liver transplant recipients: QT dispersion in electrocardiogram.##Increased QT dispersion, the interlead variability of the QT interval length in the 12-lead electrocardiogram, reflects uneven ventricular repolarization as a sign of cardiomyopathy. We analyzed QT dispersion in the preoperative electrocardiogram of 100 adult liver transplant recipients and 20 healthy control subjects. In 12% of the liver recipients, QT dispersion was increased above 65 ms (mean + 3SD). Six of these patients had a liver storage disease (haemochromatosis, Wilson's disease or amyloidosis). Five had a history of cardiac disease. Severe intraoperative cardiac complications occurred in three patients with markedly increased QT dispersion (&gt; or = 99 ms). In conclusion, in liver storage diseases the heart may be affected, leading to increased risk of cardiac complications, which might be predicted from increased QT dispersion. Analysis of QT dispersion, a noninvasive inexpensive technique, can be recommended to be included in the cardiac screening of liver transplant candidates.
8911863##1996-10-1##Defective biliary copper excretion in Wilson's disease: the role of caeruloplasmin.##Previous studies have failed to explain the link between copper accumulation and abnormal caeruloplasmin expression in Wilson's disease. Furthermore, despite the isolation of a candidate gene for Wilson's disease, which predicts a defective copper transport protein, the localization of this putative protein and its relationship to the pathway involved in copper excretion and to caeruloplasmin remain unknown. We now present evidence that caeruloplasmin, the major plasma copper-carrying protein, is present in the liver in Wilson's disease, and thus that reduced circulating levels of the protein result from a post-translational defect in the secretory pathway. We have also identified a novel form of caeruloplasmin, molecular weight 125 kD, which we propose may act as the carrier for excretory copper into bile, since it is normally present in both liver and bile, although largely absent from serum, and undetectable in bile from Wilson's disease patients. The presence of this form of caeruloplasmin in Wilson's disease liver suggests that a related post-translational defect may also be responsible for its absence from bile in Wilson's disease. This study thus provides the first plausible explanation of a link between the defective copper excretion and the reduced plasma caeruloplasmin, which characterize Wilson's disease.
8921375##1996-10-1##Genomic organization of the mottled gene, the mouse homologue of the human Menkes disease gene.##The mouse homologue of the Menkes gene has been shown to span 120 kb of genomic DNA and to be similar in structure to both its human MNK homologue (ATP7A) and the Wilson disease gene (WD; ATP7B). Conservation of the majority of intron/exon boundaries among the three genes was also observed. The high overall conservation of both the Atp7a gene and the direction of transcription of the Atp7a, Pgk1, and Xnp genes between human and mouse is compatible with the evolution of an ancestral gene subject to strong evolutionary constraints lying within a locally relatively conserved region of the X chromosome.
8894697##1996-10-1##The toxic milk mouse is a murine model of Wilson disease.##Wilson disease (WD) is an autosomal recessive defect of copper transport characterized by massive accumulation of copper in the liver, which can lead to liver failure. Mutations in a copper transporting ATPase (WND or ATP7B) have been shown to cause the disease. The toxic milk mouse mutant (tx) accumulates copper in the liver in a manner similar to that observed in patients with WD. However, some physiological differences between tx mice and human WD patients have cast doubts on whether this mutant mouse is a valid model for WD. In this paper we report the isolation of cDNA clones encoding the murine homologue of WND. The predicted amino acid sequence is 1462 amino acids and contains the same functional domains identified in human and rat WND. As in the rat, the fourth metal binding domain is apparently non-functional. Similar levels of a 7.5 kb WND mRNA were detected in liver and kidney from normal and tx mice, indicating that transcription of this gene was unaffected in the mutant mice. The coding sequence of WND cDNA from the tx mouse liver identified a single nucleotide difference between the normal DL mouse and the tx which is predicted to change methionine 1356 in the eighth transmembrane domain to valine. This methionine is conserved in all copper ATPases including those from bacteria and yeast. The conclusion that this is the causative mutation is supported by the recent mapping of tx and WND to the same region of mouse chromosome 8. Thus the tx mouse is presented as a valid model for studies of the role of WND in copper transport and for investigation of different treatment strategies for WD.
21584132##2011-5-18##The psychiatric aspects of wilson's disease-a study from a neurology unit.##A series of 31 cases of Wilson's disease (WD) were assessed retrospectively on a range of variables including psychiatric, neurologic and biochemical data recorded at index admission over a period of 7 years. 18 patients (58%) showed psychopathological features. 5 patients (16.1%) were reported to have poor scholastic performance at the onset of illness and 1 patient (3.2%) had abnormal behaviour (mania like) many years prior to the appearance of neurological symptoms. The most common psychiatric features were cognitive impairment (45.2%), affective symptomatology (41.9%) and behavioural abnormalities (29%). Only one patient had a schizophrenia like psychosis. The psychiatric manifestation of Wilson's disease as they present in our setting and their clinical relevance are discussed.
9057376##1996-10-1##Problems in diagnosis and management of Wilson's disease in India.##
8903079##1996-10-1##Reversible magnetic resonance imaging lesions in Wilson's disease: clinical-anatomical correlation.##Described herein is a patient with Wilson's disease who had tremor as a prominent neurological manifestation. T2-weighted magnetic resonance imaging showed abnormal high signal intensities in the bilateral lenticular nuclei, thalami, and red nuclei of the midbrain. Improvement of tremor with copper chelating agents was well correlated with a decrease of the abnormal signals in the thalami and the red nuclei.
8912298##1996-10-1##Finding the optimal multiple-test strategy using a method analogous to logistic regression: the diagnosis of hepatolenticular degeneration (Wilson's disease).##Finding the optimal strategy among a battery of tests may be cumbersome for decision analytic models. The authors present a method of examining multiple test combinations that is based on a modified Bayes' formula analogous to logistic regression. They examined all 16 combinations of four tests used to diagnose hepatolenticular degeneration. The four tests examined were: serum ceruloplasmin level, 24-hour urinary copper excretion, free serum copper level, and liver biopsy copper concentration. They also simulated the diagnostic workup of the disease for a hypothetical cohort of 15,000 patients at risk. Assuming the disutilities of false positives and false negatives to be equal, and considering sensitivity analysis of test characteristics, the following test combinations were found to be optimal for making the diagnosis at a prior probability of disease equal to 0.05: positive serum ceruloplasmin and 24-hour urinary copper excretion, combined with either positive liver biopsy or free serum copper (or both). The strategies obtained by the modified Bayes' formula were the same as those found using the simulated data set with a standard logistic-regression software package. The logistic model's diagnostic accuracy is 0.98 as measured by the area under the receiver operating characteristic curve. The optimal strategy for diagnosing hepatolenticular degeneration varies with the prior probability of disease. For prior probabilities of 0.05, 0.25, and 0.9, and the optimal strategy, model sensitivities are 0.801, 0.880, and 0.997, and model specificities are 0.991, 0.985, and 0.814, respectively. The new method provides a convenient alternative to decision trees when examining multiple diagnostic tests.
8781331##1996-9-1##Hepatocyte growth factor and c-met expression in Long-Evans Cinnamon rats with spontaneous hepatitis and hepatoma.##The Long-Evans Cinnamon (LEC) rat is characterized by the spontaneous onset of acute and chronic hepatitis, followed by occurrence of liver cancer, and is thus able to provide a unique experimental model for human genetical liver disease, Wilson's disease. Hepatocyte growth factor (HGF) is a potent hepatotrophic factor in liver regeneration, and its expression is up-regulated in response to liver injuries. We found that the plasma HGF level in LEC rats rose markedly during the fulminant hepatitis phase, fell during the phase of chronic/cholangiofibrosis, and fluctuated during the hepatoma phase. Immunohistological staining of the liver revealed that the number of HGF-positive cells increased remarkably during the fulminant hepatitis phase, and that many of these cells were localized at the portal triads. Fewer HGF-positive cells were observed during the phase of chronic hepatitis. The surface of the hepatocellular carcinoma (HCC) cells and the cytoplasm of the nonepithelial cells in cancerous liver tissues were HGF-positive. The HGF-messenger RNA (mRNA) level in the liver rose in the fulminant hepatitis phase, fell in the chronic hepatitis phase, and was intermediate or high during the hepatoma phase. The expression of c-met mRNA was strong in the tissues of LEC rats with fulminant hepatitis and, especially, in the cholangiofibrosis tissues. c-met mRNA was also detected in HCCs. These results suggest that the HGF-c-met system may play an important role in the regeneration of hepatocytes as well as in the development of HCC in paracrine or autocrine mechanisms.
8866435##1996-9-1##Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders.##We used a paired-pulse magnetic stimulation technique to study ipsilateral cortico-cortical inhibition of the motor cortex in 48 patients with various neurological disorders and in 20 normal volunteers. In the normal subjects, the first subthreshold conditioning stimulus suppressed responses to the second suprathreshold test stimulus at interstimulus intervals (ISIs) of 1-5 ms (inhibition at short intervals), and facilitated them at ISIs of 8-15 ms (facilitation at long intervals). Patients with motor neuron disease, except those in whom brain stimulation produced control responses that were generated by direct activation of corticospinal neurons (D-waves), had normal inhibition at short intervals. Facilitation at long intervals was not elicited in some patients with amyotrophic lateral sclerosis. Less inhibition at short intervals and normal facilitation at long intervals was found for all the patients with progressive myoclonic epilepsy, a condition in which the excitability of cortical inhibitory interneurons is thought to be affected. Inhibition at short intervals was disturbed, but facilitation at long intervals was intact in the patients with movement disorders (Parkinson's disease, corticobasal degeneration, and Wilson's disease). In these patients, positron emission tomography (PET) studies showed decreased regional cerebral blood flow (rCBF) in the basal ganglia in the relaxed state. However, normal suppression was elicited in the patients with Parkinson's disease with normal rCBF. In four patients with chorea, the time-course of inhibition and facilitation was normal, even though PET studies showed decreased rCBF in the basal ganglia in two of them. Normal inhibition could not be elicited in patients who had a small lesion in the basal ganglia or in the pathway from basal ganglia to the primary motor cortex; the putamen, globus pallidus, and supplementary motor cortex. In contrast, patients who had a lesion in a sensory system (sensory cortex or sensory thalamus) or in the pontine nucleus had normal suppression. We conclude that the results of ipsilateral cortico-cortical inhibition with paired magnetic stimulation reflect the excitability of inhibitory interneurons in the motor cortex and that outputs from the basal ganglia markedly affect this inhibition, but outputs from somato-sensory systems or cerebellum do not. Moreover, dysfunction of the corticospinal tract or spinal motoneurons does not affect results obtained by the paired magnetic stimulation technique when the control responses are generated by I-waves (i.e. descending volleys are produced by transsynaptic activation of the corticospinal tract neurons.
8831241##1996-9-1##[A nation-wide survey for neurologic and hepato-neurologic type of Wilson disease: clinical features and hepatic copper content].##A nation-wide survey for Wilson disease was performed from 1990 to 1991. We studied clinical features and copper content in liver for the neurologic and hepato-neurologic types. A questionnaire was sent to more than five thousand hospitals in Japan. Thirty-three percent of physicians completed the questionnaire. Four hundred and twenty-five cases were studied for the onset age, primary symptoms, prognosis and hepatic copper content. The onset age of neurologic and hepato-neurologic type of Wilson disease was usually 6 years or older. The most common initial symptom was dysarthria. Gait disturbance, flapping tremor and Kayser-Fleischer rings were also very common symptoms. We conclude that in patients with dysarthria and/ or extra pyramidal symptoms over 6 years of age, Wilson disease should be considered. The prognosis quod vitam of patients with neurologic and hepato-neurologic Wilson disease is not always fatal. However, many patients required prolonged treatment at either a hospital, sanatorium or at home due to irreversibility of their severe neurological defects. This result shows that early detection is the most important factor for a promising prognosis. Copper content in liver was examined for each type of Wilson disease. Neurologic type of Wilson disease had the highest copper content, followed by hepato-neurologic type. Hepatic type had the lowest copper level out of these three forms of the disease. The mechanism of onset for each type of Wilson disease should be studied using these results.
9139791##1996-9-1##[A case of Wilson's disease with an atypical clinical course].##The case of atypical course of Wilson's disease in a 31 years old woman was reported. Basing on its clinical presentation it was classified as a liver form. The laboratory criteria necessary for the diagnosis of this disease are as follows: increase of cooper concentration in liver tissue (above 500 micrograms copper per gram dry substance), defect of copper incorporation into ceruloplasmin in 24 hours copper excretion test in urine (above mumol/24 h). In this report the main principles of pharmacotherapy were summarized, with particular stress on the necessity throughout the patient's life.
8784399##1996-9-1##Laparoscopic partial hepatectomy and left lateral segmentectomy: technique and results of a clinical series.##
8801078##1996-8-16##[Wilson's disease].##
9119926##1996-8-15##Case in point. Wilson's disease.##
8770863##1996-8-15##Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats.##Several clinical studies have suggested that excess hepatic iron accumulation is a progressive factor in some liver diseases including chronic viral hepatitis and hemochromatosis. However, it is not known whether iron-induced hepatotoxicity may be directly involved in hepatitis, cirrhosis, and liver cancer. The Long-Evans Cinnamon (LEC) rat, which accumulates excess copper in the liver as in patients with Wilson's disease, is of a mutant strain displaying spontaneous hemolysis, hepatitis, and liver cancer. We found previously that LEC rats harbored an additional abnormality: accumulation of as much iron as copper in the liver. In the present study, we compared the occurrence of hepatitis and liver cancer in LEC rats fed an iron-deficient diet (ID) with those in rats fed a regular diet (RD). The RD group showed rapid increments of hepatic iron concentrations as the result of hemolysis, characteristics of fulminant hepatitis showing apoptosis, and a 53% mortality rate. However, no rats in the ID group died of fulminant hepatitis. Hepatic iron, especially &quot;free&quot; iron concentration and the extent of hepatic fibrosis in the ID group were far less than those of the RD group. At week 65, all rats in the RD group developed liver cancer, whereas none did in the ID group. These results suggest that the accumulation of iron, possibly by virtue of synergistic radical formation with copper, plays an essential role in the development of fulminant hepatitis, hepatic fibrosis, and subsequent hepatocarcinogenesis in LEC rats.
9275468##1996-8-1##[Gene diagnosis for hepatolenticular degeneration by genetic linkage analysis with four short tandem repeat polymorphisms].##
8757902##1996-7-22##[Recurrent arthritis in a child. A rare manifestation of Wilson's disease].##Wilsons disease is a rare autosomal recessive disorder of copper transportation, which is fatal if not treated. The disease often starts in adolescence, and most common symptoms are due to liver-and/or brain involvement. This paper deals with an adolescent with Wilsons disease. His clinical presentation was joint complaints for almost two years. The final diagnosis was made by mutation analysis. It is stressed that the clinician should consider Wilson's disease in cases of unexplained liver- and neurological involvement as well as cases of repetitive unexplained joint symptoms in the pubertal period.
8678016##1996-7-1##Rupture of the spleen as the initial manifestation of Wilson's disease.##
8884310##1996-7-1##Liver transplantation--perspective from Hong Kong.##
8757970##1996-7-1##Acquired sideroblastic anaemia induced by a copper-chelating agent.##Acquired sideroblastic anaemia may be related to drugs and other chemicals that inhibit the activity of mitochondrial enzymes involved in haem synthesis. We report a case of secondary acquired sideroblastic anaemia following administration of triethylene tetramine dihydrochloride (trientine), a second-line copper-chelating agent used in the treatment of Wilson's disease. The anaemia improved after dose reduction of trientine. The mechanism of induction of sideroblastic anaemia in this case is unclear, but trientine does not appear to alter the function of two key mitochondrial haem enzymes, and may instead act directly on mitochondrial iron metabolism.
8836899##1996-7-1##Adenosine triphosphate-dependent copper transport in human liver.##
8765339##1996-7-1##CD1b is expressed in multiple sclerosis lesions.##Recent observations have shown that CD1 molecules act as restriction elements in the presentation of antigens to specialized subsets of T cells. To examine the expression of CD1 molecules in multiple sclerosis (MS) lesions, frozen sections of central nervous system (CNS) tissues from nine MS and three other neurological disease (OND) patients, one patient with Wilson's disease, and one non-neurological control were stained by immunocytochemistry. In chronic-active MS lesions, CD1b immunoreactivity was prominent on perivascular inflammatory cells whereas macrophages within the lesion showed little reactivity. At the lesion edge, intense immunoreactivity for CD1b was found on hypertrophic astrocytes. High level expression of CD1b in MS lesions was found to colocalize with the presence of GM-CSF in astrocytes. In chronic-silent lesions, CD1b expression was found on only a few perivascular astrocytic foot processes and the occasional perivascular macrophage. CD1b was not found in the tissues studied for control purposes. In contrast, MHC class II expression was detected on microglia in all tissues examined. The relatively low level expression of CD1b in normal-appearing tissues, chronic-silent lesions and in the OND controls supports the conclusion that the expression of CD1b in active MS lesions is significantly upregulated and could contribute to lesion development.
9045066##1996-7-1##[Disorders of mental functioning in Wilson's disease].##In this article we have presented a review of the literature on psychopathology in Wilson's disease. The descriptions of disorders connected with this disease are sometimes ambiguous, but they cover changes in behaviour and personality, affective disorders and deterioration of cognitive functioning. Psychopathological picture is being correlated with damages in certain cerebral sites and structures. It requires further study to learn about the role of the basal ganglia in higher mental functioning. Wilson's disease is one of the disorders to be analysed in order to broaden our knowledge about behavioral changes caused by damages in the basal ganglia.
18591031##1996-1-3##Outcome of liver transplantation in Wilson's disease: A demonstrative case.##A Wilson's disease (WD) patient developed a progressive liver cirrhosis and a disabling 'rubral' tremor, despite decoppering therapy, and subsequently underwent orthotopic liver transplantation (OLT). This case illustrates the outcome of OLT in WD, by demonstrating: (a) correction of the metabolic syndrome without further deposition of copper in the transplanted liver, (b) improvement of the neurological condition, (c) concomitant mobilization of copper deposits, as suggested by the fading of the Kayser-Fleischer corneal rings, (d) fading of brain MRI signal abnormalities on T2 weighted images. This case illustrates that OLT can be considered in WD, but only with caution because of the significant morbidity of the procedure.
8759497##1996-7-1##Treatment of Wilson's disease: the historical background.##
8964439##1996-6-1##Diagnosis of Wilson's disease using DNA linkage analysis.##
8782057##1996-6-1##High frequency of two mutations in codon 778 in exon 8 of the ATP7B gene in Taiwanese families with Wilson disease.##The gene for Wilson disease (WD) has been cloned as a P type copper transporter gene (ATP7B). To elucidate the possible genetic mechanism for the diversity of clinical manifestations, we characterised 22 Taiwanese families with WD by microsatellite haplotyping of close DNA markers D13S314-D13S301-D13S316. We also screened for mutations of codon 778 in the transmembrane region. There were at least 15 haplotypes within eight broad subgroups observed among 44 WD chromosomes. Among the 22 unrelated patients, we found that six patients (27%) carried a codon 778 mutation. Nucleotide sequence analysis showed there were two different mutations: the previously reported Arg778Leu mutation in four patients and Arg778Gln, a new mutation, in two patients. The two different mutations of the same codon occurred in two distinct microsatellite haplotypes.
8658851##1996-6-1##Changes in neuroimaging in Wilson's disease following orthotopic liver transplantation.##
8623723##1996-5-1##Evaluating asymptomatic patients with abnormal liver function test results.##Asymptomatic patients with abnormal results on liver function test pose a diagnostic challenge. In general, determinations of routinely ordered tests of liver function are neither sensitive nor specific for liver disease. Fatty liver, alcohol-related liver damage and chronic viral hepatitis are the most common causes of abnormal liver function test results in asymptomatic patients. Causes of asymptomatic liver disease include hemochromatosis, Wilson's disease, drug toxicity, chronic autoimmune hepatitis, biliary cirrhosis, sclerosing cholangitis, alpha1-antitrypsin deficiency and sarcoidosis. The most efficient screening tests for liver damage are alanine transaminase, alkaline phosphatase and bilirubin. Repeat testing when results are abnormal, and use of ancillary tests, such as creatine phosphokinase or gamma-glutamyl-transferase, may confirm liver damage. Imaging studies help exclude biliary obstruction or neoplasm. Treatable illnesses should be ruled out. Three to six months of observation for progressive symptoms and liver dysfunction may follow. After the period of observation, further laboratory tests, a diagnostic liver biopsy and/or referral to gastroenterologist may be needed.
8615373##1996-5-1##Limits of metabolic tolerance to copper and biological basis for present recommendations and regulations.##Acute copper toxicity is infrequent in humans. The evidence for chronic toxicity is derived principally from patients with Wilson disease and cases of infantile cirrhosis that were related to excessive copper intakes. The evaluation of the safety of a nutrient requires toxicologic studies to determine the limits of safe exposure. The acceptable daily intake (ADI) is calculated by determining the highest no-observed-adverse-effect level (NOAEL). When it is not possible to identify the NOAEL, the lowest observed-adverse-effect level (LOAEL) may be used. For the calculation of human ADI, the NOAEL or LOAEL obtained is divided by an arbitrary safety factor to provide an adequate margin of security. Drinking water standards have been adopted by the United States, the European Community, the World Health Organization, and other countries. The upper limits of copper concentration in water are based on organoleptic considerations and on debatable toxicity information. Given the importance of copper as an essential mineral for human health, it is conceivable that this and other essential minerals with health significance should be approached differently from nonessential minerals.
8615372##1996-5-1##Wilson disease and idiopathic copper toxicosis.##The pathogenic agent of both Wilson disease (WD) and non-Indian childhood cirrhosis (which we term idiopathic copper toxicosis, or ICT) is copper accumulating to excess in the liver. Inheritance of a pair of alleles of an autosomal recessive gene on chromosome 13 is necessary and sufficient to cause such copper accumulation in WD; reducing the dietary intake of copper cannot prevent the development of WD. In contrast, the lethal accumulations of copper in children with ICT have been attributed primarily to an increased dietary intake of copper. However, 64 124 child-year exposures of children under the age of 6 y to drinking water containing a copper concentration of approximately 125.9 micromol/L (8 mg/L) produced no deaths from any form of liver disease. Moreover, the ICT of seven infants was attributed primarily to drinking water containing &lt; 110.2 micromol Cu/L (7 mg/L) despite evidence of the presence of a genetic defect in three of the patients, one of whom was exclusively breast-fed. These data suggest that ICT cannot be caused solely by increased dietary intake of copper and occurs only in children with an identified genetic defect.
8615371##1996-5-1##Genetic and molecular basis for copper toxicity.##Recent studies resulted in the cloning of the genes responsible for Menkes syndrome and Wilson disease. Despite the distinct clinical phenotypes of these disorders, each gene encodes a highly homologous member of the cation-transport P-type ATPase family. The remarkable evolutionary conservation of these proteins in bacteria, yeast, plants, and mammals reveals a fundamental protein structure essential for copper export in all life forms. Characterization of a molecular defect in the rat homologue of the Wilson ATPase in the Long-Evans Cinnamon rat identifies an animal model of Wilson disease and will permit experimental analysis of the precise role of this ATPase in copper transport, the effects of specific inherited mutations on transport function, and the cellular and molecular mechanisms of tissue injury resulting from copper accumulation. Finally, recent molecular genetic analysis of a distinct group of patients with low serum ceruloplasmin and basal ganglia symptoms identified a series of mutations in the ceruloplasmin gene. The presence of these mutations in conjunction with the clinical and pathologic findings clarifies the essential biological role of this abundant copper protein in metal metabolism and identifies aceruloplasminemia as a novel autosomal recessive disorder of iron metabolism.
8615370##1996-5-1##Present interpretation of the role of copper in Indian childhood cirrhosis.##A common killer disease of the past, Indian childhood cirrhosis (ICC), which became preventable and treatable in the early 1990s, is now rare. ICC must be clearly distinguished in Indian children from other chronic liver disorders including Wilson disease. Grossly increased hepatic, urinary, and serum copper concentrations are characteristic of ICC. These increased concentrations are easily demonstrated histologically with orcein-rhodanine staining. Environmental ingestion of copper appears to be the most plausible explanation for ICC, as shown by feeding histories, the prevention of ICC is siblings and in the Pune district by a change in feeding vessels, and the dramatic reduction in incidence of ICC throughout India. The nature and role of a second factor in the causation of ICC remains unclear, although an inherited defect in copper metabolism is strongly suspected. ICC, however, does not appear to be a straightforward early onset of Wilson disease because ceruloplasmin is consistently normal and clinical and histologic recovery is maintained in the long term despite withdrawal of D-penicillamine therapy. Descriptions of an ICC-like illness in the West suggest that different mechanisms (environmental, genetic, or both) can lead to the same end-stage liver disease: copper-associated childhood cirrhosis. ICC probably represents a specific form of copper-associated childhood cirrhosis that requires high environmental copper ingestion for its full expression.
8615367##1996-5-1##Copper biochemistry and molecular biology.##In this review, our basic and most recent understanding of copper biochemistry and molecular biology for mammals (including humans) is described. Information is provided on the nutritional biochemistry of copper, including food sources, intestinal absorption, transport, tissue distribution, and excretion, along with descriptions of copper binding proteins and other factors involved and their roles in these processes. The metabolism of copper and its importance for the functions of a roster of vital enzymes is detailed. Its potential toxicology is also addressed. Alterations in copper metabolism associated with genetic and nongenetic diseases are summarized, including potential connections to inflammation, cancer, atherosclerosis, and anemia, and the effects of genetic copper deficiency (Menkes syndrome) and copper overload (Wilson disease). Understanding these diseases suggests new ways of viewing the normal functions of copper and provides new insights into the details of copper transport and distribution in mammals.
8645167##1996-5-1##New insights into the pathogenesis of copper toxicosis in Wilson's disease: evidence for copper incorporation and defective canalicular transport of caeruloplasmin.##Previous studies have suggested that copper is incompletely incorporated into caeruloplasmin, the major plasma form of copper-transporting protein, in the genetic copper toxic condition, Wilson's disease. In this paper we have investigated the role of copper and caeruloplasmin in the abnormal biliary copper transport and characterizes Wilson's disease. Using SDS/PAGE and Western blotting, we have demonstrated the presence of holocaeruloplasmin in liver samples from patients with Wilson's disease (abnormal biliary copper excretion) and in control patients (normal biliary copper excretion). The presence of holocaeruloplasmin was also confirmed by measurement of caeruloplasmin oxidase activity using staining with o'Dianisidine. In contrast with the findings in liver tissue, holocaeruloplasmin was absent from bile from patients with Wilson's disease, but as expected it was present in the bile from control subjects. We have also identified and partially characterized a 189-200 kDa protein from purified human biliary canalicular membranes which binds copper and possesses caeruloplasmin-like activity when probed with a specific human anti-caeruloplasmin antibody. In conclusion, we have demonstrated that copper incorporation in caeruloplasmin is normal in patients with Wilson's disease contrary to previous reports. Secondly, we have shown that the defect in Wilson's disease appears to lie in the biliary canalicular excretion of holocaeruloplasmin resulting in its retention within the hepatocyte causing copper toxicosis. Finally we have identified and partially characterized a caeruloplasmin-binding protein from biliary canalicular membranes which may provide a link to the gene defect in Wilson's disease.
8861522##1996-5-1##Treatment of ascites: old and new remedies.##Ascites is a common complication of chronic liver disease. Treatment of the underlying liver disease with modalities such as abstinence from alcohol in Laennec's cirrhosis, phlebotomy in hemochromatosis, copper removal in Wilson's disease, and steroids in autoimmune liver disease, can improve survival in many patients. In addition, therapy of ascites alleviates the symptoms and improves the quality of life of the patients, and probably decreases the incidence of life-threatening conditions including spontaneous bacterial peritonitis and hepatorenal syndrome. The mean survival rate at 2 years is approximately 50%. Precipitating factors such as gastrointestinal bleeding, nonsteroidal anti-inflammatory drugs and infections, should be identified, since most of them can be corrected. Most cirrhotics with ascites can be managed with a 'step-by-step' approach, including dietary salt restrictions, aldosterone antagonists, and loop diuretics. When tense or refractory ascites is present, large-volume paracentesis is safe and effective. Peritoneovenous shunting (i.e. Denver, LeVeen) is less frequently used because of perioperative morbidity and mortality, and thrombotic complications with occlusion of the stent. Reinfusion of concentrated ascites is of potential benefit and has been used in Europe. Transjugular intrahepatic portosystemic shunt (TIPS) is an alternative procedure performed by interventional radiologists that allows decompression of portal hypertension. In many cases, ascites is improved after TIPS, but long-term randomized trials for tense or refractory ascites comparing TIPS with standard therapy are not conclusive. Liver transplantation is the ultimate step for the treatment of ascites, providing the cure for the underlying liver disease as well. Transplantation is indicated when quality of life of the patient is impaired due to recurrent episodes of ascites, or in the presence of spontaneous bacterial peritonitis and hepatorenal syndrome.
8752527##1996-5-1##[Aging of brain and the maintenance of the function].##Some diseases develop dementia, but they may be dementia-like-situation, such as depression and drugs induced one. There are many causes as an etiology of dementia. Among them a lots of diseases are treatable dementia, like chronic subdural hematoma, normal pressure hydrocephalus, brain abscess, syphilis, herpetic encephalitis, Wilson's disease, hypothyroidism, parathyroid disease, vitamin B12 deficiency, pellagra etc. In examination of patients with dementia, exact history taking, physical examination and laboratory examination should be done carefully. In the patients with Alzheimer's dementia and cerebrovascular disease's dementia, as many risk factors are known, we must try to treat and exclude each risk factor and protect the dementia. Inactivity of physical and mental function is reported to induce the dementia, so activation of them could prevent the development and the progression of dementia. In future the methods of the prevention of apoptosis and cell death would be found in order to prevent the dementia. Free radical scavenger, nerve trophic factor, cytokine, antagonist of glutamate etc. will have the possibility to become the medicine for the dementia. The nerve transplantation, nerve transmitter, nerve peptide etc. might serve as the allopathic treatment for the dementia.
8743927##1996-5-1##Paediatric liver transplantation: a 10 year experience in Taiwan.##Between March 1984 and August 1994, 13 orthotopic liver transplantations were performed in 13 patients &lt; or = 25 years of age. The indications included Wilson's disease (n = 7), biliary atresia (n = 4), choledochal cyst (n = 1) and hepatitis C cirrhosis (n = 1). Technical variants included full-size (n = 11), reduced-size (n = 1) and living-related (n = 1) liver transplantation. These recent technical innovations have offered an expanded donor pool for earlier transplantation, shorter waiting times and excellent quality grafts. Surgical complications occurred in six patients; all required additional surgery. Biliary complications were encountered more commonly in our earlier patients. Our actuarial patient and graft survival rate is 92% at 2 years. The long-term follow-up of our liver-transplanted Wilson's disease patients provides confirmatory evidence that orthotopic liver transplantation cures the underlying metabolic defect with complete normalization of biochemical abnormalities of copper metabolism, reversal of neurological impairments and the disappearance of Kayser-Fleischer corneal rings. The high rate of patient survival and excellent rehabilitation indicate that with prudent clinical judgement, liver transplantation can be achieved with an acceptable rate of morbidity, mortality and cost in a setting where manpower and donor organs are very limited.
8926957##1996-5-1##[Chronic idiopathic hypertransaminasemia].##The elevation of aminotransferase serum levels is frequently encountered in pediatric practice. We have retrospectively evaluated the clinical patterns of 108 patients with chronic, so called &quot;idiopathic&quot;, alterations of aminotransferases, by sending a questionnaire to 11 Italian Pediatric Centers. The average period of follow-up was 22 months. Patients, whose ages ranged through all pediatric ages, were mostly asymptomatic and with a rather insignificant physical examination. The average rise of aminotransferases value was generally limited within 2 times the upper normal level and the highest value, during the period of follow-up, never exceeded 5 times the upper normal level. Other liver function tests did not result generally altered significant. Just 25,9% of the patients normalized aminotransferases serum level during the follow-up period. All maintained good physical status with no clinical signs of liver disease. A muscular cause of hyper-transaminasemia was excluded in all the cases. Possible infective causes (HBV and HCV) autoimmune hepatitis, Wilson disease, alfa1 antitripsine deficiency and hyperammoniemia were excluded. Ultrasound investigation did not seem to be a sensitive investigation, resulting negative in 54/82. Histologic liver examination was more informative. This evaluation, performed in 46/108 patients, showed infarct metabolic alterations (steatosis, nucleus glucogenic degeneration, cytoplasmatic clarification) in 65% of cases and inflammatory findings in only 13% of cases. In conclusion, our results suggest the opportunity to enclose liver histologic study in the diagnostic approach of children with hepatic idiopathic chronic hypertransaminasemia. This approach may address the clinician, in a more aimed way, towards further investigations.
8618573##1996-5-1##Neuromuscular transmission and acetylcholine receptor antibodies in penicillamine-treated Wilson's disease patients.##
8628510##1996-5-1##Misdiagnosis revealed by genetic linkage analysis in a family with Wilson disease.##
8644107##1996-4-15##Accumulation of orally given cadmium in Long-Evans Cinnamon (LEC) rats with an inherently abnormal copper metabolism.##An inherent defect of biliary Cu excretion and subsequent Cu deposition in the liver have been found in Long-Evans Cinnamon (LEC) rats, which are promising models of Wilson disease. LEC and Fischer rats were given water containing Cd (CdCl2) at a level of 5 ppm for 30 days. Regardless of drinking Cd water, LEC rats showed a very high concentration of Cu (200 to 250 microgram/g) and Cu-metallothionein (Cu-MT) (18 mg/g) in the liver. There was no difference of Cd accumulation in the liver between the two strains exposed to Cd (2.6 and 2.7 microgram/g in the Fischer and LEC groups, respectively). However, the renal Cd concentration was slightly but significantly higher in LEC rats (3.5 microgram/g) than in Fischer rats (2.0 microgram/g). The ratio of renal Cd contents to the sum of renal and hepatic Cd contents was significantly higher in LEC rats (0.25) than in Fischer rats (0.15). The serum Cd concentration in Cd-treated LEC rats increased threefold compared to Cd-treated Fischer rats. It seems likely that Cd from the liver is transported into the kidney in the form of Cd, Cu-MT. There was no difference in uptake of Cd in the hepatic MT fraction between the two strains. Although biliary Cu excretion in LEC rats was significantly lower than that in Fischer rats, reduced excretion of Cd into bile was not found in LEC rats. The gross amounts of Cu and Cu-MT influenced the accumulation of Cd in the kidney rather than in the liver when Cd was given orally at a low level to LEC rats. Our results suggest tht Cu and Cd do not share the same sites of hepatobiliary excretion in rats, although the main route of their excretion is via bile.
8732640##1996-4-1##Menkes disease: recent advances and new insights into copper metabolism.##Copper is a trace element necessary for the normal function of several important enzymes but copper homeostasis is still poorly understood. In recent years remarkable progress has been made in this field following the isolation of the gene defective in Menkes disease. Menkes disease and occipital horn syndrome are X-linked recessive disorders, demonstrating the vital importance of copper, which is also highly toxic in excessive amounts. Its destructive effects are reflected in the autosomal recessive Wilson's disease. Progressive neurodegeneration and connective tissue disturbances are the main manifestations of Menkes disease. Although many patients present a severe clinical course, variable forms can be distinguished, and the occipital horn syndrome has been suggested to be a mild allelic form. The Menkes locus is mapped to Xq13.3 and the gene defective in Menkes disease has been isolated by positional cloning. The gene is predicted to encode an energy-dependent copper-binding protein, the first intracellular copper transporter described in eukaryotes. Isolation of the gene and subsequent characterization of the exon-intron organization now enables the establishment of DNA-based diagnostic methods. Furthermore, identification of the Menkes disease gene led to other important findings, such as isolation of its mouse homologue, confirming the allelic relationship between Menkes disease and occipital horn syndrome, and isolation of the defective genes in Wilson's disease and its rat homologue.
8740136##1996-4-1##Extrapyramidal disorder secondary to cytomegalovirus infection and toxoplasmosis after liver transplantation.##A boy underwent liver transplantation for postnecrotic cirrhosis secondary to Wilson's disease. The patient had no neurological clinical manifestations prior to the transplantation. The patient developed dysarthria, dysphagia, spasticity, rigidity, and intention and resting tremor of all extremities. Cranial computerized tomography revealed hypodensity of the thalamus, basal ganglia and external capsule. Anti-cytomegalovirus IgM became positive. At autopsy, there were severe pathological changes at the thalamus and basal ganglia.
8666330##1996-4-1##Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride.##Trientine dihydrochloride (trientine) is an alternative medicinal copper chelating agent for patients with Wilson's disease of penicillamine intolerance. We examined the effects of trientine on the spontaneous development of hepatitis and hepatic tumors, by its short-term and long-term administration to Long-Evans cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models of Wilson's disease. Male rats were given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in the long-term experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high levels of plasma transaminases (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]), and on pathological examination, hepatocyte destruction was observed. Histological findings revealed that short-term administration of trientine inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels of treated animals were only slightly higher than those of normal LEA (Long-Evans with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the liver were decreased by a maximum of 50 percent. In the long-term administration of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7 +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis in LEC rats was completely prevented by long-term administration of the agent. The copper level in the liver of treated rats was reduced by 33 percent at 87 weeks of age. Development of HCC in LEC rats might be partly, but not totally, because of copper accumulation. No effects on the levels of copper, iron, or zinc in the liver of LEA rats was detected, and no adverse effects were detected in either LEC or LEA rats after both short- and long-term administration of trientine in drinking water.
8734560##1996-4-1##Neuropsychological aspects of Wilson's disease.##A consecutive series of 34 patients with confirmed diagnoses of Wilson's disease (WD) was administered complete neuropsychological examinations upon admission to a university medical center for routine laboratory tests. Twenty-five patients with neurological and/or hepatic symptoms (symptomatics) revealed frequent and severe motor deficits and infrequent and mild cognitive deficits in contrast to nine patients with genetic findings of Wilson's disease but no symptomatic findings (asymptomatics). Somato-sensory tests were normal in all. One of the most intriguing findings was the absence of a significant correlation between the level of copper toxicity and the degree, nature, and frequency of associated neurological deficits in both symptomatic and asymptomatic patients. Fifty per cent of the present sample received psychiatric treatment, including hospitalization, for schizophrenia, depression, anxiety, and related disorders prior to confirmed diagnosis of WD. The present findings provide additional evidence that patients with the initial presenting psychological symptoms may be easily misdiagnosed and mistreated if the possibilities of Wilson's disease are not ruled out first.
8780087##1996-4-1##Neurologic presentation of Wilson disease without Kayser-Fleischer rings.##A 41-year-old woman presented with a 6-month history of gradually progressive postural instability and dysarthria associated with cerebellar and extrapyramidal signs. No Kayser-Fleischer (K-F) rings were observed on biomicroscopic examination of each cornea. The only evidence of hepatic dysfunction was a modest elevation of alanine-aminotransferase. The diagnosis of Wilson disease (WD) was based on low serum ceruloplasmin, abnormal serum copper and urinary copper excretion, and DNA marker segregation analysis. WD should be considered in the presence of characteristic neurologic and laboratory features, regardless of age at onset, evidence of hepatic dysfunction, or absence of K-F rings.
8694740##1996-4-1##[A clinicopathological study of primary liver cancer associated with alcoholic liver injury].##We described a clinicopathological study of primary hepatoma associated with alcoholic liver diseases without viral liver diseases. In 150 patients with primary hepatoma, 6 patients (4%) have hepatoma associated with pure alcoholic liver disease, although 143 hepatoma were associated with chronic viral liver diseases and one was with primary biliary cirrhosis. All patients were male. The diagnosis of hepatoma was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Three cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in 3 cases and liver cirrhosis was in 3 cases. Chronic infections of hepatitis B and C viruses were ruled out by assaying serum virus markers. Autoimmune hepatitis and primary biliary cirrhosis were neglected by serum autoantibody. Hemochromatosis and Wilson's disease were also excluded. Hepatocellular carcinoma was diagnosed histologically in all the cases. Serum alpha-fetoprotein and PIVKA-II were positive in patients with advanced hepatocellular carcinoma. In cases with small hepatoma, the tumor was resected surgically in two cases and percutaneous ethanol injection against hepatoma was performed in one case. In these cases with small hepatoma, the patients were alive without tumor recurrence during observation period. In advanced hepatoma, transcatheter arterial infusion of anticancer agent was performed in two cases and no therapy was performed due to poor general condition in one case. One case was alive with recurrent hepatoma for 27 months, during which a therapy was repeated five times. Other 2 cases were died. The clinicopathological features of hepatoma associated with alcoholic liver disease were essentially same as those associated with chronic viral infection, although the incidence of hepatoma in alcoholic liver disease was lower than in viral liver disease. The mechanism of hepatocarcinogenesis in alcoholic liver disease was unclear and, therefore, further study of molecular biology and biochemistry was necessary.
8927444##1996-4-1##[The role of the pathologist in the diagnosis and monitoring of Wilson's disease].##Wilson's disease (WD) is an inherited disorder of copper metabolism, characterized by copper accumulation in different organs. The clinical presentation of WD is variable: juvenile cirrhosis, with or without neurological symptoms, fulminant hepatitis, acute intravascular hemolysis or late onset with neurological or psychiatric symptoms. The histological picture, the histochemical stains and the ultrastructural findings of the liver are variable in WD. The recent cloning of the WD gene and the report of several mutations (at least 25) of the WD gene suggest the hypothesis that the clinical and pathological variability of this disease is related to a genetic polymorphism. These data may explain why the diagnosis of WD is often extremely difficult for the pathologist, since histochemical stains for copper may be highly variable or negative, despite increased levels of tissue copper concentrations. The most important pathological data are: 1) the evaluation of liver architecture, relevant in the staging of liver disease in three stages; 2) histochemistry for copper, which is variable and needs the use of multiple methods: Timm's method is probably the most useful one, since it shows copper deposits even in the first stage of WD, when liver changes are often reversible; 3) the determination of copper concentration may be crucial in WD diagnosis; copper levels exceeding 250 ug/g of dry tissue are considered diagnostic for the disease; 4) transmission electron microscopy shows, mainly in youngsters, mitochondrial changes considered typical of WD; the ultrastructural picture may be diagnostic for WD in cases with not specific histology and negative histochemical stains; 5) scanning electron microscopy after osmic maceration may be a new useful tool in the study of this liver disease: this technique may give both panoramic and high-power enlargements and allows the localization in the acinar zones of the intracellular hepatocytic changes. Finally, only the optimal approach to liver biopsy, obtaining the highest number of histological, histochemical, quantitative and ultrastructural data, may allow the pathologist to an early diagnosis of WD.
8705261##1996-4-1##Preneoplastic conditions of the liver.##Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The majority of patients who develop HCC have underlying cirrhosis, which suggests that cirrhosis itself represents a preneoplastic condition. Nevertheless, whereas patients with cirrhosis of any origin are at increased risk of developing HCC, those with chronic hepatitis B or C infection seem to be at greatest risk. Patients with cirrhosis resulting from chronic alcohol use, hemochromatosis, autoimmune hepatitis, or alpha-1 antitrypsin deficiency have less risk of developing this cancer, and some hepatic diseases, such as primary biliary cirrhosis and Wilson's disease, do not predispose affected persons to an appreciable risk of developing HCC. Certain histological features, such as liver cell dysplasia and macroregenerative nodules, may represent preneoplastic alterations of hepatocytes, but these changes do not seem to be a necessary step in the evolution of liver cancer. The pathogenesis of HCC is unclear, but seems to involve several steps. Hepatitis B virus infection may result in the malignant transformation of hepatocytes by some directly oncogenic mechanism, whereas other necroinflammatory conditions probably predispose to the development of HCC through the introduction of genetic alterations coupled with a reduction of genetic repair functions. Screening patients at risk for the development of HCC using alpha fetoprotein measurements and ultrasonography is widely practiced despite inconclusive evidence of efficacy. If screening is performed, the program used should be tailored to the perceived risk for a particular patient.
8758271##1996-4-1##[Liver transplantation report of 23 cases].##
8622393##1996-3-30##Excess zinc associated with severe progressive cholestasis in Cree and Ojibwa-Cree children.##
8737509##1996-3-1##[Hemochromatosis, Wilson's disease. Some diseases which are not often considered].##
8705963##1996-3-1##Wilson's disease and mental disturbances.##
8681776##1996-3-1##[Wilson's disease].##
8641677##1996-3-1##[Disposition behavior and absorption mechanism of trientine, an orphan drug for Wilson's disease].##The disposition behavior of trientine, a selective copper-chelating drug for Wilson's disease, and its metabolites in normal patients with Wilson's disease and rats were studied. A high concentration of metabolites appeared in blood samples of patients and rats in the early stage after administration of trientine. Furthermore, large amount of trientine metabolites were excreted into the urine of patients. These results suggest that trientine is remarkably subjected to a first-pass effect. The drug concentration area under the curve (AUC) of the unchanged form and the metabolites of trientine in patients was not dependent on the administered dosage. It seems that the absorption process is an important factor for the disposition behavior of trientine, we have also investigated the uptake characteristics of trientine by rat intestinal brush-border membrane vesicles. The uptake characteristics of trientine were similar to the physiological polyamines, spermine and spermidine. The uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Moreover, spermine competitively inhibited the uptake of trientine with a Ki value of 18.6 muM. This value is very close to the Km value for spermine (30.4 muM). These data suggested that the uptake mechanism of trientine in rat small intestinal brush-border membrane vesicles was almost identical to that of spermine and spermidine, and that the physiological polyamines seem to have the ability to inhibit the absorption of trientine from the gastrointestinal tract.
8801280##1996-3-1##Acute viral hepatitis types E, A, and B singly and in combination in acute liver failure in children in north India.##The aetiological agents responsible for, and the outcome of, acute liver failure were investigated prospectively in 44 children (29 males, 15 females) attending a tertiary health care facility in India. The children were between the ages of 2 months and 13 years. Studies for viral infections and other etiologies could be carried out in 40 patients. Specific aetiological labels were possible in 35 (87.5%) patients. Thirty (75%) had evidence of acute viral hepatitis. Acute hepatitis E virus (HEV) infection was found in a total of 18 children, with hepatitis A (HAV) in 16, hepatitis B in 5, and C in 1. Seven had isolated infection with hepatitis E, five with A, and four with B. Nine had both E and A infection. Superinfection of HEV was observed in a child with Indian childhood cirrhosis (ICC). Acute HEV infection was confirmed by immunoblot assay in all the patients and in eight of these, HEV-RNA was also detected in the serum. HAV was involved in 37.5% of cases with isolated infection in 10% (4 of 40). The aetiological factors associated with acute liver failure, apart from HAV and HEV, were other hepatotropic viruses (22.5%), Wilson's disease (5%), ICC (5%), and hepatotoxic drugs (7.5%). In five patients, no serological evidence of acute viral hepatitis could be found, neither did the metabolic screen yield any result. It was observed that enterically transmitted hepatitis viruses (HAV and HEV) were associated with 60% of acute hepatic failure in children. Mixed infection of HAV and HEV formed the single largest aetiological subgroup. In developing countries, where hepatitis A and E infections are endemic, severe complications can arise in the case of mixed infection. This may contribute to most of the mortality from acute liver failure during childhood.
8936358##1996-3-1##Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate.##The results of treatment with D-penicillamine (D-P) or zinc sulphate (Zn) in 67 newly diagnosed cases of Wilson's disease have been compared. All patients (7 with hepatic, 1 with psychiatric and 59 with neurological or preclinical forms) were fully compliant. During 12 years of observation, 34 patients received d-P and 33 Zn as the primary treatment. Fifteen patients (44%) discontinued D-P, in 10 cases owing to side effects. Four (12%) patients discontinued Zn, in 2 cases because of side-effects. One patient who received Zn deteriorated during the first few months after the initiation of therapy. The effectiveness of long-term treatment with D-P and Zn was similar in those patients who were able to continue the initial therapy. Zn was tolerated better than D-P; we suggest, therefore, that it may be recommended as an initial therapy for patients in the preclinical stage of Wilson's disease or with neurological presentation of the disease. More observation is needed for patients with the hepatic and psychiatric forms of the disease.
8815159##1996-3-1##Neurological impairment and recovery in Wilson's disease: evidence from PET and MRI.##We studied the relationship of regional cerebral glucose consumption (rCMRGlc) and striatal dopamine D2 receptor binding as assessed with positron emission tomography (PET) with the structural abnormalities of the brain in magnetic resonance images (MR), and the degree of neurological impairment in 18 patients with Wilson's disease (WD). The rCMRGlc was determined in the basal ganglia, the thalamus, the cerebral cortex, and the cerebellar hemispheres. The severity of neurological signs, defined by semiquantitative motor impairment scores, correlated highly (r = -0.80) with the reduction of striatal rCMRGlc. Clinical scores, striatal rCMRGlc, and the degree of MRI abnormalities showed no correlation with different indices of dopamine D2 receptor binding. Sequential PET measurements in three patients during treatment with chelating agents revealed a moderate increase of striatal rCMRGlc (in two patients) and a moderate to marked increase of striatal D2 receptor binding (in three patients) in association with clinical improvement. Our data suggest that the rCMRGlc represents a sensitive and objective measure for assessing and monitoring striatal and extrastriatal involvement in WD. The lack of correlation between the dopamine D2 receptor binding and striatal rCMRGlc and structural abnormalities may be explained by the wide spectrum of clinical manifestations and different responses to treatment in WD patients.
8904208##1996-3-1##[Diseases caused by disorders of membrane transport: an overview].##Transport proteins such as channels and transporters play important roles in the maintenance of intracellular homeostasis. Genes for transport proteins have been cloned one after the other in recent years, and mutations in these transport protein genes have been identified in the pathogenesis of a number of hereditary diseases. These diseases include Liddle's syndrome, long QT syndrome, hyperkalemic periodic paralysis, cystic fibrosis, myotonia congenita, nephrogenic diabetes inspidus, glucose/galactose malabsorption, cystinuria, and Wilson's disease. Gene mutations in several receptors, including vasopressin V2 receptor, dihydropyridine receptor, and Ca2+ -sensing receptor, also cause disorders of membrane transport, leading to diseases. Further advances in basic science are expected to provide us with a detailed understanding of the abnormality in the 3rd/4th structure of mutated transport proteins.
8714034##1996-2-25##[Diagnostic problems of Wilson disease].##A family (three siblings) of Wilson's-disease is described. The authors review the pathogenesis, diagnostics, pathology and treatment of Wilson's-disease. The diagnostic difficulties are emphasised. The variety of liver lesions are demonstrated in the different grades of the disease. The importance of the early diagnosis is stressed.
8741147##1996-2-1##Wilson's disease: resolution of MRI lesions following long-term oral zinc therapy.##A 28-year-old man with Wilson's disease developed neurological deterioration after a low-dose of d-penicillamine treatment for 2 weeks. He showed an akinetic rigid syndrome with generalized dystonia. Brain magnetic resonance images (MRI) on T2 and proton weighted images showed an increased signal intensity over the thalamus, basal ganglia and brainstem, especially the midbrain and pons. After treatment had been changed to zinc sulphate, the akinetic-rigid syndrome and dystonia were improved slowly in the following 4 years. Serial MRI studies showed a gradual resolution of the lesions. His current neurological status was almost normal except for dysarthria and mild intention tremor.
8742314##1996-2-1##Subchronic toxicity of triethylenetetramine dihydrochloride in B6C3F1 mice and F344 rats.##Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04), a chelating agent used to treat Wilson's disease patients who are intolerant of the drug of choice, was tested for subchronic toxicity in B6C3F1 mice and F344 rats. Mice and rats received trien-2HCl in the drinking water at concentrations of 0, 120, 600, or 3000 ppm for up to 92 days. Twenty mice and 18 rats of each sex were assigned to each dose group fed either a cereal-based (NIH-31) or a purified (AIN-76A) diet, both containing nutritionally adequate levels of copper. An additional control group of rats and mice received a Cu-deficient AIN-76A diet. This low copper diet resulted in Cu-deficiency symptoms, such as anemia, liver periportal cytomegaly, pancreatic atrophy and multifocal necrosis, spleen hematopoietic cell proliferation, and increased heart weight, together with undetectable levels of plasma copper in rats but not in mice. Trien-2HCl lowered plasma copper levels some-what (at 600 and 3000 ppm) in rats fed the AIN-76A diet, but did not induce the usual signs of copper deficiency. Trien-2HCl caused an increased frequency of uterine dilatation at 3000 ppm in rats fed AIN-76A diet that was not noted in females fed the Cu-deficient diet. Trien-2HCl toxicity occurred only in mice in the highest dose group fed an AIN-76A diet. Increased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration were seen in both sexes, and hematopoietic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasmic vacuolization. There were no signs of copper deficiency in mice exposed to trien-2HCl. The only effect of trien-2HCl in animals fed the NIH-31 diet was a reduced liver copper level in both rat sexes, noted at 3000 ppm.
8636833##1996-2-1##Successful medical treatment of severely decompensated Wilson disease.##Delayed response to medical treatment sometimes leads to unnecessary liver transplantation in patients with severely decompensated Wilson disease. We report the course of five patients (mean age 13.4 years, range 11 to 15 years) with severely decompensated Wilson disease who were successfully treated medically. Prothrombin time improved after a minimum of 1 month and returned to normal within 3 months to 1 year or more.
8676842##1996-2-1##Diagnostic testing in movement disorders.##The diagnosis of movement disorders is essentially clinical. Work-up depends on patient age, part of the body affected, drug response, and presence of other systemic or neurologic symptoms and signs. Typical Parkinson's disease, essential tremor, and tics need only minimal work-up if any. Brain magnetic resonance imaging/computed tomography, positron emission tomography and single photon emission computed tomography, and DNA studies are promising diagnostic tools. Exclusion of Wilson's disease and neuroacanthocytosis is emphasized in children and young adults with movement disorders.
8596684##1996-2-1##Pediatric gastroenterology. Update on metabolic liver disease.##Wilson's disease, genetic and neonatal hemochromatosis, protoporphyria, tyrosinemia, and alpha1-antitrypsin deficiency are updated. Cost effectiveness of screening is discussed. Current therapies are evaluated, including the role of transplantation. The molecular biologic technique PCR is covered. Gene therapy is introduced.
8596862##1996-2-1##Wilson disease: findings at MR imaging and CT of the brain with clinical correlation.##
8723326##1996-2-1##Wilson disease: genetic basis of copper toxicity and natural history.##The discovery that the gene for Wilson disease encodes a copper-transporting ATPase has greatly improved our understanding of the pathophysiology of this disorder and of copper metabolism in humans. The abundance of disease-specific mutations and their location at multiple sites across the genome have limited molecular genetic diagnosis to kindred of known patients, and confirm the necessity for de novo screening by well-proven clinical and biochemical means. It is uncertain whether the variety of specific mutations will account for the wide range of presenting clinical signs and symptoms of Wilson disease, and environmental and extragenic factors are likely to be important contributing factors. Chelation therapy with penicillamine and trientine remain effective treatment for most symptomatic hepatic and neurologic Wilson disease. Zinc salts may be used for some asymptomatic patients, and OLT for fulminant hepatitis and patients for whom pharmacotherapy is ineffective. The chelating agent tetrathiomolybdate is under investigation for the treatment of neurologic Wilson disease. Gene therapy is the new horizon for treatment of Wilson disease. However, the ability to treat this disorder effectively by this means awaits further characterization of the gene product and more efficient methods for gene delivery to all hepatocytes in the liver.
8723319##1996-2-1##Metal-induced hepatotoxicity.##Figure 3 summarizes several proposed mechanisms of iron- or copper-induced hepatotoxicity. It has long been suspected that free radicals may play a role in iron- and copper-induced cell toxicity because of the powerful prooxidant action of iron and copper salts in vitro. In the presence of available cellular reductants, iron or copper in low molecular weight forms may play a catalytic role in the initiation of free radical reactions. The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates, resulting in wide-ranging impairment in cellular function and integrity. However, cells are endowed with cytoprotective mechanisms (antioxidants, scavenging enzymes, repair processes) that act to counteract the effects of free radical production. Thus, the net effect of metal-induced free radicals on cellular function will depend on the balance between radical production and the cytoprotective systems As a result, there may be a rate of free radical production that must be exceeded before cellular injury occurs. Evidence has now accumulated that iron or copper overload in experimental animals can result in oxidative damage to lipids in vivo, once the concentration of the metal exceeds a threshold level. In the liver, this lipid peroxidation is associated with impairment of membrane-dependent functions of mitochondria (oxidative metabolism) and lysosomes (membrane integrity, fluidity, pH). Although these findings do not prove causality, it seems likely that lipid peroxidation is involved, since similar functional defects are produced by metal-induced lipid peroxidation in these organelles in vitro. Both iron and copper overload impair hepatic mitochondrial respiration, primarily through a decrease in cytochrome c oxidase activity. In iron overload, hepatocellular calcium homeostasis may be impaired through damage to mitochondrial and microsomal calcium sequestration. DNA has also been reported to be a target of metal-induced damage in the liver; this may have consequences as regards malignant transformation. The levels of some antioxidants in the liver are decreased in rats with iron or copper overload, which is also suggestive of ongoing oxidative stress. Reduced cellular ATP levels, lysosomal fragility, impaired cellular calcium homeostasis, and damage to DNA may all contribute to hepatocellular injury in iron and copper overload. There are few data addressing the key issue of whether free radical production is increased in patients with iron or copper overload. Patients with hereditary hemochromatosis have elevated plasma levels of TBA-reactants and increased hepatic levels of MDA-protein and HNE-protein adducts, indicative of lipid peroxidation. Mitochondria isolated from the livers of Wilson disease patients have evidence of lipid peroxidation, and some patients with Wilson disease have decreased hepatic and plasma levels of vitamin E. Additional investigation will be required to fully assess oxidant stress and its potential pathophysiologic role in patients with iron or copper overload.
8567646##1996-1-26##Reconstitution of ceruloplasmin by the Cu(I)-glutathione complex. Evidence for a role of Mg2+ and ATP.##The copper-glutathione complex (Cu(I)-GSH) efficiently acted in vitro as the source of Cu(I) in the reconstitution of apoceruloplasmin. Copper was found to reinstate in the various sites in a multistep process, with metal entry into the protein in a first phase, and a second step involving conformational changes of the protein leading to the recovery of the native structural and functional properties. This latter phase was found to be strongly facilitated by Mg2+ or Ca2+ and by ATP. Both Mg2+ and ATP had to be present for optimal reconstitution. These results may shed some light on the mechanisms governing the biosynthesis of ceruloplasmin in vivo. Cu(I)-GSH was the only complex able to reconstitute ceruloplasmin at neutral pH. Glutathione may thus function to shuttle the metal from the membrane copper pump, as the Wilson disease ATPase, and ceruloplasmin in the secretory compartments of the cell. The finding that ceruloplasmin acquires the native conformation after metal entry through a complex pathway triggered by Mg2+ and ATP suggests that they may act as physiological modulators of this process in vivo.
8905098##1996-1-1##Bacterial heavy metal resistance: new surprises.##Bacterial plasmids encode resistance systems for toxic metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, CO2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+, and Zn2+. In addition to understanding of the molecular genetics and environmental roles of these resistances, studies during the last few years have provided surprises and new biochemical mechanisms. Chromosomal determinants of toxic metal resistances are known, and the distinction between plasmid resistances and those from chromosomal genes has blurred, because for some metals (notably mercury and arsenic), the plasmid and chromosomal determinants are basically the same. Other systems, such as copper transport ATPases and metallothionein cation-binding proteins, are only known from chromosomal genes. The largest group of metal resistance systems function by energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The CadA cadmium resistance ATPase of gram-positive bacteria and the CopB copper efflux system of Enterococcus hirae are homologous to P-type ATPases of animals and plants. The CadA ATPase protein has been labeled with 32P from gamma-32P-ATP and drives ATP-dependent Cd2+ uptake by inside-out membrane vesicles. Recently isolated genes defective in the human hereditary diseases of copper metabolism, Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to the bacterial CadA and CopB ATPases than to eukaryote ATPases that pump different cations. The arsenic resistance efflux system transports arsenite, using alternatively either a two-component (ArsA and ArsB) ATPase or a single polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As (V)] to arsenite [As (III)], the substrate of the efflux system. The three-component Czc (Cd2+, Zn2+, and CO2+) chemiosmotic efflux pump of soil microbes consists of inner membrane (CzcA), outer membrane (CzcC), and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell. Finally, the first bacterial metallothionein (which by definition is a small protein that binds metal cations by means of numerous cysteine thiolates) has been characterized in cyanobacteria.
8574093##1996-1-1##The application of laser microprobe mass analysis to the study of biological material.##Laser microprobe mass analysis (LAMMA) is an investigational method which is a powerful tool for the identification and quantitation of various elements present in small volumes of tissue. LAMMA is highly sensitive and capable of rapidly detecting concentrations of 1-3 p.p.m. of most metallic elements, in precisely localized cellular compartments. In order to further assess its value, cultured skin fibroblasts and biopsy tissues from human subjects and experimental animals were probed by LAMMA, and the results were correlated with ultrastructural findings. Biopsy samples were obtained from patients suffering from Gaucher disease, and from patients and animals with pathologic iron or copper metabolism. No significant abnormalities were detected in the cultured fibroblasts from patients with Gaucher disease, in contrast to the iron content of tissue biopsy Gaucher cells, which was markedly increased, apparently as a consequence of erythrophagocytosis. Particularly intense iron-related peaks were found in liver cytosiderosis due to neonatal or genetic haemochromatosis, thalassaemia major and in animal models of iron overload. An additional finding was the presence of aluminium accumulation in siderosomes of different cells. In liver biopsy samples from human Wilson's disease and from rats with an inherited disorder causing copper toxicosis, copper-containing compounds were identified and localized, and their relative concentration was estimated by LAMMA. The present study showed that LAMMA is a valuable technique for the localization and estimation of relative abundance of trace elements in various tissues containing excessive amounts of metals.
8689295##1996-1-1##[Indications and contraindications for liver transplantation].##Liver transplantation (LT) is a therapeutic method in many, otherwise infaust diseases of the liver. During the recent decade the experimental therapeutic procedure has become a routine therapeutical method. The stage of clinical experiment was ultimated by the Washington Conference held on the consensus in LT indications (1983). Large centries (USA, England, Germany) yield 80-100 liver transplantations per year. The recent years have recorded a change in some principal opinions on LT. It is possible to state that liver transplantation is being abstained from cases with more extensive primary neoplamatic affliction of the liver. Conservative therapy in primary biliary cirrhosis of the liver by means of ursodeoxycholic acid has shifted the LT indication into the later stages of the disease. The opinions on the meaning of LT in alcoholic cirrhosis remain still unsettled. LT remains unambiquously indicated in life-endangering fulminant and subfulminant liver failures. Among the viral diseases, attention is paid to liver cirrhosis caused by infection by the hepatitis C virus. Cirrhosis due to hepatitis B has a better prognosis, owing to the complex antiviral therapy. Liver transplantation represents, beside the main indications, the therapy of first selection, e.g. also in Wilson's disease, alpha-1-antitrypsin deficiency, alveolar echinococcosis etc. (Tab. 1, Fig. 2, Ref. 54.)
8954310##1996-1-1##A Wilson's disease patient with prominent cerebral white matter lesions: five-year follow-up by MRI.##
8739856##1996-1-1##Gamma delta + T cells in Wilson's disease.##Little is currently known about the role of gamma delta + T cells in disease pathogenesis. We have demonstrated elevated levels of gamma delta + T cells in the peripheral blood and cerebrospinal fluid of patients with Wilson's disease compared with other neurological diseases. The percentage of V delta 1 +/ gamma delta + T cells was between 20% and 50% in all patient groups; gamma delta + T cells in blood correlated with copper concentrations. The antigen reactivity of gamma delta + T cells and how the antigens relate to the gamma delta + T cells found in WD remains unknown. It remains unclear whether there is a direct reason for the elevated gamma delta + T cells population found in WD. Immunohistochemistry of frozen autopsy material from brain and liver of WD patients could allow exact localization of gamma delta + T cells and heat shock proteins in future studies.
8836887##1996-1-1##Histopathologic findings in chronic hepatitis C.##Evaluation of liver biopsies in hepatitis C is aimed at confirming the clinical and serologic diagnosis, grading of necroinflammatory activity, staging of consecutive fibrosis, ruling out or confirming liver diseases of different etiology, and assessment of therapeutic effects. Usually, the course of chronic hepatitis C virus (HCV) infection is slow, with mild inflammatory changes. Nevertheless, even in mild asymptomatic chronic hepatitis C episodes of higher inflammatory activity associated with extensive piecemeal necrosis and porto-central bridging, necrosis can accelerate the course of the disease. For this reason, the traditional, morphologically based classification of chronic hepatitis and the term &quot;chronic persistent hepatitis&quot; have lost their predictive usefulness, especially in hepatitis C. Chronic hepatitis should be characterized by etiologic designation as well as grade and stage of the disease. Portal lymphoid aggregates, some inflammatory bile duct damage and mild steatosis are the most characteristic features by which hepatitis C can be differentiated from other progressive inflammatory liver diseases. Antibodies directed against HCV antigens allow identification of viral proteins by immunohistochemistry. Immunostaining for hepatitis B antigens, for alpha-1-antitrypsin and copper staining are helpful in detecting hepatitis B and congenital liver diseases (Wilson's disease, alpha-1-antitrypsin deficiency) as possible causes of chronic progressive inflammatory liver disease. Centrilobular Mallory's hyalin, identified by immunostaining for ubiquitin in combination with perivenular fibrosis, is helpful in diagnosing concomitant alcoholic liver disease. In our own biopsy material (n = 100) and autopsy material (n = 58), HIV/HCV-coinfected patients have a significantly higher rate of fibrosis and cirrhosis than HIV patients without HCV infection. Hepatitis C can apparently aggravate the course of HIV infection. Our morphologic findings support the clinical observation that chronic HCV infection seems to be the main cause of liver failure, especially in the risk group of HCV/HIV-coinfected hemophiliacs.
9013397##1996-1-1##Dopamine D2 receptor binding is reduced in Wilson's disease: correlation of neurological deficits with striatal 123I-iodobenzamide binding.##To visualise and quantify dopamine D2 receptor binding in the corpus striatum of patients with neurological Wilson's disease (WD) 123I-Iodobenzamide (IBZM) binding was measured using single photon emission computer tomography (SPECT). Ratios of striatal to frontal countrates were calculated in 8 patients and in 21 healthy control subjects. We found reduced IBZM binding ratios in all patients with WD in comparison to those in controls (1.48 +/- 0.13 vs. 1.73 +/- 0.09). The reduction in IBZM binding was correlated with the overall severity of neurological deficits and the severity of dysarthria (correlation coefficients -0.86 [p &lt; 0.01] and -0.79 [p &lt; 0.01], respectively). When patients of three different subgroups of neurological WD were compared no differences in IBZM binding were found. We conclude that assessing basal ganglia function in vivo using IBZM-SPECT is a valuable diagnostic tool in WD.
8832611##1996-1-1##Recurrent hypokalemic muscle weakness as an initial manifestation of Wilson's disease.##A 24-year-old man had several episodes of hypokalemic muscle weakness of undetermined etiology since the age of 13 years. Wilson's disease (WD) was not diagnosed until the age of 18 when wing-beating tremor in the left upper limb was noted. Renal function study revealed incomplete proximal renal tubular acidosis. The hypokalemic muscle weakness and wing-beating tremor had subsided after long-term penicillamine therapy. The present case indicates that recurrent hypokalemic paralysis due to renal tubular acidosis is a rare initial presentation of WD and may respond to penicillamine therapy.
9153015##1996-1-1##Motor cortex threshold in Wilson's disease (transcranial magnetic stimulation).##
8587213##1996-1-1##[Essential trace element and skin diseases].##We have described herein various skin diseases which are caused by essential trace element deposition, deficiency, allergy, etc. Pigmentation of hemochromatosis and hemosiderosis are recognized by hemosiderin deposition in the dermis. Acrodermatitis enteropathica is caused by a deficiency of Zn and is classified as either a hereditary type or as an acquired type. The former is autosomal recessive and the latter is caused by a low intake of Zn. Wilson's disease and Menkes' kinky hair syndrome, which are caused by abnormal Cu metabolism, elicit hyperpigmentation and morphological changes of the hair, respectively. It appears that kinky hair formation results from low activity of sulfhydryl oxidase which is a Cu enzyme. Bowen disease, which is carcinoma in situ, is caused by As toxicosis. Some cases, such as palmo-plantar-pustulosis, lichen planus and oral lichen planus are caused by allergies to metals used in dental surgery, especially Ni, Co, Cr and Sn.
8587176##1996-1-1##[Inherited neurological disease--relationship between an essential trace elements and Wilson/Menkes disease].##Because copper is an integral component of various enzymes in every cells, it has been known to be essential for cell activities. Copper is also a very toxic ion, so a specific series of copper transport process must exist to carry copper to the sites where it is required, and to ensure copper homeostasis without allowing toxic accumulation. Wilson disease and Menkes disease are the inherited diseases caused by genetic defects in copper metabolism. Wilson disease is related to the toxic effects of copper accumulation in liver, which leads to progressive liver damage and subsequent overflow to brain causing a loss of coordination and involuntary movement. Menkes disease is caused by the deficiency of serum copper and of copper-dependent enzymes, in various tissues except liver which characterized by neurologic degeneration and mental retardation, connective tissue and vascular defects, characteristic brittle and depigmented hair, and death in early childhood.
9055581##1996-1-1##Molecular advances in Wilson disease.##
8763104##1996-1-1##[Subcortical dementia].##Subcortical dementia, a concept introduced 20 years ago, is a clinical entity characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia or depression), slowed thought processes (or bradyphrenia). It is also marked by overwhelming signs of frontal dysfunction. Cognitive and behavioural disturbances are frequently combined to movement disorders (tremor, chorea, dystonia etc). Anatomical, clinical and scintigraphic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. Therefore it is probably more accurate to use the term subcortico-frontal dementia. This pattern of dementia, clearly different from a cortical dementia as dementia of Alzheimer's disease, may be described in a wide range of diseases which mainly involve the subcortical areas: some cases of Parkinson's disease, Progressive Supranuclear Palsy, Huntington's disease, Wilson's disease, the état lacunaire, multiple sclerosis and so on. The concept of subcortical dementia has allowed a better understanding of the role of the basal ganglia and their cortical connections in cognition and behavior. Its neurochemical substrate remains poorly characterized, although the ascending dopaminergic and cholinergic pathways seem to be good candidates, at least in Parkinson's disease.
19864842##2009-10-30##Pattern of liver disease in a Saudi patient population: a decade of experience at security forces hospital, Riyadh, KSA.##We report the pattern of liver disease revealed by a study of liver biopsies of 277 adults aged 16-85 years old from January 1983 - December 1993. The most common histological diagnoses were: cirrhosis in 22.3%, chronic active hepatitis (CAH) 16.6%, hepatocellular carcinoma (HCC) in 7.2%, fatty changes in 12% of patients. Less common diagnoses included: Cholestasis in 8 (2.8%), Hemochromatosis in 7 (2.5%), periportal fibrosis in 4 (1.4%), Wilson's disease in 3 (1%), Alcoholic hepatitis in one patient and lymphoma in one patient. Inadequate specimens were encountered in 7 (2.5%). The commonest causes of liver cirrhosis were: Hepatitis C virus (HCV) in 73.3% of patients tested for it and hepatitis B virus (HBV) in 23.2%. Complications related to the procedures were exceedingly low. One patient, with Budd-Chiari Syndrome required emergency laparotomy to control bleeding. In conclusion, liver cirrhosis, CAH and HCC were common patterns of chronic liver disease in this series. HCV was the most common cause of CAH and liver cirrhosis.
8701265##1996-1-1##[Ectopic varices, a rare cause of digestive hemorrhage].##From January 1986 to September 1995, 4 patients were hospitalized in our ward for gastrointestinal bleeding from ectopic varices. The patients were all female, aged 30 to 65 years. The etiology of portal hypertension in these patients was alcoholic cirrhosis, cirrhosis in Wilson's disease and previous alveolar echinococcosis treated by right hepatectomy, complicated by post-operative portal thrombosis. Clinical presentation in all 4 cases was lower gastrointestinal bleeding. Diagnosis was by emergency arteriography in 3 cases; no source was found in one case with recurrent hemorrhage. The 4 patients had a history of abdominal surgery. The location of the ectopic varices was small bowel and cecum. 3 patients were treated surgically: right colectomy, partial small bowel resection and porto-caval shunt with complete lysis of adhesions. One patient was treated conservatively with emergency placement of a TIPS (transjugular intrahepatic porto-systemic shunt), with simultaneous embolization of cecal varices. Upon laparotomy, all 3 surgical cases presented ectopic varices in post-operative adhesions. In conclusion, in a patient with portal hypertension presenting with lower gastrointestinal bleeding, hemorrhage from ectopic varices should be kept in mind and investigated by arteriography. A history of abdominal surgery seems to be a predisposing factor in development of ectopic varices by adhesion formation.
8754071##1996-1-1##[Molecular genetic analysis--a new stage in the study of hereditary diseases of the central nervous system].##Molecular genetics is currently the most powerful tool for studying hereditary diseases of the central nervous system: Huntington's disease, dopa-nonresponsive dystonia, Friedreich's disease, etc. The review presents the most important results obtained in this field by the Department of Neurogenetics, Institute of Neurology, in collaboration with several Russian and foreign research institutes. The authors were the first to perform a molecular analysis of mutations and haplotypes in Huntington's disease, dopa-nonresponsive dystonia, Wilson's disease and studied the frequencies of various mutations and main genotype-phenotype correlations in the Russian population. The first direct diagnosis of Huntington's disease in Russia, as well as indirect diagnosis of Friedreich's disease, dopa-nonresponsive dystonia and Wilson's disease have been made. The authors began to investigate trinucleotide repeat expansion in dominant spinocerebellar ataxias and related disorders. The Department of Neurogenetics collected a valuable bank of DNA samples, which is sufficient to perform linkage analysis in essential tremor, novel forms of congenital cerebellar atrophy and progressive muscular atrophy.
8526905##1995-12-5##A novel RNA splicing mutation in Japanese patients with Wilson disease.##Deletion/insertion mutation of Wilson disease (WD) gene in 16 Japanese patients with Wilson disease was studied. A truncated size in a region of exon 4 to 6 was found by reverse transcription-polymerase chain reaction (RT-PCR) covering entire 21 exons except exon 1 for liver cDNA of one patient with a late onset neurologic type. Sequence analysis of the cDNA revealed that this truncation was occurred by skipping of exon 5, though any mutation in exon 5 of genomic DNA was failed to detect. T to G transversion in 5 bp upstream from a junction of intron 4 and exon 5 was found in genomic DNA of the patient. Further, results obtained by RT-PCR and the sequence analysis in intron 4 indicate that the mutation of the patient is homozygous. Since same mutation in one allele of another patient out of 15 patients was found, allele frequency of the splicing mutation in Japanese patients is 9.4%. These results suggest that the point mutation in intron 4 of WD gene causes the skipping of exon 5 and the splicing mutation affects the phenotype of Wilson disease.
8540540##1995-12-1##Mechanisms of pennicillamine and zinc in the treatment of Wilson's disease.##
8533760##1995-12-1##Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.##We analyzed mutations and defined the chromosomal haplotype in 127 patients and Mediterranean descent who were affected by Wilson disease (WD), 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. Haplotypes were derived by use of the microsatellite markers D13S301, D13S296, D13S297, and D13S298, which are linked to the WD locus. There were five common haplotypes in Sardinians, three in Italians, and two in Turks, which accounted for 85%, 32%, and 30% of the WD chromosomes, respectively. We identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, we detected the previously described mutations: 2302insC, 3404delC, Arg1320ter, Gly944-Ser, and His1070Gin. Of the new mutations detected. two, the 1515insT on haplotype I and 2464delC on haplotype XVI, accounted for 6% and 13%, respectively, of the mutations in WD chromosomes in the Sardinian population. Mutations H1070Q, 2302insC, and 2533delA represented 13%, 8%, and 8%, respectively, of the mutations in WD chromosomes in other Mediterranean populations. The remaining mutations were rare and limited to one or two patients from different populations. Thus, WD results from some frequent mutations and many rare defects.
7503362##1995-12-1##Chronic hepatitis. An update on terminology and reporting.##The terms chronic active hepatitis (CAH), chronic persistent hepatitis (CpH), and chronic lobular hepatitis (CLH) have become obsolete, and their use without further specifications should be discontinued. This recommendation has become necessary because these names have changed from descriptive terms, intended for grading, to terms that are used either as morphologic diagnoses or disease designations or both, depending on individual preferences. Because this practice has caused serious misunderstandings, many authors and two international groups have recommended the use of a clear etiologic terminology. For the reporting practice of pathologists, we recommend that the pathologist routinely sign out biopsy samples with features of chronic hepatitis by indicating etiology, grade, and stage. An example would be autoimmune hepatitis, severe, stage 3. The stage in this case would indicate the presence of well-developed septal fibrosis but no nodular regeneration. Obviously, for the etiologic diagnosis, morphologic findings must be integrated with clinical and laboratory data. If this information is not available, clear morphologic diagnoses should be reported. Thus, instead of CPH, the diagnosis should be portal hepatitis, cause undetermined. This reporting practice eliminates ambiguous terminology and avoids the risk of inappropriate treatment as might occur, for example, when a term such as CAH is used to describe Wilson's disease and is misunderstood to mean autoimmune hepatitis. For a transitional period and to facilitate relearning, the terms CAH, CPH, and CLH can be reported in parentheses behind the etiologic diagnosis.
7498669##1995-12-1##Diagnosis of Wilson's disease in an asymptomatic sibling by DNA linkage analysis.##The molecular genetic diagnosis of Wilson's disease in the 5-year-old sister of a patient with Wilson's disease is reported. The girl was clinically free of disease and had no conventional biochemical markers of Wilson's disease (i.e., normal ceruloplasmin, normal copper in the serum, normal 24-hour urinary copper excretion). Diagnosis with restriction fragment length polymorphisms and a nonradioactive polymerase chain reaction-based analysis with microsatellite markers showed her to be homozygous for the disease-associated markers. A liver biopsy was performed, and a 20-fold increased liver copper content confirmed the diagnosis. The child was treated with chelation therapy with D-penicillamine. The report of this study clearly shows the advantage of DNA linkage analysis (especially polymerase chain reaction) over conventional laboratory methods for presymptomatic diagnosis of Wilson's disease before irreparable liver and neurological damage occurs. The only limitation of this DNA-based diagnosis is the fact that it is only applicable in siblings of an index patient whose diagnosis was made by phenotypic criteria.
7489989##1995-12-1##An array of mitochondrial alterations in the hepatocytes of Long-Evans Cinnamon rats.##In an attempt to identify the cellular targets of copper toxicity, we studied the ultrastructure of hepatocytes in the livers of 23 Long-Evans Cinnamon (LEC) rats ranging in age from 10 to 89 weeks. The hepatic copper concentration ranged from 325 to 2,126 (mean, 930) micrograms/g dry weight. Thirteen rats displayed varying degrees of jaundice at the time of killing. Numerous nuclei were indented by cytoplasmic invaginations. Conspicuous abnormalities were displayed by mitochondria. These included marked pleomorphism; increased or diminished matrical density; rearrangement, elongation, dilatation, stacking, or disappearance of cristae; absence of matrical granules; presence of matrical inclusions of flocculent electron-dense deposits; and degenerative changes. The severity of the ultrastructural changes did not correlate with the hepatic copper concentration but did correlate with the degree of the icterus displayed by the rats. Certain mitochondrial changes resembled those encountered in the hepatocytes of patients with Wilson's disease, confirming that these organelles are important targets of copper toxicity.
8808193##1995-12-1##Chemometric methods applied to an ICP-AES study of chemical element distributions in autopsy livers from subjects affected by Wilson and beta-thalassemia.##The concentrations of seven elements (Ca, Cu, Fe, Mg, P, S and Zn) in three autopsy livers (from two beta-thalassemic patients and one Wilson's disease patient) were determined by ICP-AES technique. At autopsy the three livers were subdivided into a large number of samples for a detailed study of the distribution of Fe and Cu, the accumulation of which characterizes the two diseases. In the same samples Ca, Mg, P, S and Zn concentrations were also determined in order to study significant variations or anomalous trends that could help identify these diseases. Our results generally show a good coincidence with literature data within the limits of sample variability. Based on Factor Analysis as well as Regression Analysis there is evidence of a high correlation between Fe and P contents in beta-thalassemia. The latter finding led us to propose tentatively an accumulation of Fe as a complex with P-containing molecules.
8847998##1995-12-1##Accumulation of manganese and copper in pallidum of cirrhotic patients: role in the pathogenesis of hepatic encephalopathy?##Concentrations of zinc, copper and manganese were measured by atomic absorption spectrometry in samples of globus pallidus obtained at autopsy from 9 patients with chronic liver disease and an equal number of age-matched controls. Manganese concentrations were significantly increased several fold (p &lt; 0.01) in globus pallidus of liver disease patients accompanied by smaller but significant 2-fold increases of copper. Zinc concentrations, on the other hand, were within normal limits. Increased pallidal manganese offers a cogent explanation for the observed T1-weighted MRI signal hyperintensity in pallidum of cirrhotic patients. Increased copper content in brain suggests the existence of common pathophysiologic mechanisms in inherited (Wilson Disease) and acquired hepatocerebral disorders.
8577061##1995-12-1##[Medicinal therapy for lysosomal storage diseases].##Lysosomes contain several dozen different enzymes, mostly acid hydrolases. Materials not digested due to deficient lysosomal enzymes are usually large cellular molecules, which are deposited within the cells. The strategy for medicinal therapy of lysosomal storages disease may be to develop the activators of enzymes, to promote coenzyme and cofactor supplementation and to eliminate undegraded materials from blood into urine. In the last several decades, many trials for these strategies has been done. Cysteamine for cystinosis and penicillamine for Wilson's disease has proved useful in treating these patients. Recently, DMSO has been proved to be an activator of acid sphingomyelinase and to accelerate the intracellular mobilization of LDL-derived cholesterol. We treated patients with Niemann-Pick disease type C by oral administration of DMSO, resulting in some clinical benefits such as decreased size of hepatosplenomegaly, and lesser frequency of seizures with improved EEG. However, the progressive clinical course has not been changed although it appeared to slow down. New activators of lysosomal enzymes should be developed for medicinal therapy of lysosomal storage diseases.
8752442##1995-12-1##[Multiple Sclerosis--diagnosis and its problems].##Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) demyelinating disease, though the etiology still remains unknown. To make a diagnosis of MS is largely based on clinical features which are characterized by multiplicity of CNS symptoms and signs in time and space. However, there have been some questions and problems about the diagnosis of MS. There are a great diversity of MS clinical forms, such as relapsing and remittent type, chronic progressive type (primary or secondary), Devic type or Balo type, so on. In particular, optic-spinal form of MS is undoubtedly common in Japan and other Asian countries, compared with American and Northern European countries. To make a correct diagnosis of MS, it is important to rule out other diseases mimicking MS, such as tumors, cerebrovascular diseases, several myelopathies, collagen diseases, sarcoidosis, Wilson disease, so on. Nevertheless, it is hard to differentiate MS from some other MS-mimicking diseases, for example CNS Sjögren disease and antiphospholipid antibody syndrome. Since MRI detects demyelinating lesions within CNS with high sensitivity, MRI examination has a great impact on the diagnosis, etiological investigation and therapeutic trial of MS.
8610495##1995-11-1##No neurological improvement after liver transplantation for Wilson's disease.##Orthotopic liver transplantation (OLT) represents the sole etiological treatment for Wilson's disease (WD), but its efficacy in resolving the neurological symptoms is still a matter of debate. We present the case of a young male affected with WD with hepatic and neurological involvement, who underwent OLT for subacute liver failure. Clinical, neuropsychological and neuroradiological assessment were performed before and after OLT. OLT had no effect on neurological symptoms, suggesting that the basal ganglia damage may be irreversible. Nineteen months after OLT, the patient went on to develop new permanent extrapyramidal symptoms. We postulate a sequela of an early post-operative central pontine and extrapontine myelinolysis.
8585490##1995-11-1##Cranial MR in Wilson disease: abnormal white matter in extrapyramidal and pyramidal tracts.##
17589031##1995-11-1##Clinical and magnetic resonance imaging findings in a case of Wilson disease.##
7586683##1995-11-1##Significance of extractable nuclear antigens in childhood autoimmune liver disease.##Antinuclear antibody (ANA) is found in connective tissue disorders and in autoimmune liver disease. While ANA-positive connective tissue disorders are subdivided according to possession of specific antibodies to extractable nuclear antigens (ENA) (anti-ribonucleoprotein (anti-RNP), anti-Smith (anti-Sm), anti-Ro, anti-La), little is known about the presence and significance of ENA in autoimmune liver disease. To investigate this, we have tested 35 children with autoimmune hepatitis (AIH) (19 ANA and/or smooth muscle antibody-positive (ANA/SMA+ve); 16 liver kidney microsomal 1-positive (LKM-1 + ve)) and 14 with ANA/SMA+ve autoimmune sclerosing cholangitis (ASC), using both double dimension immunodiffusion and ELISAs. Eighty children with non-autoimmune liver disease (20 alpha 1-antitrypsin deficiency, 20 Wilson's disease, 20 Alagille's syndrome and 20 chronic hepatitis B virus infection) and 20 healthy controls were also tested. ENA were detected in seven (20%) patients with AIH: two ANA-positive, one SMA-positive and four LKM-1-positive. Three were positive for anti-Sm, two for anti-La, one for anti-Sm/anti-La and one for anti-Sm/anti-La/anti-Ro. ENA-positive had more severe liver disease than ENA-negative patients (P &lt; 0.03). ENA were not detected in ASC, non-autoimmune liver diseases and controls. Our results indicate that ENA reactivity, including anti-Sm and anti-La, characteristic of systemic lupus erythematosus and Sjögren's syndrome, respectively, are present in some patients with AIH even in the absence of ANA, and may characterize a particularly severe form of the disease.
8565366##1995-11-1##Brain SPECT in Wilson's disease.##
8545467##1995-11-1##Proline, ascorbic acid, or thioredoxin affect jaundice and mortality in Long Evans cinnamon rats.##The Long Evans Cinnamon (LEC) rat spontaneously develops fulminant hepatitis, which is usually lethal due to excess copper accumulation in the liver and is considered an animal model of Wilson's disease. LEC rats show a strong appetite for proline solution. Daily oral (p.o.) administration of proline resulted in significant delay of mortality. Feeding a copper-deficient diet greatly delayed the onset of jaundice and mortality and voluntary consumption or p.o. administration of proline further delayed jaundice and prevented mortality. LEC rats also consume ascorbic acid solutions, and p.o. administration of ascorbate also results in a significant delay in the appearance of jaundice and mortality. Combined treatment with ascorbic acid and proline is additive to delay further jaundice and mortality. An endogenous antioxidant protein, thioredoxin, when infused by minipump IP, could also inhibit the incidence of jaundice. These results indicate that antioxidant treatment combined with proline may be of benefit in Wilson's disease and possibly other forms of hepatic dysfunction.
8588032##1995-11-1##[Differential diagnosis of focal liver lesions with MRI using the superparamagnetic contrast medium endorem].##
8747789##1995-11-1##Abnormal hepatic copper accumulation of spheroid composed of liver cells from LEC rats in vitro.##The LEC rat is a mutant strain displaying hereditary hepatitis, and shows abnormal accumulation of copper (Cu) similar to that occurring in Wilson's disease. We prepared a multicellular spheroid composed of LEC rat liver cells to investigate the mechanism for abnormal accumulation of Cu. These multicellular spheroids were prepared by detaching the monolayer on the collagen-conjugated thermo-responsive polymer coated culture dish at a temperature below the critical solution temperature and culturing on the non-adhesive substratum. Long-term cultured spheroids of LEC rat liver cells as well as SD rat liver cells were attempted. Non-parenchymal cells obtained by collagenase perfusion from the LEC liver were fewer than those from the SD liver. Cells from the LEC rat, over 11 weeks of age, did not form a cell sheet; however, a mixture of parenchymal cells from LEC rats over aged 11 weeks and non-parenchymal cells from SD rats of any age yielded intact spheroids. We examined the toxicity, the accumulation and distribution of Cu in spheroids. The accumulation of Cu in LEC spheroids was higher than that in SD spheroids. Results suggest that spheroids consisting of LEC liver cells are useful as an alternative model to in vivo tests to investigate the mechanism for abnormal accumulation of Cu in liver.
16296246##1995-11-1##[Niemann-Pick disease (type C)].##A 15-year old girl with slowly progressive gait and speech disorders, and with impairment of mental ability, is decsribed. The disease appeared 18 months before the first hospitalization at the Department of Neurology and Physchiatry for Children and Young People. Neurological and other examinations confirmed extrapyramidal and cerebellar signs, conspisuous knee and ankle reflexes, marked splenomegaly, slightly enlarged liver, sometimes emotional incontinence and global physic deterioration. The clinical picture was similar to Wilson's disease. However, in liver and bone marrow, as well as during sternal pincture macrophages (foam cells) were detected as characteristic elements of Niemann-Pick disease. The authors conclude that the patient belongs to type C of Niemann-Pick disease with a relatively benign course.
8555409##1995-10-1##Effects of some chelating agents on urinary copper excretion by the rat.##In order to estimate the potential advantages of new chelating agents which can enhance copper excretion in the chronic copper intoxication arising in Wilson's disease, the relative ability of none chelating agents to induce the urinary excretion of copper was compared with that of D-penicillamine (DPA) and triethylenetetramine.2HCl (TRIEN), all given ip at 1 mmol/kg to male Sprague-Dawley rats. The compounds examined were as follows: tris(2-aminoethyl)-amine.3HCl (TREN), tetraethylenepentamine.5HCl (TETREN), pentaethylenehexamine.6HCl (PENTEN), 1,4,7,11-tetraazaundecane.4HCl (TAUD), 1,5,8,12-tetraazadodecane.4HCl (TADD), 1-N-benzyltriethylenetetramine.4HCl (BzTT), 4,7,10,13-tetraazatridecanoic acid.2H2SO4 (TTPA), 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane.4HCl (BPTETA), and N,N-bis(2-pyridylmethyl)-4-(aminomethyl)benzoic acid (4ABA). Of these, BzTT, TTPA, and 4ABA are new chelating agents not previously reported. The factors by which these chelating agents enhanced copper excretion over control (untreated) levels were as follows: DPA, 7.2; TREN, 1.6; TRIEN, 4.0; TETREN, 10.1; PENTEN, 7.8; TAUD, 7.8; TADD, 2.6; TTPA, 5.6; BzTT, 1.8; and 4ABA, 5.5. The results indicate that it may well be possible to develop additional chelating agents which are equal or superior to those now used in the treatment of Wilson's disease, as well as structural types whose immunological properties may be significantly different from DPA or TRIEN, the compounds currently used in the clinic for this disorder.
8655953##1995-10-1##Liver transplantation for Wilson's disease.##
8605607##1995-10-1##Molybdenum and copper kinetics after tetrathiomolybdate injection in LEC rats: specific role of serum albumin.##Chelation therapy with tetrathiomolybdate (TTM) was applied to Long-Evans rats with a cinnamon coat-color (LEC rats), an animal model for Wilson disease, to remove copper (Cu) accumulated in the liver in a form bound to metallothionein (MT). Changes in molybdenum (Mo) and Cu concentrations and their biological forms in serum of LEC rats determined at different times after a single intraperitoneal injection were compared with those of Wistar (normal) rats. The change in Mo concentration in serum of normal rats was mono-phasic, whereas in LEC rats it was bi-phasic. The phase in normal rats and the first phase in LEC rats appeared to reflect the process of uptake and disappearance of TTM in the livers of Wistar and LEC rats. On the other hand, the second phase in LEC rats paralleled the changes of Cu and appeared to reflect the complex formation (Cu/thiomolybdate complex) between Mo and Cu accumulated in the liver. The complex was specifically bound to albumin as determined by high performance liquid chromatography with inductively coupled plasma-mass spectrometry (HPLC/ICP-MS). The results suggested that the changes in the Mo concentration in serum reflected the amount of Cu in the liver.
8605606##1995-10-1##Systemic dispositions of molybdenum and copper after tetrathiomolybdate injection in LEC rats.##Mutant Long-Evans rats with a cinnamon coat-color (LEC rats) have been established as an animal model for Wilson disease, a genetic disorder of copper (Cu) metabolism. Systemic disposition of molybdenum (Mo) and altered distributions of Cu were compared in eight organs between LEC rats and Wistar rats (normal) at different times after a single intraperitoneal injection of tetrathiomolybdate (TTM) for chelation therapy. Excretion through urine and feces was also examined. Hepatic disposition of Mo was dramatically increased in LEC rats, suggesting that the interaction of TTM with Cu results in enhanced uptake of Mo. Concentrations of Mo and Cu decreased in the liver of LEC rats over time, whereas those in the spleen increased. Although the concentration of Mo taken up by the kidney decreased over time after an initial increase in both rats, Cu concentration increased over time. Cu was not redistributed to the brain. Excretion of Mo through urine was decreased and that into feces was increased in LEC rats compared with those in Wistar rats. These results indicate that TTM is taken up by the liver depending on the Cu content, and the Cu and Mo removed from the liver are mostly excreted through feces. Redistribution of Cu was observed in the spleen and kidneys, but not in the brain.
7483606##1995-10-1##Inherited liver diseases in adults.##Important inherited disorders causing acute and chronic liver disease include hemochromatosis, Wilson's disease, alpha 1-antiprotease (antitrypsin) deficiency, and cystic fibrosis. The detection of an index case has implications for screening family members. A normal life span can be expected with treatment in asymptomatic patients with Wilson's disease and hemochromatosis. We present a clinical approach to disease recognition, investigation, and screening.
8666408##1995-9-20##The toxic milk mutation, tx, which results in a condition resembling Wilson disease in humans, is linked to mouse chromosome 8.##
8534043##1995-9-1##Atypical copper cirrhosis in Indian children.##In addition to ten children with Wilson's disease and one with Indian childhood cirrhosis, nine Indian children, aged from 4 to 15 years, with cryptogenic cirrhosis had significant deposits of stainable copper in their hepatocytes. These nine children had normal or elevated serum caeruloplasmin levels, absence of Kayser-Fleischer rings and a history of sibling death owing to liver disease in four cases. Histologically, fatty change was absent from all the biopsies but Mallory's hyaline, pericellular fibrosis and ballooning of hepatocytes were present in some. Since these children did not conform to the accepted clinical or histological definitions of either Indian childhood cirrhosis or Wilson's disease, they were designated as having atypical copper cirrhosis. The relationship of this group of cases to other types of copper cirrhosis is unknown.
7493698##1995-9-1##Wilson's disease in pregnancy.##Patients with Wilson's disease contemplating pregnancy should have their hepatic function and copper status assessed. We report a case of a pregnant woman with Wilson's disease with compromised hepatic function. The medical problems and controversy of prescribing treatment are discussed.
10829919##1995-9-1##Autoimmune hepatitis.##Autoimmune hepatitis can present as either acute or chronic disease in children. Clinical and laboratory features, including association with extrahepatic autoimmune syndromes and prompt response to immunosuppressive treatment, circulating autoantibodies and hypergammaglobulinemia, suggest an immune etiology. However, the disease mechanism remains uncertain. Different types of autoimmune hepatitis are defined on the basis of which autoantibodies are present: anti-smooth muscle (type 1), anti-liver/kidney microsomal (type 2), or anti-soluble liver antigen (type 3). Diseases which may be clinically similar to autoimmune hepatitis must be excluded before the diagnosis of autoimmune hepatitis is established: Wilson's disease, primary sclerosing cholangitis, chronic hepatitis B or C, and drug-induced liver disease are among the most important entities. Corticosteroids alone or with azathioprine constitute the usual treatment for autoimmune hepatitis. Although some children achieve a complete remission, or even recovery, and can stop immunosuppressive treatment, others required low-dose prednisone treatment indefinitely.
8563007##1995-9-1##Non-alcoholic steatohepatitis. Report of five cases and review of the literature.##We describe three men and two women, aged 18-50, with an occasional finding of increased aspartate and alanine aminotransferase and gamma-glutamyl transpeptidase levels in the absence of any drug treatment and past or current alcohol abuse. Two patients were overweight (body mass index 29 and 32, respectively) and physical examination was normal in all but one case. Tests for hepatitis A, B and C, Epstein-Barr virus, cytomegalovirus, toxoplasma and autoimmune hepatitis were negative and metabolic diseases (Wilson's disease, haemochromatosis, alpha-l-antitrypsin deficiency) were excluded by specific tests. Ultrasound liver scan revealed massive steatosis in all patients. Liver histology showed diffuse steatosis and parenchymal inflammation in all cases, with concomitant fibrosis and Mallory bodies in three of them. Findings were consistent with non-alcoholic steatohepatitis, a rare condition with potential progression to cirrhosis in a minority of cases. This disease, for which no treatment is currently available, must be considered in all subjects with elevated aminotransferases, in the absence of known causes of liver damage.
8577018##1995-9-1##Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers.##
8552111##1995-9-1##Neurological Wilson's disease studied with magnetic resonance imaging and with positron emission tomography using dopaminergic markers.##Four patients with neurological Wilson's disease were investigated using magnetic resonance imaging (MRI) and positron emission tomography (PET). All patients had dystonia as their major clinical manifestation but also had dysarthria and at the presentation of the disease had choreoathetoid movements in at least one limb. A multitracer approach with PET was used to visualize various aspects of dopaminergic function; [11C]-(+)-nomifensine (NMF), [11C]raclopride (RAC) and [11C]-L-DOPA (one patient). Correlation analysis of RAC and NMF binding as well as putamen/caudate uptake ratios showed corresponding reductions. The patient investigated with [11C]-L-DOPA had a normal striatal uptake. Generally, structural changes as shown by MRI corresponded to reductions both in NMF and RAC binding. There was no evident correspondence between PET findings and the severity of clinical symptoms seen in the individual patient. In two patients with discrete neurological impairment at the time of investigation, PET showed serious presynaptic dopaminergic lesions in the putamen. Our data suggest that the striatal degeneration seen in Wilson's disease comprises a complex pathology involving both afferent and efferent projections. The discrete neurological impairment seen in some patients with gross striatal pathology might be due to concomitant lesions in functionally counteracting basal ganglia circuits.
7565916##1995-9-1##Enhanced cyto- and genotoxicity of tetracycline in Wilson disease fibroblasts.##Tetracycline (TC) exerts DNA damaging properties which are accelerated in the presence of copper(II). Thereby, reactive oxygen species are generated. We investigated, if copper-accumulating cells show a higher sensitivity to TC compared to normal cells. Fibroblasts with an increased copper content were derived from patients of two genetic disorders, Wilson disease (WD) and Menkes disease (MD). Cytotoxic and genotoxic effects of TC were investigated in different human fibroblasts. The inhibition of cell growth by TC was measured in two normal fibroblast lines, fibroblast lines of two patients with WD and one patient with MD. While TC inhibited cell growth at similar concentrations in normal fibroblasts and the MD fibroblasts, the WD cells were much more sensitive. Furthermore, an increased inhibition of DNA synthesis and an enhanced induction of unscheduled DNA synthesis (UDS) was found in WD cells after a TC-treatment compared to normal cells.
8650042##1995-9-1##[Wilson's disease in personal material--disturbances in hemostasis].##Genetically determined impairment of copper excretion from the liver into the bile in Wilson's disease (WD) cause that &quot;free copper&quot; is accumulated in toxic amounts not only in the liver, but also in other organs. In WD liver biopsy often could not be made because of serious disturbances in hemostasis. The aim of the study was: a) to demonstrate our 9 patients with various form of WD. b) to examine some blood clotting factors and compare the results with these obtained in other liver diseases. The diagnosis of Wilson's disease was made on the basis of disturbed copper metabolism. Among our 9 patients (8 women and 1 man, between 17-33 years old) we diagnosed: 3 patients with fulminant Wilson's disease with all day deep jaundice, hemolytic anemia, haemorrhagic diathesis and liver failure, died, 2 patients with active chronic hepatitis, hemolytic anemia and haemorrhagic diathesis, 2 patients with liver cirrhosis, haemorrhagic diathesis, Kayser-Fleisher ring, neuropsychiatric syndrome, 2 asymptomatic patients without haemorrhagic diathesis. The prothrombin index and the factors of prothrombin stem (II, V, VII, X) were lower than in other kinds of cirrhosis. After treatment with d-penicillamine the clothing factors returned near to the norm, similar as the biochemical and immunological results.
7583074##1995-9-1##Long-term treatment of Wilson's disease with triethylene tetramine dihydrochloride (trientine).##Long-term treatment with triethylene tetramine dihydrochloride, (trientine, TETA) was evaluated in 19 patients with Wilson's disease (WD). Two were given the drug as first choice and 17 after treatment with penicillamine. The change was made because of side-effects, lack of improvement or worsening of neurological symptoms. All penicillamine-induced side-effects reverted. Thirteen patients still receive trientine, and the mean total observation time on this treatment is 8.5 years/patient. Seven of the 13 are free from symptoms related to WD, five have mild to moderate neurological symptoms, mainly dysarthria. One patient with neurological symptoms who received trientine from the start of treatment deteriorated rapidly and is now severely dystonic. The symptoms initially worsened and later improved in one patient. All other patients improved during trientine treatment. Three patients died: two from a multifocal cancer including the liver and one non-complier from a ruptured spleen. Two patients underwent liver transplantation for progressive liver failure: one non-complier and one with liver cirrhosis whose liver function deteriorated despite treatment; both are now free from symptoms. Unexpectedly, two patients developed a serious colitis, one with duodenitis as well, that improved after withdrawal of the drug. No other unfavourable effects of trientine were recorded.
8680810##1995-9-1##The rat homologue of the Wilson's disease gene was partially deleted at the 3' end of its protein-coding region in Long-Evans Cinnamon mutant rats.##LEC mutant rats exhibit an abnormal hepatic copper accumulation, due to the defection of the rat homologue of the Wilson's disease gene. In this study, we found a definitive evidence that the rat Wilson's disease gene of LEC rats was partially deleted at the 3' end of its protein-coding region, by performing Southern blot analysis. Furthermore, in Northern blot analysis, we confirmed that expression of the rat Wilson's disease gene was deficient in the liver of LEC rats. The partial deletion of the rat Wilson's disease gene should be responsible for the deficient expression of that gene in LEC rats.
8728733##1995-9-1##[Wilson's disease: a review apropos of a clinical experience in 16 patients].##Wilson's Disease is an inherited disorder of copper metabolism. We report 16 patients (6 males) with the disease; 6 had hepatic involvement exclusively, 4 had neurological involvement, 3 had a neurological and hepatic involvement and 3 were asymptomatic. The age onset was 9 years for hepatic and 17 years for neurologic involvement. The mean delay in diagnosis was 14 months. Chronic hepatitis, cirrhosis and fulminant hepatic failure were the clinical forms of liver disease. Patients with neurologic disorders had behavioral disturbances and extrapyramidal manifestations such as dystonia and parkinsonism. Patients had a good response to penicillamine, except 3 that died of liver complications, in whom the treatment was delayed or discontinued. We conclude that this metabolic disease must be suspected in pubertal children and in adults of less than 30 years old with liver disease of unknown origin or behavioral alterations associated to an extrapyramidal syndrome.
19864849##2009-10-30##Wilson's disease: a new direction.##Wilson's disease, first described in 1912, is a familial disease involving copper metabolism. This article reviews recent developments in the genetics of the disease and their implications for the diagnosis and treatment.
8578646##1995-9-1##Wilson's disease-like lesion in a calf.##Wilson's disease-like lesion was seen in a 2-month-old calf. Fibrosis was apparent in the liver, but there was no cholestasis or icterus. Marked spongy degeneration was seen in the central nervous system. Hepatic and brain copper values were significantly higher than normal: 1970 and 113 ppm dry matter, respectively. Serum ceruloplasmin was lower than normal: 17.5 U/liter. Etiology of this disease was unknown, but there is no evidence that the calf ingested a large quantity of copper.
7553746##1995-8-23##[Chronic hepatitis--diagnosis and differential diagnosis].##Since the first classification of chronic hepatitis (CHH) more than 25 years have elapsed. Since then conditions for assessment of the etiology, pathogenesis and therapy of the disease have improved. These findings must be applied in the contemporary diagnosis of CHH. The first task is to assess the correct etiology of the disease because it is decisive for treatment, development and prognosis of the disease. The most important cause of CHH is viral hepatitis. Hepatitis B and C are frequently occurring diseases and may develop into CHH and cirrhosis of the liver. New therapeutic procedures, using interferons, can prevent this. Idiopathic autoimmune hepatitis is a serious form where interferon therapy is contraindicated, while the condition usually responds very well to treatment with corticoids and immunosuppressive substances. It is important to take into consideration also possible liver damage by drugs and the fact that the clinical picture is associated with a certain stage of metabolically conditioned changes, in particular Wilson's disease. It is important to examine carefully the histological finding and laboratory results, as it is possible to evaluate from them the severity of the disease. We should also attempt to evaluate these changes quantitatively.
7565403##1995-8-15##[Acute liver failure as the initial manifestation of Wilson disease].##
7490097##1995-8-10##Mapping of the mouse homologue of the Wilson disease gene to mouse chromosome 8.##ATP7B, the gene altered in Wilson disease (WD) patients, lies in a block of homology shared between human chromosome 13q14 and the central region of mouse chromosome 14. However, we have mapped the murine homologue of ATP7B (Atp7b) to mouse chromosome 8 by somatic cell hybrid analysis. Analysis of 80 interspecific backcross offspring was used to position Atp7b close to D8Mit3 and another ATPase locus, Atp4b, on mouse chromosome 8. ATP4B lies in 13q34 and is separated from ATP7B by several loci whose mouse homologues map to mouse chromosome 14. The assignment of Atp7b to mouse chromosome 8 identifies a previously unrecognized region of homology between this chromosome and human chromosome 13. This assignment suggests a possible location for the toxic milk mutation in the mouse, which has been proposed as a homologue of WD.
7490081##1995-8-10##Molecular structure of the Menkes disease gene (ATP7A).##We report a detailed molecular analysis of the genomic structure of the Menkes disease gene (MNK; ATP7A). There are 23 exons in ATP7A covering a genomic region of approximately 140 kb. The size of the individual coding exons varies between 77 and 726 bp, and introns vary in size between 196 bp and approximately 60 kb. All of the splice sites obey the consensus GT-AG rule except the splice donor of intron 9, which is GC instead of GT. The exon following this rare splice donor variant is alternatively spliced. A PGAM pseudogene and two highly polymorphic CA repeats map to introns within the gene. The structure is very similar to that of the closely related Wilson disease gene (WND; ATP7B). From exon 5 (exon 3 in ATP7B) to the end, all of the splice sites occur at exactly the same nucleotide positions as in the WND gene, except for the boundary between exons 17 and 18 (exons 15 and 16 in ATP7B) and a single codon difference at the boundary between exons 4 and 5 of the MNK gene (exons 2 and 3 in ATP7B). In contrast to the WND gene, in which the first four of six metal binding domains are contained in 1 exon, metal binding domains 1 to 4 are divided over 3 exons. The striking similarity of the MNK and WND genes at the genomic level is consistent with their relatively recent divergence from a common ancestral gene.
7484624##1995-8-1##Juvenile Huntington disease: CT and MR features.##
8534585##1995-8-1##Initial clinical experiences with dopamine D2 receptor imaging by means of 2'-iodospiperone and single-photon emission computed tomography.##Dopamine D2 receptor imaging was performed with 123I labeled 2'-iodospiperone (2'-ISP) and single-photon emission computed tomography (SPECT) in 9 patients: 4 with idiopathic Parkinson's disease, 2 with parkinsonism, 1 with Wilson's disease and 2 with pituitary tumor, and the results were compared with the data for 9 normal subjects. Following an intravenous injection of 123I-2'-ISP, early (within 30 min) and late (between 2 and 4 hr) SPECT images were obtained by means of a multi-detector SPECT scanner or a rotating gamma camera. In normal subjects, early SPECT images demonstrated uniform distribution of radioactivity in the cerebral gray matter and cerebellum reflecting regional cerebral blood flow, whereas late SPECT images showed high radioactivity only in the basal ganglia. All the patients with Parkinson's disease also demonstrated symmetrical basal ganglia uptake in the late SPECT images, but it was diminished in parkinsonism and Wilson's disease. One patient with a growth hormone-producing pituitary tumor had a positive uptake in the tumor. These preliminary clinical data demonstrated that 2'-ISP can be used for SPECT imaging of D2 dopamine receptors and may be of clinical value for the diagnosis and planning of the treatment of neurological diseases.
8521757##1995-8-1##Practical recommendations and new therapies for Wilson's disease.##Wilson's disease is an inherited disorder of copper accumulation. The basic defect is a failure of excretion of excess copper in the bile by the liver for loss in the stool. The accumulating copper causes damage primarily to the liver and the brain. Patients typically present in the second to the fourth decades of life with liver disease, a neurological disease of the movement disorder type, or a wide array of behavioural disturbances. Because the manifestations of Wilson's disease are so protean, and the disease masquerades so well as something else, recognition of the possibility of Wilson's disease is a major problem, leading to serious underdiagnosis of the disease. Excellent therapies exist for both the prophylaxis and treatment of Wilson's disease. The longer recognition and diagnosis are delayed, the greater the risk of permanent damage to liver and/or brain. The availability of effective therapy and the risks in delay or therapy make the earliest possible diagnosis critical. Once the disease comes under consideration, a series of diagnostic steps can be undertaken which almost always establish or rule out the diagnosis of Wilson's disease. These include urine copper, blood ceruloplasmin, slit lamp examination for Kayser-Fleischer rings, and liver biopsy with quantitative copper assay. Currently, there are 4 drugs being used as anticopper agents in Wilson's disease. These are zinc, which blocks intestinal absorption of copper, penicillamine and trientine, both of which are chelators that increase urinary excretion of copper, and tetrathiomolybdate which forms a tripartite complex with copper and protein, and can block copper absorption from the intestine, or render blood copper non-toxic. Zinc is clearly the treatment of choice, in our opinion, for maintenance therapy, for the treatment of the presymptomatic patient from the beginning and for the treatment of the pregnant patient, because of its complete efficacy and lack of toxicity. For the initial treatment of the patient presenting with mild liver failure, we empirically use a combination of trientine and zinc. Trientine gives a strong, fast, negative copper balance, and zinc induces hepatic metallothionein, which sequesters hepatic copper. For the initial treatment of patients presenting with neurological disease we use an experimental drug, tetrathiomolybdate, which provides rapid, safe control of copper. These latter patients are at great risk of serious permanent neurological worsening with penicillamine, and zinc is too slow-acting, in our judgment, to be optimal.
7552582##1995-8-1##Wilson's disease: a new gene and an animal model for an old disease.##Wilson's disease is an autosomal recessive, inherited disorder of copper metabolism. In normal individuals, copper homeostasis is controlled by the balance between intestinal absorption of dietary copper and hepatic excretion of excess copper in bile. In Wilson's disease, hepatic copper is neither excreted in bile nor incorporated into ceruloplasmin and copper accumulates to toxic levels. The Wilson's disease gene (WND) encodes a putative copper-transporting protein that is expressed almost exclusively in the liver. The predicted structure of the protein product is that of a P-type ATPase with striking homology to bacterial copper transporters and the gene product of another inherited disorder of copper metabolism, Menkes' disease. A rat model of Wilson's disease has recently been identified. The Long-Evans Cinnamon (LEC) rat manifests elevated hepatic copper, defective incorporation of copper into ceruloplasmin, and reduced biliary excretion of copper. The rat homologue of the WND is abnormal in LEC rats. Clinical manifestations of Wilson's disease arise directly from copper-induced damage to hepatocytes (hepatic presentation) or indirectly after the release of copper from the liver with subsequent damage to the brain (neuropsychiatric presentation) and other organs. Genetic heterogeneity (different mutations in a single gene) may account for some of the variability in Wilsonian presentations. The diagnosis of Wilson's disease depends on the demonstration of disordered copper metabolism, manifested as elevated urinary and hepatic copper and low ceruloplasmin levels. However, none of the abnormal findings in Wilson's disease is pathognomonic. Genetic diagnosis, in the absence of family studies, is likely to be difficult since many different mutations result in the disease. Management of Wilson's disease involves decreasing excess levels of copper accumulated in the liver, brain, and other organs. Copper chelation therapy, to increase urinary excretion of copper, is the mainstay of treatment. In addition, oral zinc therapy may be useful at decreasing absorption of dietary copper and rendering tissue copper nontoxic, by increasing the formation of complexes with copper-binding proteins. Liver transplantation can be necessary for individuals with acute hepatic failure or complications of cirrhosis. Gene therapy may evolve in the future; however, medical management is effective in most patients.
8531837##1995-8-1##Isolation of candidate genes by subtractive and sequential (Boolean) hybridization: an hypothesis.##This paper describes a theoretical method of isolating candidate disease-specific genes by polymerase chain reaction (PCR)-based subtractive hybridization and subsequent (Boolean) hybridization of the subtracted library to arrays of chromosome-specific cosmid clones. A specific application of this technique to isolate genes potentially related to Wilson's disease is outlined.
8556276##1995-8-1##Disordered copper metabolism in LEC rats, an animal model of Wilson disease: roles of metallothionein.##Disordered copper (Cu) metabolism in LEC rats, an animal model of Wilson disease, was characterized by specifying Cu in the liver, bloodstream and kidneys during the accumulation process and at the onset of jaundice; Cu accumulates in the liver with age in a form bound to metallothionein (MT). Massive Cu is liberated from MT when Cu accumulates beyond the capacity of MT synthesis. Cu bound to MT is not supplied to ceruloplasmin (Cp) during its maturation process, while the metal is transferred to Cu,zinc (Zn)-superoxide dismutase (SOD) directly from MT. Cu ions not bound to MT are transferred to Cp and the holo-Cp is excreted into the bloodstream near and at the onset of jaundice. Cu accumulated in the liver in a form bound to MT is removed selectively by tetrathiomolybdate (TTM), and the animal at the beginning of the onset of jaundice recovers by the chelation therapy. Mechanisms of the removal reaction were proposed to involve formation of MT/TTM, Cu/TTM, and/or polymeric Cu/TTM complexes according to the stoichiometry of TTM to Cu. The Cu/TTM complex was assumed to be effluxed into the bloodstream and to bind specifically to albumin. TTM is taken up by the liver in accordance with the Cu content. The toxicity of Cu was explained by the active oxygen species produced in Cu-mediated reactions, and the participation of MT.
7652819##1995-8-1##Does orthotopic liver transplantation normalize copper metabolism in patients with Wilson's disease?##
7483744##1995-8-1##7th International Symposium Wilson's Disease. Baden/Vienna, Austria, 25-27 August 1995. Abstracts.##
7601360##1995-7-1##Clues in the eye: ocular signs of metabolic and nutritional disorders.##Ocular signs and symptoms provide clinical clues to many of the more common metabolic and nutritional disorders seen in older adults. Diabetes mellitus can affect all parts of the eye and orbit. Complications include refractive visual loss, macular edema, retinopathy, increased risk of fungal infection, and diplopia. In patients with gout, urate crystals may precipitate in the eye and cause conjunctivitis, uveitis, or scleritis. Other problems are seen with Wilson's disease, hyperlipidemia, and albinism. Nutritional disorders usually arise from malabsorption, gastrointestinal surgery, and alcohol abuse. Deficiencies in vitamins A, B1 (thiamine), B12, and C may be manifest in the eye.
7672657##1995-7-1##Serum neopterin concentrations in chronic liver disease.##Neopterin is produced by macrophages after stimulation with interferon gamma or lipopolysaccharide. Its production is increased in many infectious, autoimmune, and malignant diseases. The aim of this study was to examine whether, on the basis of neopterin as a marker, liver diseases could be classified according to aetiology and stage of disease. A cohort of 264 patients with chronic liver diseases (viral, metabolic, autoimmune, toxic) and 150 normal controls were studied; 136 of the patients had cirrhosis. Increased serum neopterin concentrations were found in 41% of all patients (controls 6.0 (2.2) nmol/l), with patients in the cirrhotic stage of disease showing higher neopterin values (mean (SD) 15.7 (23.6) nmol/ml) than those in the non-cirrhotic stage (9.9 (5.5)). There were no statistically significant differences in the serum neopterin concentrations that could be considered characteristic for different stages of disease classified according to the Child criteria. Such differences in concentrations of neopterin that were found in patients with liver diseases grouped according to underlying causes were only marginal. Serum neopterin concentrations were found to be significantly lower than in any other disease group only in patients with Wilson's disease. The results suggest that activated macrophages participate in the development of chronic liver disease. Measurement of serum neopterin does not offer a reliable method for differentiating between various aetiologies of chronic liver diseases and does not help to predict severity of cirrhosis.
7622700##1995-7-1##MRI of the brain in Wilson disease: T2 signal loss under therapy.##Repeat examinations in a de novo patient with Wilson disease revealed an expansion of decreased signal intensities in the basal ganglia on T2-weighted imaging after initiation of copper trapping therapy. Since marked clinical improvement was associated with continued urinary copper excretion, iron depositioning in exchange for copper might explain these findings.
7580202##1995-1-1##Results of ECT for a case of depression in Wilson's disease.##
7617179##1995-7-1##Kayser-Fleischer ring: hepatolenticular degeneration (Wilson's disease).##
18591001##1995-2-13##Psychosis and epileptic seizures in Wilson's disease with predominantly white matter lesions in the frontal lobe.##Although psychiatric symptoms are not rare in Wilson's disease (WD), their association with epileptic seizures has not been reported. We describe three patients with such clinical manifestations who had predominantly cerebral white matter lesions in the frontal lobe. There were two men and one woman with ages ranging from 20 to 26 yr. The early presentations were psychiatric symptoms and epileptic seizures with or without secondary generalization. The psychiatric features were usually misinterpreted as schizophrenia-like disease and the diagnosis was delayed. The cerebral white matter lesions on magnetic resonance imaging (MRI) were usually asymmetric and mainly restricted to the frontal lobes. The present observation suggests that early onset of psychiatric manifestations and seizures commonly occur in WD with frontal white matter lesions.
7554299##1995-6-30##Low serum alkaline phosphatase activity associated with severe Wilson's disease. Is the breakdown of alkaline phosphatase molecules caused by reactive oxygen species?##
7671287##1995-6-28##[The human genome--chromosome 13 with an addendum on the repair system].##The chromosome number 13 which has been investigated least so far is known above all due to two loci: WND-responsible for Wilson's disease caused by impaired copper metabolism and RB1 which as to its effects belongs among so-called anti-oncogenes, i.e. suppressors of oncogenic processes. A special section of the paper deals with DNA - repair systems and their hereditary disorders.
7771405##1995-6-1##The mechanisms of penicillamine, trientine, and zinc in the treatment of Wilson's disease.##
7762553##1995-6-1##Haplotypes and mutations in Wilson disease.##Wilson disease is a disorder of copper transport, resulting in neurological and hepatic damage due to copper toxicity. We have recently identified &gt; 20 mutations in the copper-transporting ATPase defective in this disease. Given the difficulties of searching for mutations in a gene spanning &gt; 80 kb of genomic DNA, haplotype data are important as a guide to mutation detection. Here we examine the haplotypes associated with specific mutations. We have extended previous studies of DNA haplotypes of dinucleotide-repeat polymorphisms (CA repeats) in the Wilson disease region to include an additional marker, in 58 families. These haplotypes, combining three markers (D13S314, D13S316, and D13S301), are usually specific for each different mutation, even though highly polymorphic CA repeat markers have been used. Haplotypes, as well as their accompanying mutations, differ between populations. In the patients whom we have studied, the haplotype data indicate that as many as 20 mutations may still be unidentified. The use of the haplotypes that we have identified provides an important guide for the identification of known mutations and can facilitate future mutation searches.
7551824##1995-6-1##Biliary excretion of copper, metallothionein, and glutathione into Long-Evans Cinnamon rats: a convincing animal model for Wilson disease.##Long-Evans Cinnamon (LEC) rats, characterized by a gross accumulation of hepatic Cu and the spontaneous onset of hepatitis, have been established to be an animal model for Wilson disease. They were used to estimate the relationships among copper (Cu), metallothionein (MT), and reduced glutathione (GSH) in biliary excretion in this study. Even though a huge amount of MT existed in the LEC rat liver (5016 micrograms/g liver) compared to that (63 micrograms/g liver) of controls (Fischer rats), the biliary excretion of MT (65 ng/ml bile) did not reflect the accumulated MT level in LEC rats. It seems likely that MT does not excrete intrinsically into the bile. Biliary excretion of Cu (0.17 microgram/ml) in LEC rats was significantly lower than that (0.57 microgram/ml) in Fischer rats. The difference in biliary excretion of GSH between the two groups was significant but slight. The reduced excretion of GSH into bile in LEC rats may be due to increased hepatic gamma-glutamyltransferase but not to hepatic GSH levels. There were no differences in biliary potassium and inorganic phosphorous between the two groups. On the other hand, excretion of lysosomal enzymes such as beta-N-acetylglucosaminidase into bile was much lower in LEC rats (15.6 units/liter) than in controls (42.5 units/liter). The defective biliary excretion of Cu may be due to impaired lysosomal exocytosis, rather than canalicular membrane impairment. The LEC rat is very useful for research into the dynamics of metal excretion via the hepatobiliary system.
7634759##1995-6-1##Use of a stable copper isotope (65Cu) in the differential diagnosis of Wilson's disease.##1. 65Cu/63Cu stable-isotope ratios have been measured in blood serum after oral administration of the stable isotope 65Cu. The incorporation of the isotope into the plasma protein pool was followed at various times for up to 3 days. The resulting patterns of enrichment in healthy control subjects, in Wilson's disease patients and in heterozygotes for the Wilson's disease gene, were similar in appearance to those found by others using copper radioactive isotopes. After an initially high enrichment at 2 h after dosage, the Wilson's disease cases, in contrast to the control subjects, did not show a secondary rise in isotope enrichment of the plasma pool after 72 h, demonstrating a failure to incorporate copper into caeruloplasmin. The Wilson's disease heterozygotes had variable degrees of impairment of isotope incorporation, not always distinguished from those of control subjects. 2. The stability of the isotope also permits the copper tracer to be followed for a longer period. Ten healthy subjects were studied for over 40 days, allowing the biological half-time of an oral dose of copper to be determined (median 18.5 days, 95% confidence interval 14-26 days). Known heterozygotes for the Wilson's disease gene were found to have a significantly increased biological half-time for removal of copper from the plasma pool (median 43 days, 95% confidence interval 32-77 days). 3. The incorporation of 65 Cu in patients with diseases of the liver (other than Wilson's disease) was found to be similar to that in control subjects, aiding differential diagnosis.
7666402##1995-6-1##H714Q mutation in Wilson disease is associated with late, neurological presentation.##Wilson disease is an autosomal recessive copper storage disease resulting from an inability of the liver to excrete copper. Patients can present at a young age, generally with symptoms of liver copper intoxication, or later on, generally with neurological symptoms. The gene for Wilson disease has recently been cloned. Five mutations have been described so far, but only one is found frequently, H714Q. We analysed 38 Dutch symptomatic Wilson disease patients for the H714Q mutation and correlated this finding with age and symptoms at presentation. Ten patients homozygous for the H714Q mutation presented at a mean age of 20.3 (SD 6.1) years, with either neurological symptoms or a Kayser-Fleischer ring. Six patients with a H714Q mutation in one chromosome and an unknown mutation in the other chromosome presented at a mean age of 17.8 (SD 5.8) years, with either neurological or hepatic symptoms. With the exception of one, all 22 patients with an uncharacterised mutation in both chromosomes presented with liver involvement, at a mean age of 9.9 (SD 2.4) years. The difference in age at presentation between the H714Q/H714Q group and the patients with an unknown mutation was highly significant (p &lt; 0.0001). This suggests that the H714Q mutation represents a relatively mild mutation, possibly with some residual function in the copper transporting protein, resulting in a slower build up of copper.
7674840##1995-6-1##Defective copper binding to apo-ceruloplasmin in a rat model and patients with Wilson's disease.##To examine the mechanism of decrease in serum ceruloplasmin (Cp) in Long-Evans Cinnamon (LEC) rats, a proposed model of Wilson's disease, we analyzed Cp products at the stages of transcription and translation. Northern blot analysis and immunoblot analysis showed that the level and the molecular size of Cp mRNA and protein in LEC rats were similar to those in control Long-Evans-Agouti (LEA) rats. However, the ferroxidase activity of Cp was significantly decreased in LEC rats. We separated serum Cp into two forms by native polyacrylamide gel electrophoresis with pH modification: one was a holo-Cp with copper and ferroxidase activity, and the other was an inactive apo-Cp without copper. Holo-Cp was the predominant form in LEA rats and normal humans, whereas apo-Cp was the major form in LEC rats and patients with Wilson's disease. The cosegregation of apo-Cp predominance with the disease in LEC rats was analyzed using backcross rats. Apo-Cp was dominant in 8 of 11 offspring with disease but in none of 19 normal offspring. These results indicate that a genetic disturbance of copper binding to apo-Cp may be closely associated with the pathogenesis in LEC rats, and probably in Wilson's disease.
7618310##1995-6-1##Tremor disorders. Diagnosis and management.##Tremor is commonly encountered in medical practice, but can be difficult to diagnose and manage. It is an involuntary rhythmic oscillation of a body part produced by reciprocally innervated antagonist muscles. Tremors vary in frequency and amplitude and are influenced by physiologic and psychological factors and drugs. Categorization is based on position, posture, and the movement necessary to elicit the tremor. A resting tremor occurs when the body part is in repose. A postural tremor occurs with maintained posture and kinetic tremor with movement. Various pathologic conditions are associated with tremors. Essential tremor, which is the most common, is postural and kinetic, with a frequency between 4 and 8 Hz, and involves mainly the upper extremities and head. Essential tremor responds to treatment with primidone, beta-blockers, and benzodiazepines. Parkinson's disease causes a 4- to 6-Hz resting tremor in the arms and legs that responds to the use of anticholinergics and a combination of carbidopa and levodopa. Tremor can also be a manifestation of Wilson's disease, lesions of the cerebellum and midbrain, peripheral neuropathy, trauma, alcohol, and conversion disorders. Treatment should be directed to the underlying condition. Stereotactic thalamotomy of thalamic stimulation is a last resort.
7726170##1995-5-1##Wilson disease in Iceland: a clinical and genetic study.##A survey of Wilson disease in Iceland has revealed two large kindreds with affected individuals. We have carried out studies of haplotypes of dinucleotide repeat polymorphisms (CA repeats) flanking the Wilson disease gene. The same mutation, a 7-bp deletion, is present in both families, and the clinical features are similar. The haplotype data and nature of the mutation support the existence of a founder chromosome carrying the mutation. This Icelandic mutation was not found in patients of Irish or Scottish origins, who could share some of the Icelandic ancestral genes. Although the protein function is predicted to be completely abolished by the deletion, predicting early-onset liver disease, we find that the patients present with later-onset neurological and psychiatric symptoms. We show that alternative splicing of the transcript in the region of the deletion could contribute to later onset, suggesting that alternative isoforms of the protein might have some functional significance.
7788231##1995-5-1##Measurement of human pancreatic perfusion using dynamic computed tomography with perfusion imaging.##Absolute quantification of pancreatic perfusion in man has been extremely difficult to date. This paper describes a relatively simple application of dynamic computed tomography to provide perfusion imaging of the human pancreas. Values for perfusion in eight normal pancreases ranged between 1.25 and 1.66 ml min-1 ml-1 (mean: 1.52 ml min-1 ml-1). Increased perfusion values were present in a patient with an islet cell tumour (overall perfusion 2.11 ml min-1 ml-1) and a patient with Wilson's disease (3.43 ml min-1 ml-1). Pancreatic perfusion was reduced in a patient with diabetes (0.60 ml min-1 ml-1) and in a failing pancreatic transplant (0.97 ml min-1 ml-1). The combination of functional information and good spatial detail afforded by computed tomography (CT) perfusion imaging means the technique is well suited for the evaluation of the human pancreas. It is currently the only technique which allows non-invasive absolute quantification of pancreatic perfusion.
9081968##1995-5-1##Wilson's disease: an update.##
8692598##1995-5-1##[Wilson disease with HCV infections].##In this paper we describe liver-related Wilson's disease in two sisters. The elder died of liver failure. Our patient, a 13-year old girl has hepatitis C coinfection. Gradual improvement was observed after Cuprenil, Zincteral and interferon (Intron A).
7733979##1995-4-26##Neuromedin C binds Cu(II) and Ni(II) via the ATCUN motif: implications for the CNS and cancer growth.##Neuromedin C is a bombesin-like neuropeptide of the sequence Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2. Characterization of the amino terminal Cu(II), Ni(II) binding motif in albumins led us to predict that any other peptides or proteins with the same motif would also bind Cu(II) and Ni(II) specifically (1). The primary sequence of neuromedin C contains the motif in the form Gly-Asn-His. Neuromedin C was therefore predicted to bind Cu(II) and Ni(II) specifically. The studies presented here confirm that prediction. These findings may have implications for the transport of Cu(II) within the central nervous system as well as both Menkes disease and Wilson disease. Both are genetic copper metabolism disorders which are characterized by severe neurological symptoms. In addition, Cu(II) may interfere with the neurotransmission or growth factor effects of neuromedin C.
7723883##1995-4-15##[Wilson's disease; diagnosis with the aid of magnetic resonance tomography].##In a 21-year-old woman with a smaller and sloppy handwriting, drooling especially when stooping, sporadic choking, clumsiness, and frequent stumbling, Wilson's disease was diagnosed. The medical history disclosed a short period of haemolytic anaemia with transient hepatic failure, and irregular menstruation periods with infertility. On examination there were no signs of liver or spleen enlargement. She was slow, had an expressionless face and mild dysarthria, and slight impairment of the coordination of the limbs. Magnetic resonance imaging of the brain showed bilateral hyperintensive lesions of the basal ganglia on T2W images. Zinc therapy induced a good biochemical response and there was also some clinical improvement. Linkage analysis within the family identified one other asymptomatic homozygotically affected sister. A diagnostic delay occurs frequently due to relative unfamiliarity with this rare disease and due to its variable clinical expression.
7607665##1995-4-10##Characterization of the exon structure of the Menkes disease gene using vectorette PCR.##The gene defective in Menkes disease, an X-linked recessive disturbance of copper metabolism, has been isolated and predicted to encode a copper-binding P-type ATPase. We determined the complete exon-intron structure of the Menkes disease gene, which spans about 150 kb of genomic DNA. The gene contains 23 exons, and the ATG start codon is in the second exon. All of the exon-intron boundaries were sequenced and conformed to the GT/AT rule, except for the 5' splice site of intron 9. A preliminary comparison demonstrated a striking similarity between the exon structures of the Menkes and Wilson disease genes, giving insight into their evolution.
7625159##1995-4-1##Late diagnosis of Wilson's disease in a case without onset of symptoms.##Wilson's disease (WD) was diagnosed on the basis of a liver biopsy, blood investigations and a radio copper test in a 60-year-old, neurologically normal female with uncharacteristic gastrointestinal complaints. Since this patient never developed symptoms indicative for WD this case suggests the possibility of a subclinical course of untreated WD.
7793244##1995-4-1##Analysis of seven pedigrees of childhood Wilson's disease characterized by abdominal symptoms.##In a survey of childhood Wilson's disease (WD) characterized by abdominal symptoms, three patients with high levels of immunologically detectable ceruloplasmin (CP) in serum were found. These three cases were compared with typical cases of WD in which serum CP level was low. In order to clarify the cause of WD, serum CP levels were quantified by two methods, an immunological protein assay and an oxidase activity assay. Using the results of these two assays, WD cases were classified into three groups on the basis of CP content; the first group consisted of patients with low enzyme activity and low CP protein content, the second group consisted of patients with low enzyme activity and normal CP protein content, and the third group, those patients with normal enzyme activity and normal CP protein content. No significant difference in symptoms was observed between these three groups. Since relatively high levels of CP were detected in some WD patients, genetic variation in CP in WD patients was examined by restriction enzyme fragment length polymorphism analysis using CP cDNA. However, no large deletion in the CP gene was detected. Using four types of gene probes for chromosome 13 known to be related to WD, the DNA of WD patients was examined in a similar fashion, but no significant difference was observed between the groups.
7900739##1995-4-1##D-penicillamine-induced myasthenia gravis: diagnosis obscured by coexisting chronic obstructive pulmonary disease.##D-penicillamine, a drug used to treat rheumatoid arthritis, Wilson's disease, and cystinuria, can cause myasthenia gravis. Fortunately, the myasthenia typically resolves after discontinuation of the drug. The diagnosis may be missed if weakness is blamed on a patient's underlying disease(s), in particular, rheumatoid arthritis. Reported here are the cases of two patients with chronic obstructive lung disease who were taking D-penicillamine for rheumatoid arthritis, then experienced increasing respiratory failure. At first, their problem seemed to stem from chronic lung disease, but further evaluation revealed the cause of the hypoventilation to be D-penicillamine-induced myasthenia gravis.
7710368##1995-4-1##Treatment of the neurologic manifestations of Wilson's disease.##
7705796##1995-4-1##Genetic hemochromatosis and Wilson's disease: role for oxidant stress?##
7705774##1995-4-1##Pretransplantation clinical status and outcome of emergency transplantation for acute liver failure.##Emergency transplantation for acute liver failure has a significantly inferior outcome than transplantations performed for elective indications. The severity of the pretransplantation clinical illness in this group will contribute to the reduced patient survival. We have reviewed the outcome of our first 100 consecutive adult patients who received transplants for acute liver failure and have evaluated and determined which recipient clinical parameters present on admission and at transplantation act as risk factors in early posttransplantation outcome. In patients who received transplants for nonacetaminophen-induced liver failure (n = 79), no static variable determinable on admission (including age, sex, year of transplantation, hospital admission to transplantation period, and fulminant or late-onset presentation) other than cause was predictive of 2-month patient survival. Fulminant Wilson's disease and idiosyncratic drug reactions with 2-month survival rates of 100% and 12.5%, respectively, had significantly different outcomes from other causes. By the time of transplantation, of four dynamic variables significant in a univariate analysis (serum creatinine, encephalopathy grade, Apache 111 and organ system failure scores, and P values &lt; .05), only the creatinine level was an independent variable in a stepwise logistic regression for 2-month survival (r = .33). In patients who received transplants for acetaminophen hepatotoxicity (n = 21), overdose to hepatectomy period was the only significant static variable, with no parameter predictive of outcome present on admission.(ABSTRACT TRUNCATED AT 250 WORDS)
7725405##1995-4-1##Responsible gene for hepatitis of the LEC rat (hts) is the homolog of the human Wilson's disease (WD) gene.##
7706313##1995-3-31##Excess copper and ceruloplasmin biosynthesis in long-term cultured hepatocytes from Long-Evans Cinnamon (LEC) rats, a model of Wilson disease.##Immortalized hepatic cell lines obtained from laboratory animals or patients with defects in copper metabolism in the liver provide new approaches to examine related metabolism and toxicity. We established a series of hepatic cell lines from the liver of Long-Evans Cinnamon (LEC) rats, using recombinant adenovirus which expresses SV40 large T. Cells from the LEC rats were cultured and accumulated larger amounts of copper than did control cells, when the concentrations of copper in the culture medium exceeded 5 microM. The secretion of ceruloplasmin (CP) from the cultured cells was not reduced in hepatocytes from LEC cells, as compared with the control cells. As accumulation of copper did not affect CP secretion, CP production was not likely to be affected by the accumulation of copper in LEC rat hepatocytes. The production of holo-CP was further investigated by transfection of human CP cDNA and detection of human holo-CP by immunological procedures and use of a monoclonal antibody (mAb CP60) which recognizes human holo-CP but not human apo-CP and rat CP. Hepatocytes from the LEC rats processed and secreted holo-CP into the medium, even with excess copper present in the medium. These observations suggest that the genetic defect in LEC rats did not alter biosynthetic and secretory pathways of CP and that the intracellular copper concentration did not regulate the synthesis and processing of CP in the cultured hepatocytes. Low ceruloplasmin levels are observed in most, but not all, patients with Wilson disease, as well as in LEC rats. Our results do suggest that the copper transporting ATPase encoded in the Wilson disease gene is not a integral part of the biochemical mechanism of copper incorporation into apoprotein. The cell lines and immunological procedures we used are expected to add to information on biologically important process related to copper metabolism and to CP biosynthesis.
7708696##1995-3-28##The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-like oxidase required for iron uptake.##The CCC2 gene of the yeast Saccharomyces cerevisiae is homologous to the human genes defective in Wilson disease and Menkes disease. A biochemical hallmark of these diseases is a deficiency of copper in ceruloplasmin and other copper proteins found in extracytosolic compartments. Here we demonstrate that disruption of the yeast CCC2 gene results in defects in respiration and iron uptake. These defects could be reversed by supplementing cells with copper, suggesting that CCC2 mutant cells were copper deficient. However, cytosolic copper levels and copper uptake were normal. Instead, CCC2 mutant cells lacked a copper-dependent oxidase activity associated with the extracytosolic domain of the FET3-encoded protein, a ceruloplasmin homologue previously shown to be necessary for high-affinity iron uptake in yeast. Copper restored oxidase activity both in vitro and in vivo, paralleling the ability of copper to restore respiration and iron uptake. These results suggest that the CCC2-encoded protein is required for the export of copper from the cytosol into an extracytosolic compartment, supporting the proposal that intracellular copper transport is impaired in Wilson disease and Menkes disease.
7708681##1995-3-28##Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.##Ceruloplasmin is an abundant alpha 2-serum glycoprotein that contains 95% of the copper found in the plasma of vertebrate species. We report here on the identification of a genetic defect in the ceruloplasmin gene in a patient previously noted to have a total absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration. In this patient T2 (transverse relaxation time)-weighted magnetic resonance imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410, resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patient's daughter, which revealed heterozygosity for this same 5-bp insertion. The presence of this mutation in conjunction with the clinical and pathologic findings demonstrates an essential role for ceruloplasmin in human biology and identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism. These findings support previous studies that identified ceruloplasmin as a ferroxidase and are remarkably consistent with recent studies on the essential role of a homologous copper oxidase in iron metabolism in yeast. The clinical and laboratory findings suggest that additional patients with movement disorders and nonclassical Wilson disease should be examined for ceruloplasmin gene mutations.
7882336##1995-3-15##Deletion cartography around the D13S25 locus in B cell chronic lymphocytic leukemia and accurate mapping of the involved tumor suppressor gene.##The presence of an unidentified tumor suppressor gene on the long arm of chromosome 13 which could be involved in the development of B cell chronic lymphocytic leukemia has been suspected because of frequent deletions of the locus D13S25 which lies 1.6 cM telomeric to the retinoblastoma gene. In order to accurately map this gene, cells from 25 B cell chronic lymphocytic leukemia tumors have been analyzed for allelic loss using a panel of microsatellite markers located in this region. These markers, which stretch from the retinoblastoma gene to the Wilson disease gene, have been ordered for their rank from centromere to telomere. In addition to the data obtained from deletion pattern of these markers, results from preliminary pulse-field electrophoresis studies enable us to redefine the minimal deleted area from more than 1 cM to 280 kilobase around D13S25.
7741229##1995-3-1##Analysis of copper and lead in hair using the nuclear microscope; results from normal subjects, and patients with Wilson's disease and lead poisoning.##We have recently developed a technique utilizing the nuclear microscope to analyse accurately the trace element content of hair at concentrations of ppm and to differentiate between the levels within hair and those due to surface contamination. Hair was analysed from four patients with Wilson's disease (systemic copper overload), one patient with sub-acute lead poisoning, and three control subjects, and the concentrations and distributions of lead and copper across the hair shafts were shown. However, there was no increase in the copper content of hair from patients with Wilson's disease compared with those of normal subjects, indicating that the high copper levels of many tissues in this disease are not reflected in hair. In contrast, hair samples from the patient with lead poisoning showed maximum concentrations of 14 (+/-2) micrograms g-1, compared with normal levels of less than 1 micrograms g-1. Further, the composition of the hairs along the shaft reflected the temporal changes of lead levels in the patient during lead elimination.
7875493##1995-3-1##Copper-induced acute rhabdomyolysis in Wilson's disease.##Wilson's disease is a lethal defect in copper metabolism causing a continual increase in tissue copper concentrations that become toxic to the liver, brain, kidney, eye, skeletal system, and several other tissues and organs. The liver is unique among these in being both the site of the etiologic biochemical abnormality and the organ that is always affected by copper toxicosis. Although myocardial muscle involvement has been reported in association with Wilson's disease, copper deposits in peripheral muscle tissue have not yet been described. A case of a young patient with Wilson's disease who developed recurrent episodes of acute rhabdomyolysis is presented, and the accumulation of copper in muscle tissue as a possible complication is discussed.
7608481##1995-3-1##Uneven hepatic copper distribution in Wilson's disease.##
7727159##1995-3-1##[Wilson's disease--evolutive panorama of diagnosis and treatment in the last forty years].##In 1912, Wilson and Fleischer independently reported autopsied patients with progressive neurological disorder associated with cirrhosis of the liver, and they proposed that the syndrome could be a specific disease of toxic origin. In 1952, Scheinberg demonstrated a deficiency of serum ceruloplasmin in Wilson's disease, and it became possible to diagnose the illness while the patient was still asymptomatic. In 1956, Walshe introduced penicillamine as the most excellent drug for treatment of the disease. These epoch-making discoveries encouraged Japanese physicians to make early diagnosis and to try prevention of the disease. This lecture was to review the changing panorama in the diagnosis, treatment and prognosis of the disease in the period of forty years focusing on the experiences in Japan. Early detection of the patients based on hypoceruloplasminemia made it possible to investigate the onset ages of an elevation of serum GOT or GPT and the appearance of Kayser-Fleischer (KF) rings. So far, the youngest patients who exhibited high GPT level and KF rings were three years and five years old, respectively. It became popular that an unexpected elevation of serum transaminase in apparently healthy children of three years or more prompted to examine the possibility of Wilson's disease, and an increasing number of non-familial patients in late infancy have been detected. Now, the mass-screening for Wilson's disease is in progress. Follow-up studies on the prophylaxis for more than thirty years definitely proved that the appearance of clinical symptoms was prevented with the continued penicillamine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
7478717##1995-3-1##Wilson's disease in Albania.##There are 40 patients with Wilson's disease diagnosed in Albania; 24 were males and 16 females with an average age 18.8 +/- 8.47 years. The incidence rate was 1:75.000 and prevalence rate 1:148.000. According to clinical data, the Kayser-Fleischer ring was found in 75% of the cases, the neurologic in 60% and mental disturbances in 27.5%. The liver was damaged in all the cases of acute and chronic hepatitis or liver cirrhosis. In 35% signs of hypersplenism were seen. Comparing these data with a control group of 60 alcoholic or viral cirrhosis with hypersplenism, it was found that hypersplenism is encountered in younger ages (p &lt; 0.0001). The platelets were lower in WD than in the control group (p &lt; 0.05), but leucocytes were lower in the control group (p &lt; 0.001). Portal hypertension was found in 42.5% of the cases. Six of these (35.3%) were complicated by gastrointestinal hemorrhage. In two twins the disease was accompanied with another congenital anomaly: genu valgum bilateralis. Two other patients had hypertrophy of the parotis gland, six patients had signs of acute haemolysis, accompanied by nonspherocytic anemia, Coombs negative.
7792379##1995-3-1##Psychosis in an adolescent patient with Wilson's disease: effects of chelation therapy.##Wilson's disease is a rare genetic disorder involving the liver and brain, with onset frequently in adolescence. Psychiatric symptoms are often the first manifestation of the disease and can obscure the diagnosis. Chelation therapy can reverse the fatal outcome of untreated patients, so early detection is critically important. This paper describes an adolescent with Wilson's disease who, after initiation of penicillamine therapy, developed florid psychosis that improved as copper levels were decreased and that did not require use of neuroleptic medication.
7785328##1995-3-1##Sequence, mapping and disruption of CCC2, a gene that cross-complements the Ca(2+)-sensitive phenotype of csg1 mutants and encodes a P-type ATPase belonging to the Cu(2+)-ATPase subfamily.##We have isolated, sequenced, mapped and disrupted a gene, CCC2, from Saccharomyces cerevisiae. This gene displays non-allelic complementation of the Ca(2+)-sensitive phenotype conferred by the csg1 mutation. Analysis of the CCC2p amino acid sequence reveals that it encodes a member of the P-type ATPase family and is most similar to a subfamily thought to consist of Cu2+ transporters, including the human genes that mutate to cause Wilson disease and Menkes disease. The ability of this gene, in two or more copies, to reverse the csg1 defect suggests that Ca(2+)-induced death of csg1 mutant cells is related to Cu2+ metabolism. Cells without CCC2 require increased Cu2+ concentrations for growth. Therefore CCC2p may function to provide Cu2+ to a cellular compartment rather than in removal of excess Cu2+.
7766211##1995-2-1##Ion efflux systems involved in bacterial metal resistances.##Studying metal ion resistance gives us important insights into environmental processes and provides an understanding of basic living processes. This review concentrates on bacterial efflux systems for inorganic metal cations and anions, which have generally been found as resistance systems from bacteria isolated from metal-polluted environments. The protein products of the genes involved are sometimes prototypes of new families of proteins or of important new branches of known families. Sometimes, a group of related proteins (and presumedly the underlying physiological function) has still to be defined. For example, the efflux of the inorganic metal anion arsenite is mediated by a membrane protein which functions alone in Gram-positive bacteria, but which requires an additional ATPase subunit in some Gram-negative bacteria. Resistance to Cd2+ and Zn2+ in Gram-positive bacteria is the result of a P-type efflux ATPase which is related to the copper transport P-type ATPases of bacteria and humans (defective in the human hereditary diseases Menkes' syndrome and Wilson's disease). In contrast, resistance to Zn2+, Ni2+, Co2+ and Cd2+ in Gram-negative bacteria is based on the action of proton-cation antiporters, members of a newly-recognized protein family that has been implicated in diverse functions such as metal resistance/nodulation of legumes/cell division (therefore, the family is called RND). Another new protein family, named CDF for 'cation diffusion facilitator' has as prototype the protein CzcD, which is a regulatory component of a cobalt-zinc-cadmium resistance determinant in the Gram-negative bacterium Alcaligenes eutrophus. A family for the ChrA chromate resistance system in Gram-negative bacteria has still to be defined.
7772379##1995-2-1##Deletion of the Wilson's disease gene in hereditary hepatitis LEC rats.##LEC rats develop disorder of cooper metabolism and hepatitis similar to those of human Wilson's disease. We recently demonstrated that the gene responsible for hepatitis (hts) of LEC rats is homologous to Wilson's disease gene (WD). The present study showed a deletion of at least 90 base pair of WD cDNA in LEC rats, which corresponds to nucleotides 3981 to 4071 in human WD cDNA sequence. This deletion was linked with hepatic copper accumulation and hepatitis, and considered to be a primary mutation for hepatic disorder in the LEC rat. The WD gene was assigned to rat chromosome 16 at band q12.2-q12.4 by fluorescence in situ hybridization (FISH).
7529889##1995-2-1##Detection of bulky DNA lesions in the liver of patients with Wilson's disease and primary haemochromatosis.##In the human metal storage disorders of Wilson's disease and primary haemochromatosis, ion transport and excretion dysfunctions result in the intracellular deposition of copper and iron, respectively. These aberrant accumulations of transition metal ions lead to extensive tissue damage, especially in the liver. In order to investigate the possible role of metal ion-mediated oxygen free radical-generated DNA damage in these processes, DNA was isolated from liver of eight Wilson's disease patients and six haemochromatosis patients. Significant levels of bulky DNA damage were detected in these samples by 32P-postlabelling analysis, but were not found in liver DNA from age-matched controls. This form of novel DNA damage was detected in six out of eight Wilson's patients, varying between approximately 1 and 100 base modifications per 10(8) nucleotides, and in all of the haemochromatosis samples examined; the levels of modified species per 10(8) nucleotides varying from approximately 2 to 50. HPLC analysis of these bulky DNA lesions demonstrated that the species formed in Wilson's disease and in haemochromatosis were chromatographically identical but were not the same as putative purine dimers that can be generated in DNA by in vitro incubation with Cu+/Fe2+ and H2O2 (although the possibility that the adducts detected are closely related has not been ruled out). Analysis of the oxidative base lesion 8-hydroxydeoxyguanosine showed that levels were not elevated in liver DNA from either Wilson's disease or haemochromatosis sufferers. In fact, a statistically significantly lower level of this lesion was found in Wilson's disease patients than in controls. These data suggest that bulky DNA damage present in the liver of both wilson's disease and primary haemochromatosis patients may play a more important role in the induction of tissue damage than 8-hydroxydeoxyguanosine. The novel DNA damage detected by 32P-poslabelling may also be a significant factor in the initiation of neoplasia leading to malignant hepatoma in haemochromatosis patients.
7626145##1995-2-1##The Wilson disease gene: spectrum of mutations and their consequences.##We have previously reported the cloning of a gene that encodes a copper transporting P-type ATPase (ATP7B) which is defective in Wilson disease. We have now identified in 58 WND patients, 20 new mutations as well as three of five previously published mutations: 11 small insertions and deletions, seven missense, two nonsense and three splice site mutations. Two of the mutations are relatively frequent, representing 38% of the mutations in patients of European origin. Our findings suggest a wider spectrum of age of onset than is considered typical of Wilson disease: mutations that completely disrupt the gene can produce liver disease in early childhood when Wilson disease may not typically considered in the differential diagnosis. The mutations identified provide an explanation for at least part of the wide phenotypic variation observed in Wilson disease.
7731761##1995-2-1##Plasma copper and antioxidant status in Wilson's disease.##It has been demonstrated that the level of serum copper unbound to ceruloplasmin (loosely bound copper) is increased in Wilson's disease, although the total serum copper concentration is usually low, reflecting a low ceruloplasmin level. To assess the contribution of free radical reactions catalyzed by nonceruloplasmin copper to the development of complications in this disease, we investigated copper and antioxidant status in four untreated patients who had hepatic dysfunction with or without hemolytic anemia and made a comparison with five patients controlled on penicillamine therapy and 19 age-matched healthy children. We found that loosely bound copper in plasma measured by the phenanthroline assay was detectable in three of four untreated patients with Wilson's disease, but was not detectable in the patients during therapy or in the healthy controls. Among the various antioxidants, the ascorbate and urate levels were markedly reduced before treatment (mean +/- SD, 23 +/- 16 microM for ascorbate and 90 +/- 59 microM for urate) compared with the values in the patients during treatment with penicillamine (67 +/- 19 and 302 +/- 78 microM, p &lt; 0.05) and in control children (60 +/- 8 and 254 +/- 48 microM, p &lt; 0.05). We also demonstrated that the plasma concentration of allantoin, an oxidation product of uric acid and a possible marker of radical generation in vivo, was markedly elevated in the untreated patients (11.0 +/- 1.8 versus 4.3 +/- 0.5 microM in patients on therapy and 6.5 +/- 0.8 microM in controls, p &lt; 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
7878838##1995-2-1##Timing of transplantation and donor selection in living related liver transplantation for fulminant Wilson's disease.##
7839442##1995-1-27##Weaning of immunosuppression in long-term liver transplant recipients.##Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to &lt; 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.
7840659##1995-1-10##Hydroxyl radical formation from cuprous ion and hydrogen peroxide: a spin-trapping study.##Copper toxicity has been presumed to involve catalytic hydroxyl radical (.OH) formation from hydrogen peroxide. Addition of Cu1+ to a solution containing ethanol or dimethylsulfoxide (Me2SO) and the spin-trapping agent alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) results in formation of the alpha-hydroxyethyl radical or methyl radical adduct of 4-POBN, respectively. Adduct formation was prevented by inclusion of catalase, but not by superoxide dismutase. Inclusion of exogenous H2O2 in the reaction mixture increased the yield of ethanol- or Me2SO-derived radical adduct and also enhanced the formation of secondary radical adducts, including 4-POBN/.H and the methyl radical adduct of 2-methyl-2-nitrosopropane. The alpha-hydroxyethyl adduct of 4-POBN is rapidly decomposed in the presence of copper, but not iron salts, whereas the methyl radical adduct is relatively stable in the presence of inorganic copper. The total concentration of radical adduct detected from the reaction between Cu1+ and H2O2, determined by comparison of the integrated spectral intensity with that of the stable 2,2,6,6-tetramethyl-1-piperidinyloxy free radical, was only 1-5% of the maximum amount predicted assuming radical adduct formation from all of the added copper. A variety of copper chelators inhibit formation of carbon-centered radical adducts of 4-POBN, including penicillamine and triethylenetetramine, which are the primary drugs used to treat the copper metabolism disorder Wilson's disease. The results provide clear evidence for hydroxyl radical formation from Cu1+ and H2O2 (either added or formed during the autoxidation of reduced copper.
7618524##1995-1-1##Studies of diagnosis and pathogenesis of Wilson's disease.##We have studied the copper and metallothionein (MT) in culture skin fibroblasts of patients and heterozygotes with Wilson's disease (WD) and controls (5 cases each) after incubation in mediums containing various concentrations of copper (C1: 15.74 mumol/L, C2: 78.70 mumol/L, C3: 157.38 mumol/L, C4: 314.76 mumol/L). The results are as follows: 1. In each of the three groups, the copper/protein ratio (Cu/P) in cytosols of 1-5 passages is significantly higher than that of 6-10, 11-15, 16-20 passages. There are no significant differences among 6-10, 11-15 and 16-20 passages. 2. In standard medium, Cu/P in cytosols of three groups are not significantly different, but Cu/P of patients is significantly higher than that of the other two groups after incubation in C4 medium for 12 or 24 hours. 3. After incubation in C1, C2, C3 and C4 mediums respectively, the Cu/P in cytosols of the three groups only increased in C4 medium with time (within 72 hours). It is higher in the patient group than the other two groups. 4. In the three groups, cytosol copper distributed similarly in two peaks after Sephadex G-75 chromatography, which are on high molecular weight (HMW) proteins and MT fractions respectively. It remained the same after incubation in various concentrations of copper. The copper content found in MT fractions in WD patients is much higher than that of controls and heterozygotes. It is even higher after incubation in various concentrations of copper but no changes was found in controls and heterozygotes.(ABSTRACT TRUNCATED AT 250 WORDS)
7484454##1995-1-1##Menkes and Wilson diseases.##
7872138##1995-1-1##Psychiatric and behavioral abnormalities in Wilson's disease.##From the literature and our experience, a relatively consistent picture of psychiatric and behavioral abnormalities in Wilson's disease emerges. The essential elements of this picture are as follows: 1. Psychiatric and behavioral abnormalities are frequent manifestations of WD. The estimates range from 30% (18) to 100% (2) of symptomatic patients. As Wilson himself was the first to state in reference to &quot;mental change,&quot; &quot;its importance should not be underestimated.&quot; 2. Psychiatric and behavioral abnormalities are often the initial manifestations of WD. Two thirds of our patients first presented with psychiatric symptoms and one third received psychiatric treatment before the diagnosis of WD was made. In the early stages of the disease, when psychiatric and behavioral symptoms predominate, the diagnosis is often missed. Of our 124 patients, WD was diagnosed in only one during this phase. Until the psychiatric presentation of WD is recognized, and the disease is included in the differential diagnosis of psychiatric symptoms, its diagnosis will be missed or delayed. In our patients, and others' (13,15), the delay in diagnosis ranged from 1 to 5 years. Such a delay is particularly tragic as favorable outcome depends upon early discovery. 3. The most common of the psychiatric and behavioral manifestations of WD include: personality changes such as irritability and low threshold to anger, depression sometimes leading to suicidal ideation and attempts, deteriorating academic and work performance that is present in almost all neurologically affected patients. We (1) have also observed, as did Scheinberg and Sternlieb (2) that WD patients exhibit increased sexual preoccupation and reduced sexual inhibition. Finally, cognitive impairment, psychosis, anxiety, and other psychiatric disorders, although less frequent, also occur. 4. Some of the psychiatric and behavioral symptoms are reversible with WD-specific therapy, whereas others are not. We are impressed with the frequency with which the behavioral and &quot;cognitive&quot; symptoms are reversed over 1 to 2 years of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
7825531##1995-1-1##Potential complication of multivitamin use in patients with Wilson's disease.##
8527222##1995-1-1##Cellular copper transport.##Cellular copper transport processes are required by all organisms for correct utilization in cell biochemical processes and avoidance of the toxicity of copper excess. Copper import into bacterial, yeast, and mammalian cells requires the coordinate function of proteins with both metal-binding and catalytic domains in mediated transport steps. Following entry, detoxification mechanisms found across species include the binding of copper to specific proteins (e.g. metallothioneins) and the transfer of copper into isolated cell compartments (e.g. periplasmic space, lysosome). Multiple proteins mediate intracellular transfers in bacteria, and glutathione may play a major role in cytosolic copper delivery to cuproenzymes in mammalian cells. Study of two human disorders of copper transport, Menkes disease and Wilson disease, led to the identification of an important category of proteins mediating cell copper export. The Menkes and Wilson disease gene products are copper-transporting ATPases of the P type, with ATPase domains and N-terminal metal-binding amino acid motifs that are evolutionarily conserved in unicellular and mammalian organisms. These observations suggest that yeast and bacterial copper transport proteins, or individual domains of these proteins, may generally have homologues in mammalian systems.
7826266##1995-1-1##Zinc-induced deterioration in Wilson's disease aborted by treatment with penicillamine, dimercaprol, and a novel zero copper diet.##
7718428##1995-1-1##Hyperlipidemia, amyloidosis, sarcoidosis, iron storage disease, and Wilson's disease.##The objective of this review is to summarize the most recent developments related to this miscellaneous group of diseases. Emphasis has been placed on information that will help the practicing physician, such as clinical observations, improved diagnostic techniques, particularly ones that are noninvasive or minor, and new therapeutic approaches. An interesting animal study that helps in the understanding of the increased frequency of coronary artery disease in patients with long-standing systemic lupus erythematosus is described.
7788483##1995-1-1##Case report: concordant traumatic brainstem contusion delayed diagnosis in a young man with Wilson's disease.##Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism. The corresponding gene locus has been localized on the long arm of chromosome 13. Three different clinical variants of the disease can be distinguished: hepato-cerebral, abdominal/hepatic, and central nervous type. The heterogeneity of symptoms can cause problems in differential diagnosis, especially when another concordant disorder can also explain the pathogenesis of symptoms. The case report of a young man who suffered from brainstem contusion demonstrates the possibilities of misinterpretation because presenting symptoms could be attributed either to traumatic brain injury followed by adjustment disorder or Wilson's disease. Clinical signs included leftsided hemiparesis, bilateral gaze direction nystagmus, marked dysarthria with consecutive pervasive mutism, choreo-athetoid movements, spasmodic torticollis and diplopia dependent on gaze direction. Slit lamp examination showed Kayser-Fleischer's corneal ring. EEG- and computer assisted tomography investigations revealed non-specific findings. The patient was treated with D-Penicillamine. Alternative treatment with oral zinc preparations is discussed.
7806169##1995-1-1##Anti-liver cytosolic antigen type 1 (LC1) antibodies in childhood autoimmune liver disease.##Antibodies to liver cytosol antigen type 1 (anti-LC1), which recognize a 60-kd peptide contained in the liver cytosolic fraction, have been reported to define a subset of autoimmune hepatitis (AIH) either negative for other autoantibodies or positive for anti-liver kidney microsomal antibody type 1 (LKM-1) and to be best detected in immunodiffusion. To analyze the prevalence of anti-LC1 in childhood liver disease, we have tested the sera of 95 patients using immunoblot, indirect immunofluorescence, and immunodiffusion. Fifteen children had smooth muscle antibody (SMA) and/or anti-nuclear antibody (ANA)-positive AIH, 13 had anti-LKM-1-positive AIH, 14 had autoimmune sclerosing cholangitis (ASC) (all SMA and/or ANA positive), and 53 had non-autoimmune liver disease (10 had alpha 1-anti-trypsin deficiency [alpha 1-ATD], 11 had Wilson's disease [WD], 14 had Alagille's syndrome, and 18 had chronic hepatitis B virus [HBV] infection). Twenty healthy children were studied as controls. Anti-LC1 positivity in immunodiffusion and strong reactivity in immunoblot were found in 4 LKM-1- and 2 SMA/ANA-positive patients with AIH and in 1 patient with ASC, but in none of the patients with other liver diseases nor in controls. A weak 60-kd band was detected by immunoblot in 6 more patients with AIH (2 were LKM-1- and 4 were SMA/ANA-positive) and 6 patients with ASC, all anti-LC1-negative by immunofluorescence and immunodiffusion. No distinct clinical features characterized the anti-LC1-positive patients.(ABSTRACT TRUNCATED AT 250 WORDS)
7649526##1995-1-1##Effect of growth hormone on IGF-I levels in a patient with growth hormone deficiency and Wilson disease.##This is a case report of a boy with a combination of two rare disorders:growth hormone deficiency (GHD) and Wilson disease. To our knowledge, no comparable case has yet been published in the literature. GHD was diagnosed at the age of 4.5 years (height standard deviation score (SDS) -4.85). However, because of a difficult family background, growth hormone (GH) therapy could not be started. The boy was not seen again until the age of 7.7 years (height SDS -4.77), when GHD was reconfirmed and GH therapy could be initiated (dose 0.6 IU/kg/week). At that time, elevated liver enzymes (GPT 128 U/l, GOT 67 U/l, gamma-GT 28 U/l) confused diagnostic procedures. On GH, growth velocity SDS increased from -1.86 to +4.50 in the first year and +3.87 in the second year, and height SDS increased to -4.26 and -3.59. However, serum IGF-I levels did not normalize (max. 67 ng/ml), and liver enzymes were still elevated. At the age of 10 years, Wilson disease was diagnosed in view of low concentration of serum ceruloplasmin, elevated urinary copper excretion and high copper content in a liver biopsy sample. Under a combined therapy with D-penicillamine and GH, serum liver enzymes decreased, and IGF-I levels increased to normal. Height SDS for chronological age has improved constantly.
9282648##1995-1-1##Leucodystrophic CT changes in Wilson's disease.##
7814642##1995-1-1##Adenosine triphosphate-dependent copper transport in isolated rat liver plasma membranes.##The process of hepatobiliary copper (Cu) secretion is still poorly understood: Cu secretion as a complex with glutathione and transport via a lysosomal pathway have been proposed. The recent cloning and sequencing of the gene for Wilson disease indicates that Cu transport in liver cells may be mediated by a Cu transporting P-type ATPase. Biochemical evidence for ATP-dependent Cu transport in mammalian systems, however, has not been reported so far. We have investigated Cu transport in rat liver plasma membrane vesicles enriched in canalicular or basolateral membranes in the presence and absence of ATP (4 mM) and an ATP-regenerating system. The presence of ATP clearly stimulated uptake of radiolabeled Cu (64Cu, 10 microM) into canalicular plasma membrane vesicles and, to a lesser extent, also into basolateral plasma membrane vesicles. ATP-dependent Cu transport was dose-dependently inhibited by the P-type ATPase inhibitor vanadate, and showed saturation kinetics with an estimated Km of 8.6 microM and a Vmax of 6.9 nmol/min/mg protein. ATP-stimulated Cu uptake was similar in canalicular membrane vesicles of normal Wistar rats and those of mutant GY rats, expressing a congenital defect in the activity of the ATP-dependent canalicular glutathione-conjugate transporter (cMOAT). These studies demonstrate the presence of an ATP-dependent Cu transporting system in isolated plasma membrane fractions of rat liver distinct from cMOAT.
7751576##1995-1-1##Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials.##Brainstem auditory (BAEPs) and somatosensory evoked potentials (SEPs) have been shown to be useful in detecting brainstem or cortical dysfunction in neurological diseases and in combination with other methods to diagnose brain death (37,38). These neurophysiological methods are simple and easy to perform. BAEPs and SEPs can even be easily recorded in intensive care units and guarantee a standardized examination. Moreover, these methods require no extensive patient cooperation and are not heavily influenced by learning effects. The role of BAEPs in the evaluation and diagnosis of hepatic encephalopathy is not clear. BAEPs are obviously strongly influenced by the etiology of liver disease and are normal in viral hepatitis, but prolonged in alcoholic liver disease, Wilson's disease or in hepatic coma (8,12). Unfortunately, BAEPs were not compared to psychometric tests. There was no clear-cut differentiation between various hepatic encephalopathy-gradings. At present, the use of BAEPs in the detection of subclinical hepatic encephalopathy cannot be recommended, whereas in comatose patients BAEPs can be useful as a prognostic marker and for follow-up examinations (12). Recently, Pozessere et al. (12) examined 13 comatose patients with advanced coma stages (Glasgow coma scale 5-10) and recorded unspecific changes in their EEG tracings. In all cases of hepatic coma and in one intoxicated patient they found prolongation of interpeak latencies. In addition, in this small study the interpeak latencies correlated well with the clinical outcome of the patients. Only two studies were performed using SEPs to detect neurophysiological alterations in hepatic encephalopathy (32,33). The design as well as the results of these studies are quite different. Despite the small number of patients (n = 10), the prolongation of late components in 50% of patients with hepatic encephalopathy stage 0 could be a promising result (32). The value of SEPs in detecting subclinical hepatic encephalopathy is rather undefined. The fact that the generation of SEPs is due to an activation of complex structures of the central nervous system justifies the need for further investigations with this modality. The recording of visual evoked potentials requires much more methodological and technical effort than the recording of BAEPs or SEPs. The discrimination between pattern reversal (PVEP) and flashlight (FVEP) stimulation is highly important for the proper interpretation of the published data. Most of the studies were done using FVEPs, which are in particular clinically relevant for comatose patients (31). The conclusions of the authors using FVEPs (22-25) are not supported by the American Electroencephalographic Society (31).(ABSTRACT TRUNCATED AT 400 WORDS)
8821069##1995-1-1##Epidemiological, genetic, pharmacological, kinesiological, nuclear medical (IBZM-SPECT), standard and functional MRI studies on Parkinson's disease and related disorders and economic evaluation of Parkinson's disease therapy--clinical projects in the BMFT-research program Munich: &quot;Parkinson's disease and other basal ganglia disorders&quot;.##The results of selected clinical research projects related to epidemiological, genetic, pharmacological, kinesiological, and neuroimaging aspects (SPECT, PET, MRI, functional MRI) of basal ganglia disorders such as Parkinson's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and Wilson's disease are summarized. A retrospective pharmacoeconomic analysis of Parkinson's disease is presented. These studies are part of a nationwide research program of the German ministry of research and technology (BMFT) entitled &quot;Parkinson's disease and other basal ganglia disorders&quot; and were carried out at the Department of Neurology, LMU München.
7711495##1995-1-1##Rate of information processing in patients with Wilson's disease.##This study investigated the rate of information processing, independent of motor speed, in neurologically affected Wilson's disease (WD) patients. Two scanning tasks based on the Sternberg item-recognition paradigm were administered to 17 neurologically symptomatic WD patients and 17 normal control (NC) subjects. Although WD subjects do have longer response latencies than NC subjects, their rate of information processing is the same as the rate of the NC subjects. The longer response latencies are attributable to their motor deficits. The clear impact of motor impairment on test performance underlines the necessity for specialized assessment measures that can accurately reflect the cognitive abilities of motor-impaired patients. These findings suggest that Wilson's disease is not characterized by slowed information processing.
7884606##1995-1-1##Wilson's disease treated with trientine during pregnancy.##
20065467##2010-1-13##[MRI of the brain as a diagnostic tool in Wilson's Disease.]##The case history of a young patient with Wilson's disease (WD) is presented. The diagnosis of WD was based on increased urinary copper excretion, the presence of Keyser-Fleisher rings, changes observed on MRI of the brain and a remote family history of WD. The patient's parents were distantly related. The MRI showed symmetrically increased signal in the basal ganglia and in the brain stem on protein density and T2 weighted images. Similar changes were later observed in the thalamic nuclei. Signal changes observed on cerebral MRI in WD and their diagnostic and prognostic significance are discussed. The importance of recognising the symptoms of WD is emphasized, as early treatment may prevent death from hepatic failure or permanent damage of the central nervous system.
7749256##1995-1-1##Interactions of zinc and molybdenum with copper in therapy of Wilson's disease.##We review two newer treatments for Wilson's disease that each use an interaction of another metal with Cu to bring about therapeutic benefit. The two metals are Zn, in the form of the acetate salt, and Mo in the form of ammonium tetrathiomolybdate (TM). Zn, which blocks absorption of Cu in the intestine by inducing intestinal cell metallothionein, is used for maintenance therapy, treatment of the presymptomatic patient from the beginning, and treatment of the pregnant patient. TM, which complexes Cu in a tripartite complex with protein, is used for the initial treatment of neurologically presenting patients.
8577445##1995-1-1##Usefulness of Scheimpflug photography to follow up Wilson's disease.##A 24-year old female with ocular changes (Kayser-Fleischer ring and sunflower cataract) indicating Wilson's disease was followed up from 9 years of age with anterior eye segment image documentation by Scheimpflug photography. A low copper diet and systemic D-penicillamine were administered after the initial diagnosis of Wilson's disease. During a 15-year follow-up period, the yellowish/brown-colored granular opacification on the anterior lens capsule and/or in the capsule has mostly disappeared and instead, the same type of opacification has emerged on the posterior lens capsule, showing rather progressive changes compared with the initial findings. These changes which had developed in the lens during the past 15 years were difficult to detect by slit lamp examination alone, but they were clearly revealed by Scheimpflug slit images. To our knowledge this is the first case report on ocular changes disclosed through the application of a newly developed anterior eye segment examination. Ergo, Scheimpflug photography is valuable for follow-up studies of ocular complications seen in patients with Wilson's disease.
7894989##1995-1-1##Not Wilson's disease: a review of misdiagnosed cases.##During the period 1957-1987, 189 patients with neurological signs and symptoms were referred to the Wilson's disease clinic at Addenbrooke's Hospital, Cambridge. The diagnosis was not confirmed in 52 patients. Thirty-three of these 52 patients were sent with a definite diagnosis of Wilson's disease, and 12 had received chelation treatment. Ten patients were labelled as probable Wilson's disease; in nine cases no diagnosis had been made but Wilson's disease was considered a possibility requiring exclusion. One patient only was mistakenly reported to have Kayser-Fleischer rings. The presenting symptoms were tremor (n = 17), involuntary movements (n = 16), difficulty in walking (n = 12), personality changes (n = 4) and epilepsy (n = 3). The mean delay in referral was 8 years (range 6 months to 20 years). Compared with the number of patients with confirmed neurological Wilson's disease seen in this period (137 patients) the referral diagnosis was correct in only 72% of cases. The reasons for error, both clinical and biochemical, are discussed.
8548611##1995-1-1##[Wilson disease: a new case treated with trientine].##Hepatolenticular degeneration, also known as Wilson's disease (WD), is an infrequent hereditary disorder which is transmitted in recessive autosomic fashion: its genetic defect is to be found in the long branch of chromosome 13 (13q14.3) and allows disorder to take place which has not been sufficiently clarified, in the bilious excretion of the copper (Cu) which is deposited in an anomalous manner on a level with different organic tissues, giving rise to characteristic clinical manifestations which are, basically, of a neurological, hepatic, psychiatric and ocular nature. We present the case of a young patient whose case began, four years ago, with depressive-type manifestations, with diagnosis only being made now. Our opinion on the early detection of asymptomatic patients is commented on, along with that concerning the effectiveness and safety of therapeutic alternatives to D-penicilamine.
7638793##1995-1-1##[The development of diffuse cholangiocarcinoma in a female patient with long-term undiagnosed Wilson's disease].##
7888050##1995-1-1##Orthotopic liver transplantation for hepatic-based metabolic disorders.##Between January 1989 and June 1993, a total of 470 liver transplantations were performed at King's College Hospital. Thirty-seven transplantations were performed in 34 patients with liver-based metabolic disease. There were 16 females and 18 males with a median age of 19 years (range 1 month to 62 years). There were 14 patients under 16 years of age. The indications for liver transplantation were Wilson's disease (n = 16), alpha 1-antitrypsin deficiency (n = 10), tyrosinaemia (n = 2), primary hyperoxaluria type 1 (PH1; n = 2), congenital haemochromatosis (n = 1), familial amyloidotic polyneuropathy (FAP; n = 1, familial hypercholesterolaemia) (n = 1) and Crigler-Najjar syndrome type I (CNS1; n = 1). These included two patients who received combined heart-liver grafts for familial hypercholesterolaemia and FAP, respectively. Two patients received combined liver-kidney transplants for PH1. There were four deaths: from sepsis (n = 2), acute hepatic vein obstruction in a left lateral segment graft (n = 1) and portal vein thrombosis with liver necrosis (n = 1). Three patients were retransplanted, one for chronic rejection and two for hepatic artery thrombosis, giving an overall graft survival of 81% and patient survival of 88% (30/34), at a mean follow-up of 34 months (range 10-64 months).
8600693##1995-1-1##[Hepatic neoductules].##Proliferation of preexisting bile ducts, ductular metaplasia of hepatocytes and proliferation and differentiation of liver stem cells are discussed in the pathogenesis of neoductular structures in the liver. Under the condition of experimental bile duct obstruction and in extrahepatic bile duct stenosis neoductular structures are first the result of proliferation and sprouting of preexisting ducts and cholangioles. Especially in later stages of cholestasis but also in other chronic progredient liver diseases such as chronic alcoholic liver disease and chronic active hepatitis periportal hepatocytes may show a phenotypic shift towards ductular epithelia. In postnatal liver diseases hepatocytes first express keratin 7 and later keratin 19 during ductular transdifferentiation. This is in contrast to embryonal cholangiogenesis. In alpha-1-antitrypsin-deficiency, hemochromatosis, Wilson's disease, and chronic active hepatitis B cellular deposites typically located in hepatocytes such as alpha-1-AT, siderin, copper, HBs-Ag, and HBc-Ag can also be found in neoductular cells close to hepatocytes. These deposites seem to be retained during the ductular transdifferentiation of hepatocytes. Expression of bile duct-type integrin subtypes and TGF beta 1 in neoductular cells are involved in the changing parenchymal/mesenchymal interplay during neoductogenesis, resulting in periductular basal membrane and periductular fibrosis. In FNH the ductular transdifferentiation of hepatocytes is integrated in the histogenesis of micronodules and portal tract equivalents of these tumor-like lesions. Ductular structures in hepatoblastomas and especially in combined hepatocellular and cholangiocarcinomas (CHCC) may reflect the common embryologic derivation of hepatocytes and biliary epithelia. Non-neoplastic liver tissue in resection specimens of our CHCC showed a lower rate of cirrhosis, and a significantly higher Ki 67-LI of neoductular cells compared to liver tissue in resection specimens of HCC and liver metastases. 3 of 10 CHCC had developed in alpha-1-AT-deficiency, in which this protease-inhibitor was predominantly retained in periportal hepatocytes. These findings in non-neoplastic tumor-bearing liver tissue suggest that CHCC include a special histogenic type of primary liver carcinoma which in analogy to some experimental liver tumors might develop from periportal parenchymal cells.
7811248##1994-12-30##Novel bacterial P-type ATPases with histidine-rich heavy-metal-associated sequences.##Menkes disease and Wilson disease are human disorders of copper metabolism. It has recently been shown that both are due to mutations in P-type ATPase copper transport molecules. Related heavy metal transporting ATPases have been described in several strains of bacteria. In an effort to isolate other mammalian metal transporters, we screened a human small intestine library with probes homologous to conserved sequences in the known proteins. Two novel cDNAs were isolated, which encode new members of this family. Surprisingly, they were both of bacterial origin, most likely derived from E. coli sequences transduced during library construction.
7866586##1994-12-1##Metabolic disorders in children.##This year has seen major progress in gene therapy, particularly that directed to the liver. Genes have been characterized for Wilson's disease, Krabbe's disease, Canavan's disease, adrenoleukodystrophy, glucose-6-phosphatase, and long-chain 3-hydroxyacyl-CoA dehydrogenase. Moreover, the identification of common mutations in many conditions promises to help with diagnosis and genetic counseling. The drama of progress in molecular biology can easily overshadow other research, but the application of tandem mass spectrometry to neonatal screening is a major advance. Other important papers concern the use of Lorenzo's oil in adrenoleukodystrophy and revised dietary recommendations for the treatment of phenylketonuria. This review focuses predominantly on diseases that affect the brain, but important advances in other conditions have been included.
7849817##1994-12-1##Genetic disorders of copper metabolism.##In this review we discuss four genetic disorders of copper metabolism. Wilson's disease and Indian childhood cirrhosis result from the toxic effects of copper accumulation in the liver. Menkes' disease and, most likely, occipital horn syndrome result from copper deficiency secondary to disturbances in copper transport. The recent cloning and sequencing of the genes defective in Wilson's disease and Menkes' disease provide the molecular basis for understanding the causes of the two major disorders of copper transport in humans. Mutations that result in Wilson's and Menkes' diseases were shown to disrupt the function of two related P-type copper transporting ATPases. Genetic analysis demonstrates that Wilson's disease and, probably, Menkes' disease are caused by a number of different mutations within a single gene (allelic heterogeneity), and that this occurrence likely explains the clinical heterogeneity of both diseases. The possibility that different mutations within the same gene account for the similar phenotypes of Wilson's disease and Indian childhood cirrhosis on the one hand and for Menkes' disease and occipital horn syndrome on the other are discussed.
7958693##1994-12-1##Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis.##
7844083##1994-12-1##Radiological case of the month. Wilson's disease.##
7849148##1994-12-1##[Wilson's disease: physiopathology, therapeutic approach and case report].##Wilson's disease is an hereditary recessive autosomal disorder which affects around five people per million inhabitants. The primary defect is localized in the liver and the disease is manifested by the accumulation of copper in tissues. The diminution of ceruloplasmin, which until a few years ago was mistakenly thought to be the pathogenetic cause of Wilson's disease, is an epiphenomenon of the underlying metabolic defect characterized by defective copper biliary excretion. There are four stages in the natural history of the disease: 1) an asymptomatic stage of hepatic copper accumulation; 2) dismission and redistribution of copper leading to hepatocellular necrosis and hemolysis; 3) extrahepatic accumulation of copper leading to the onset of cirrhosis and neurological damage; 4) stage of homeostasis following treatment but with possible irreversible neurological damage. Treatment of Wilson's disease takes the form of pharmacological, dietary and surgical therapy. Through the formation of copper and protein metal complexes D-penicillamine impoverishes copper deposits causing the reduction or disappearance of hepatic and neurological symptoms; a small percentage of patients treated develops a nephrotic syndrome requiring the compulsory suspension of the drug. In this case a valid alternative is triethylenetetramine dichlorohydrate (TETA) which provokes increased blood copper during copper diuresis. The response to pharmacological treatment is better the earlier treatment is started and the more regular its administration. Dietary intake of copper must be reduced in parallel avoiding foods with a high copper content. Liver transplant obviously leads to the &quot;resolution&quot; of the underlying metabolic problem in patients who develop fulminating hepatitis with hypercupremia and hemolysis and, of course, in cases of uncompensated cirrhosis which do not respond to chelating therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
7849147##1994-12-1##[Hepatic Wilson's disease: clinical presentation and prognosis. Indications for liver transplantation].##Wilson's disease is a hereditary disorder of biliary copper excretion. Most often the disease presents with hepatic and neurological involvement. In the hepatic forms, hypocerulo-plasminemia, the determination of eye copper and the dosage of copper in serum, urine and liver tissue are all leads to diagnosis. The presentation and the biochemistry may direct the diagnosis of the acute forms. Treatment differs according to the clinical patterns. Early diagnosis in the asymptomatic patient leads to chelating therapy to prevent copper overload. Chronic disease may benefit from chelation and liver transplant. Transplantation is the cure for fulminant forms. We report three young women with Wilson's disease; one had a fulminant form and was transplanted and the other two responded to chelation therapy. Family screening allowed the identification of an asymptomatic sibling.
7878232##1994-12-1##[Cerebral magnetic resonance in Wilson's disease].##The authors describe the typical and atypical MR findings of brain abnormalities in Wilson's disease in three patients affected with severe neurologic disturbances; a low-field MR unit was used. Radiologic findings included atrophic changes and focal lesions. Two patients had basal ganglia, brain stem and dentate alterations; lesions in the corpus callosum (a site not yet described in Wilson's disease) were seen. The third case had putaminal lesions which improved after penicillamine therapy. Cerebral abnormalities were demonstrated as areas of increased signal on T2-weighted images; T1 and T2 shortening due to magnetic susceptibility phenomena was not seen. Two major MR features were observed: high hyperintensity and peripheral location of putaminal lesions and sparing of the medial thalami in diffuse basal ganglia involvement.
7992028##1994-11-26##[Results of liver transplantations in Geneva or 32 consecutive transplantations without mortality in 2 years].##Between 1 january 1992 and 31 december 1993, 32 liver transplantations were performed in 29 patients (5 transplants in 3 children and 27 transplants in 26 adults) at Geneva University Hospital. Despite 5 super-urgent transplantations (3 fulminant hepatitis, 1 end-stage Wilson disease and 1 primary nonfunction), all patients are still alive and all have lived more than 10 months. On 1 october 1994, all patients were at home and 93% were in good general condition. No patient of this series had been transplanted for cancer and all patients positive for hepatitis B surface antigen receive long-term administration of anti-HBs immune globulin: in this respect, the long-term mortality risk of the present series of patients seems to be very low. Although these results highlight that liver transplantation can be performed safely by a competent medico-surgical team, two significant difficulties have to be outlined. First, patients are likely to die on the waiting list due to unavailable grafts, especially in emergency cases. Second, the postoperative period of patients with decompensated end-stage liver disease at the time of liver transplantation is still one of high morbidity. These facts underline that chronic liver disease patient should be evaluated for liver transplantation prior to the terminal decompensated stage of the disease, when the candidate's invariably poor general condition precludes successful liver transplantation.
7858607##1994-11-15##[Osteoarthritis of rare etiology].##Although osteoarthritis is characterized by a uniform pattern of clinical and radiological manifestations, it is a syndrome that can be produced by a variety of causative factors. Rare causes of osteoarthritis can be categorized as follows: 1) systemic metabolic disorders due to known biochemical and/or genetic abnormalities, such as hemochromatosis, ochronosis, Wilson's disease, Ehlers-Danlos syndrome (and probably the &quot;idiopathic&quot; joint hypermobility syndrome), sickle cell anemia, and thalassemia; 2) endocrine disorders, such as acromegaly, whose joint manifestations are now well-known, and hypothyroidism; 3) Paget's disease of bone, osteopetrosis (which induces changes in bone elasticity), and other systemic bone diseases; 4) dysplasias, which form a vast group including familial polyepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita (especially its milder forms), Stickler's syndrome, osteo-onychodysplasia, Kniest's dysplasia, trichorhinopharyngeal syndrome, and a group of diseases that affect the epiphyses; 5) endemic forms of osteoarthritis, e.g., Mselini disease, Kashin-Beck disease, and Malnad disease, which are unknown in western Europe but have been reported to affect thousands of individuals in endemic areas. All these disorders are usually responsible for premature osteoarthritis, whose presentation sometimes bears the imprint of the causative abnormality but can be identical to that of common osteoarthritis. The effects of toxic substances (Kashin-Beck disease) or genetically-determined collagen II abnormalities (epiphyseal dysplasias) may explain the occurrence of these rare forms of premature osteoarthritis.
7886057##1994-11-1##Newer aspects of micronutrients in chronic disease: copper.##Cu ions are pro-oxidants when added to biological material in vitro and excessive levels of Cu in the body, such as in Wilson's Disease (Yarze et al. 1992) promote oxidant-related pathologies. In contrast there is now substantial evidence that an optimum level of Cu is required to maintain antioxidant defence and that Cu deficiency in animals increases oxidant stress. There are abundant mechanistic relationships linking Cu deficiency and processes associated with IHD, some of which do not directly involve oxidant damage. These mechanistic relationships, however, have mostly been demonstrated in animal models and more information is urgently required concerning possible chronic mild Cu deficiencies in human populations. A major hurdle to advances in this area is the lack of indices of Cu status which are sensitive enough to detect marginal Cu deficiency in humans. The question, therefore, of whether or not there is a role for mild Cu deficiency in the onset of chronic disease processes, including IHD, remains unanswered.
7820540##1994-11-1##Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus.##We report two brothers with complete caeruloplasmin deficiency. The brothers presented with dementia and diabetes mellitus. Twelve relatives have partial caeruloplasmin deficiency. There is no copper overload. Transmission is autosomal recessive. DNA analysis showed genetic linkage between the deficiency and various polymorphic markers flanking the caeruloplasmin gene on chromosome 3q25. This is consistent with a mutation of the caeruloplasmin gene. Caeruloplasmin catalyses the oxidation of ferrous iron to ferric iron. Both brothers have low serum iron and increased liver iron. The index patient was given caeruloplasmin-containing, fresh-frozen plasma. A dose of 2.6 mg caeruloplasmin increased serum iron from 5 microM/l to 10 microM/l. A dose of approximately 72 mg increased serum iron from 5 microM/l to 19 microM/l. The abnormal serum and liver iron levels, and the caeruloplasmin-induced rise in serum iron, confirm a previous suggestion that caeruloplasmin maintains the normal rate of flow of iron from store to transferrin. Dementia and diabetes mellitus have been described in only one other homozygote. The absence of copper overload, and the linkage of the deficiency with chromosome 3q25, distinguish this condition from Wilson's disease.
7855342##1994-11-1##Diffuse disease of the liver: radiologic-pathologic correlation.##Cross-sectional imaging is playing an increasing role in diagnosis of diffuse liver diseases because it clarifies, in many cases, the overlap in clinical and laboratory manifestations often present in diffuse hepatic processes and thus may eliminate the need for a biopsy. Advances in cross-sectional imaging, particularly in magnetic resonance (MR) imaging, enable further characterization of hepatic parenchymal and architectural changes, allowing closer correlation with underlying pathologic changes. Advanced imaging techniques can be used to characterize a variety of metabolic, vascular, toxic, infectious, and neoplastic diffuse liver diseases. These include more common entities such as cirrhosis, Budd-Chiari syndrome, hemochromatosis, Wilson disease, fatty change, and diffuse neoplastic disease (hepatocellular carcinoma, metastasis, and lymphoma) and uncommon entities such as schistosomiasis, sarcoidosis, and amyloidosis. Correlation of computed tomographic and MR imaging findings with underlying pathologic features is helpful in understanding the gamut of diffuse diseases of the liver.
7956758##1994-10-21##[A hemolytic crisis with liver failure as the first manifestation of Wilson's disease].##An 18-year-old woman developed an acute haemolytic anaemia, acute transient renal failure and progressive hepatic failure. Coeruloplasmin and serum copper concentration were normal; a Kayser-Fleischer ring and any neurological symptoms were absent initially. Liver biopsy was contraindicated because of increased bleeding tendency. Wilson's disease was diagnosed only after the acute renal failure had regressed, on the basis of the urinary copper excretion (2890 micrograms/d, rising to 7330 micrograms/d after D-penicillamine administration). Progressive liver failure required transplantation. After it the patient quickly recovered and is now, two years later, free of disease. -This case demonstrates that Wilson's disease may be difficult to diagnose at the time of initial acute manifestation. But it can be recognized early from the pathognomonic low alkaline phosphatase and by calculation of free serum copper.
7942601##1994-10-1##The liver biopsy diagnosis of Wilson's disease. Methods in pathology.##The authors present a simple liver biopsy protocol that is a reliable and cost-effective method of diagnosing hepatic Wilson's disease. Biopsy specimens are obtained in routine fashion, without the need for copper-free solutions or instruments. The samples are then embedded in paraffin, stained for copper and copper-associated protein, and studied by light microscopy. Subsequently, a sample of hepatic parenchyma is excised from the paraffin block for chemical quantitation of tissue copper. This combination of methods generally yields reliable results and allows confirmation of the diagnosis in cases of Wilson's disease in which special stains for copper are negative. In most instances, electron-microscopic studies are not necessary.
7945006##1994-10-1##Dangers of interrupting decoppering treatment in Wilson's disease.##
7926469##1994-10-1##Wilson's disease gene is homologous to hts causing abnormal copper transport in Long-Evans cinnamon rats.##
7959213##1994-10-1##Copper associated childhood cirrhosis.##Several papers have reported severe liver disease in association with massive hepatic copper accumulation, which do not seem to be either of the recognised copper associated liver diseases, namely Wilson's disease and Indian childhood cirrhosis. A further case is reported in which novel copper kinetic studies were carried out using the stable isotope 65Cu, showing that this patient did not suffer from Wilson's disease. It is suggested that these cases can be divided into two groups on the basis of age, clinical course, and history of excessive copper ingestion. The benefits of using 65Cu for in vivo studies of copper metabolism is discussed.
7927209##1994-10-1##The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey).##To aid understanding of markers of disease and predictors of outcome in alcohol-exposed systems, we undertook a literature survey of more than 700 articles to view the morphological characteristics and the clinical and experimental epidemiology of the Mallory body. Mallory bodies are filaments of intermediate diameter that contain intermediate filament components (e.g., cytokeratins) observable by conventional light microscopy or immunohistochemical methods, identical in structure regardless of initiating factors or putative pathogenesis. Although three morphological types can be identified under electron microscopy (with fibrillar structure parallel, random or absent), they remain stereotypical manifestations of hepatocyte injury. A summary of the conditions associated with Mallory bodies in the literature and their validity and potential etiological relationships is presented and discussed, including estimates on the combined light microscopic and immunohistochemical prevalences and kinetics. Emphasis is placed on proper confounder control (in particular, alcohol history), which is highly essential but often inadequate. These conditions include (mean prevalence of Mallory bodies in parentheses): Indian childhood cirrhosis (73%), alcoholic hepatitis (65%), alcoholic cirrhosis (51%), Wilson's disease (25%), primary biliary cirrhosis (24%), nonalcoholic cirrhosis (24%), hepatocellular carcinoma (23%), morbid obesity (8%) and intestinal bypass surgery (6%). Studies in alcoholic hepatitis strongly suggest a hit-and-run effect of alcohol, whereas other chronic liver diseases show evidence of gradual increase in prevalence of Mallory bodies with severity of hepatic pathology. Mallory bodies in cirrhosis do not imply alcoholic pathogenesis. Obesity, however, is associated with alcoholism and diabetes, and Mallory bodies are only present in diabetic patients if alcoholism or obesity complicates the condition. In addition, case studies on diseases in which Mallory bodies have been identified, along with pharmacological side effects and experimental induction of Mallory bodies by various antimitotic and oncogenic chemicals, are presented. Mallory bodies occur only sporadically in abetalipoproteinemia, von Gierke's disease and focal nodular hyperplasia and during hepatitis due to calcium antagonists or perhexiline maleate. Other conditions and clinical drug side effects are still putative. Finally, a variety of experimental drugs have been developed that cause Mallory body formation, but markedly different cell dynamics and metabolic pathways may raise questions about the relevance of such animal models for human Mallory body formation. In conclusion, the Mallory body is indicative but not pathognomonic of alcohol involvement. A discussion on theories of development and pathological significance transcending the clinical frameworks will be presented in a future paper.
7529273##1994-10-1##Etiology of chronic hepatitis in France: predominant role of hepatitis C virus.##The aim of this study was to assess the causes of histologically proven chronic hepatitis in a series of 357 consecutively admitted patients. Patients with chronic alcohol intake above 50 g per day, Wilson's disease, idiopathic hemochromatosis or homozygous alpha-1 antitrypsin deficiency were excluded. Sera of all patients were tested for antibodies to hepatitis C virus with second-generation enzyme-linked immunoassay and recombinant immunoblot assay, for markers of hepatitis B and hepatitis D viruses, and for autoantibodies. Detection of hepatitis C viral RNA by polymerase chain reaction was attempted if recombinant immunoblot assay was indeterminate, or if both viral and autoimmune markers were absent. If no serum markers, including HCV RNA, were found, the cause of chronic hepatitis was considered as unknown. The cause of chronic hepatitis was found in 343 cases (96.4%), including three patients with HCV RNA as the only marker. Chronic hepatitis was related to hepatitis C virus in 51.8%, to hepatitis B virus in 32.8% (including hepatitis D infection in 3.1%), and to autoimmune hepatitis in 5.9% of cases, respectively. No case of drug-induced chronic hepatitis was observed in this series, and in 5.9% of cases, there were probably multiple causes. Finally, in 3.6% of the cases the cause of chronic hepatitis remained unknown despite extensive evaluation suggesting the existence of a non-A, non-B, non-C viral agent.
7836960##1994-10-1##Dopamine D2 receptor binding and cerebral glucose metabolism recover after D-penicillamine-therapy in Wilson's disease.##Regional cerebral glucose metabolism (rCMRGlc) and dopamine D2 receptor binding were measured in a 31-year-old, severely affected, untreated patient with Wilson's disease of 3 years' duration using positron emission tomography and 18F-deoxyglucose and 18F-methylspiperone ([18F]MSP), respectively. There was a severe reduction of striatal and extrastriatal rCMRGlc as well as of striatal [18F]MSP accumulation rate. After 1 year of treatment with D-penicillamine, striatal and extrastriatal rCMRGlc and striatal [18F]MSP accumulation rate reached almost normal levels. It is hypothesized that recovery of motor functions due to copper trapping therapy was associated with an increase in basal ganglia activity and a re-expression or upregulation of dopamine D2 receptors.
7931398##1994-10-1##Wilson's disease: neurological and magnetic resonance imaging improvement on zinc treatment.##
7838444##1994-10-1##Comparison of 123I-IBZM SPECT and 11C-raclopride PET findings in patients with parkinsonism.##We compared the results of 123I-iodobenzamide (123I-IBZM) single photon emission computed tomography (SPECT) and 11C-raclopride positron emission tomography (PET) in 22 patients with parkinsonism. Nineteen patients were clinically diagnosed as having Parkinson's disease, two patients presented with atypical parkinsonism (i.e. clinical signs of Parkinson's disease and a subsequent poor response to dopamimetic drugs) and one patient was diagnosed as having Wilson's disease. All patients were drug naive. The SPECT data were semiquantitatively evaluated by calculating the ratios of striatal (basal ganglia, BG) IBZM binding to IBZM binding in various reference areas, i.e. the frontal cortex (BG/FC), the occipital cortex (BG/OC) and the cerebellum (BG/CE). In PET studies similar regions of interest were derived and ratios of striatal to cerebellar raclopride activity were determined. 123I-IBZM SPECT results significantly correlated to specific 11C-raclopride binding. This correlation was not significantly different when the frontal cortex (P = 0.05, r = 0.42), occipital cortex (P &lt; 0.05), r = 0.44) or cerebellum (P 0.05, r = 0.45) were used as reference regions for non-specific IBZM binding. In comparison to PET ratios the SPECT BG/CE showed a higher variance (S.E.M. = 0.1) than BG/FC (S.E.M. = 0.05) and BG/OC (S.E.M. = 0.06) ratios. Thus, for the calculation of specific striatal IBZM binding one would prefer the frontal or occipital cortex as reference. However, when only those 19 patients with a clinical diagnosis of Parkinson's disease and increased specific 11C-raclopride binding were considered, no significant correlation was obtained. Qualitative changes of dopamine D2 receptor binding, such as asymmetry, were equally recognized.(ABSTRACT TRUNCATED AT 250 WORDS)
7899276##1994-10-1##Improvement of prenatal diagnosis of Wilson disease using microsatellite markers.##This paper describes a case of prenatal diagnosis for Wilson disease (WD) carried out in an at-risk couple of Sardinian descent, following non-directive genetic counselling. Diagnosis was obtained by using eight microsatellites located within or flanking the WD locus, six of which were 100 per cent and two 50 per cent informative. The use of several markers may limit the occurrence of misdiagnosis resulting from recombination or instability of repeats.
7937823##1994-9-27##P-type ATPase from the cyanobacterium Synechococcus 7942 related to the human Menkes and Wilson disease gene products.##DNA encoding a P-type ATPase was cloned from the cyanobacterium Synechococcus 7942. The cloned ctaA gene encodes a 790-amino acid polypeptide related to the CopA Cu(2+)-uptake ATPase of Enterococcus hirae, to other known P-type ATPases, and to the candidate gene products for the human diseases of copper metabolism, Menkes disease and Wilson disease. Disruption of the single chromosomal gene in Synechococcus 7942 by insertion of an antibiotic-resistance cassette results in a mutant cell line with increased tolerance to Cu2+ compared with the wild type.
7842129##1994-9-1##[Diagnosis of metabolic coma in children].##This article describes the metabolic investigations to be applied in any clinical situation consistent with a late acute form of inborn error of metabolism: unexplained coma with or without focal neurological manifestations, recurrent vomiting with lethargy, episodes of ataxia with or without behaviour disorder, fits of psychiatric troubles. In each of these situations, careful medical history is of major importance searching for previous clinical manifestations such as episodes of coma, ataxia or vomiting, anorexia, failure to thrive, developmental delay, all very suggestive of metabolic disorder. The association of neurological symptoms and abnormal hepatic tests is also of great value and must not lead to the diagnosis of Reye's syndrome without considering a metabolic defect of fatty acid oxidation, urea cycle, respiratory chain, or Wilson's disease. When looking for an etiological origin, it is mandatory to collect all the biological information at the same time, also knowing that metabolic abnormalities may be mild and transitory, and that many of them are non specific (metabolic acidosis, hyperlactacidemia, hyperammonemia, hepatic tests disturbances) being encountered in collapsus, shock and multiple organ failure syndrome.
7833924##1994-9-1##Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions.##Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver.
8051776##1994-9-1##Wilson's disease presenting as symptomatic urolithiasis: a case report and review of the literature.##Wilson's disease is a rare autosomal recessive disorder that typically presents as hepatic, neurological or psychiatric illness in late adolescence and early adulthood. Although urolithiasis has been documented in as many as 16% of patients with Wilson's disease, only 3 cases have been described that presented with stone disease. We report on a healthy 17-year-old girl who presented with renal colic and a distal ureteral calculus that was subsequently passed. The patient was hospitalized 2 months later with jaundice, ascites, hyperchloremic metabolic acidosis and elevated hepatic enzymes. She was hypophosphatemic and hypouricemic with a low serum ceruloplasmin. Diagnosis was Wilson's disease with Fanconi's syndrome, but despite penicillamine therapy and intensive care support rapidly progressive hepatic failure, coagulopathy and encephalopathy developed. The patient died before emergency liver transplantation. Our case illustrates the role urologists may have in the diagnosis of this rare but potentially treatable disease. Wilson's disease should be considered in the differential diagnosis of any adolescent or young adult with urolithiasis.
8068648##1994-8-16##Formation of mammalian Cu8-metallothionein in vitro: evidence for the existence of two Cu(I)4-thiolate clusters.##Copper accumulates in metallothionein (Cu-MT) in copper overload diseases, such as Wilson's disease and Bedlington Terriers disease. The in vitro formation of the Cu12-MT form comprising two Cu(I)6(CysS)9,11 cores is well documented. However, lysosomal Cu-MT isolated from canine liver contains 8 Cu(I) ions in two proposed adamantane-like Cu4-thiolate clusters [Freedman, J. H., Powers, L., &amp; Peisach, J. (1986) Biochemistry 25, 2342]. The present studies have been carried out in an effort to learn more about the Cu(I)-thiolate cluster species formed upon the sequential incorporation of Cu(I) ions into metal-free MT from rabbit liver. On the basis of changes in the electronic absorption, circular dichroism (CD), magnetic circular dichroism (MCD), and luminescence spectra, besides the formation of a molecular species with 12 Cu(I) equivalents, evidence for the existence of a distinct MT complex with 8 Cu(I) equivalents (Cu8-MT) was obtained. Analysis of the metal-dependent absorption envelope of Cu(I)-MT between 240 and 360 nm permitted the discrimination between predominantly CysS-Cu(I) charge-transfer (LMCT) (240-260 nm) and cluster-localized Cu(I) (d-s) transitions (260-360 nm). Accordingly, the decrease in the ratio of intensities of LMCT to d-s bands from 2.6 to 2.4 on going from 8 to 12 Cu(I) equivalents was attributed to the formation of Cu-MT species with different cysteine ligand to metal stoichiometries. The results suggest that while in Cu12-MT all 20 thiolate ligands participate in metal binding, in the Cu8-MT species between 12 and 14 cysteines take part in Cu(I) coordination.(ABSTRACT TRUNCATED AT 250 WORDS)
8048855##1994-8-1##Could the piggyback operation in liver transplantation be routinely used?##
8045023##1994-8-1##Diagnostic utility of laboratory tests in alcoholic liver disease.##Alcoholic liver disease is an important health problem in the US. A public health approach is proposed, using laboratory tests to identify patients with early fibrosis of the liver. A variety of serological markers of liver fibrosis based on collagen-related products (e.g., amino-terminal propeptides of type III procollagen) have been investigated. Further studies are needed to determine the optimal combination of tests for discriminating between steatosis and early fibrosis. Laboratory tests are also useful in excluding nonalcoholic liver diseases such as viral hepatitis, hemochromatosis, and Wilson disease. The monitoring of sobriety in patients with alcoholic liver disease by currently available tests is far from ideal. A new marker of excessive alcohol consumption, carbohydrate-deficient transferrin, is not usually affected by liver disease and thus shows promise as a marker of relapse in alcoholic patients. The development of reliable screening markers of fibrosis and sobriety could potentially reduce the health costs and suffering associated with the complications of alcoholic cirrhosis.
8045515##1994-8-1##At long last: an animal model of Wilson's disease.##
8045514##1994-8-1##Identification of the Wilson's disease gene: clues for disease pathogenesis and the potential for molecular diagnosis.##
8045756##1994-8-1##D-penicillamine-induced elastosis perforans serpiginosa and localized cutis laxa in a patient with Wilson's disease.##A patient with Wilson's disease who developed elastosis perforans serpiginosa and localized cutis laxa during prolonged treatment with D-penicillamine is described. Induction of elastosis perforans serpiginosa and of cutis laxa by D-penicillamine may be due to a similar mechanism.
7928621##1994-8-1##The WD gene for Wilson's disease links to the hepatitis of LEC rats.##LEC rats develop an autosomal recessive hepatitis and subsequently liver cancer associated with copper accumulation in the liver similar to that of Wilson's disease. Using 71 backcross [(WKAH x LEC) x LEC] rats, linkage analysis of the hepatitis with the WD gene for Wilson's disease revealed identical segregation and no recombination event between these two genes. This result indicates that the WD gene is a prime candidate for the hts gene responsible for the hepatitis of LEC rats, and suggests that the hepatitis of LEC rats may be caused by a defect in a copper-transporting ATPase expressed in the liver.
7951327##1994-8-1##The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.##The Long-Evans Cinnamon (LEC) rat shows similarity to Wilson disease in many clinical and biochemical features. We have cloned cDNAs for the rat gene (Atp7b) homologous to the human Wilson disease gene (ATP7B) and have used them to identify a partial deletion in the Atp7b gene in the LEC rat. The deletion removes at least 900 bp of the coding region at the 3' end, includes the crucial ATP binding domain and extends downstream of the gene. Our results provide convincing evidence for defining the LEC rat as an animal model for Wilson disease. This model will be important for studying liver pathophysiology, for developing therapy for Wilson disease and for studying the pathway of copper transport and its possible interaction with other heavy metals.
7754297##1994-8-1##[Consequences of lesions of the basal ganglia on cerebral metabolic activity: clinical implications].##This brief overview summarises the literature regarding the effects of lesions of the basal ganglia (BG) on brain metabolism-an index of integrated synaptic activity. Interest in this field is because to show such effects may reveal the implication of neuron networks, damaged at the level of the BG, in the neuropsychological and behavioural expression of BG lesions. As an illustration of this, a parallel is drawn between the loss of psychic self-activation (also named &quot;psychic akinesia&quot; or &quot;athymhormia&quot;) that follows bilateral lesions at variable sites of the prefrontal-striatal-pallidal-thalamic loop on one hand, and the mild prefrontal hypometabolism consistently observed in such cases. This paper also reviews the changes in brain metabolism found in progressive supranuclear palsy, Huntington's disease, Parkinson's disease, Wilson's disease and striato-nigral degeneration.
7975792##1994-8-1##[Cloning the Wilson disease gene].##
8037756##1994-7-15##The gene responsible for LEC hepatitis, located on rat chromosome 16, is the homolog to the human Wilson disease gene.##We identified the rat homolog to the human Wilson disease (WD) gene as the gene responsible for hepatitis (hts) in the Long Evans Cinnamon (LEC) rat. A genetic study using fifty-three backcross progenies showed that the rat WD gene detected by Southern blotting using the human WD gene as a probe was tightly linked to the hts phenotype of the LEC rat with no recombination. LEC is a transcriptionally deficient mutant because no transcript of the rat WD gene could be found in the LEC rat by Northern blotting. This rat WD gene was mapped to 16q12.23-12.3 by fluorescence in situ hybridization and mouse x rat somatic cell hybrid analysis.
8010238##1994-7-1##Wilson's disease: contrast enhancement of cerebral lesions on MR images after penicillamine therapy.##
7517649##1994-7-1##Living related liver transplantation in children.##We reviewed 37 living related liver transplantations (LRLT) performed by our department during the last 27 months on children with end-stage liver disease. The patients were 15 boys and 22 girls aged 7 months to 15 years with biliary atresia (27), cryptogenic cirrhosis (3), Budd-Chiari syndrome (2), progressive intrahepatic cholestasis (2), protoporphyria (1), Wilson's disease (1), and fulminant hepatitis (1). The donors were 14 fathers and 23 mothers. Grafts were made from the left lateral segment (19), left lateral segment with partial S4 (11), left lobe (6), and right lobe (1). After graft harvesting all donors resumed normal liver function and normal life. The recipient underwent total hepatectomy with preservation of the inferior vena cava. FK506 and low-dose steroids were used for immunosuppression. The survival rate was 90% (27/30) in elective cases and 57% (4/7) in emergency cases. Six recipients had functioning grafts but died of extrahepatic complications. Hepatic vein stenosis occurred in 3 cases at 3 months after LRLT and was successfully treated by balloon dilatation. Portal vein stenosis occurred in 1 case at 8 months after LRLT and was also safely dilated. We incurred no hepatic artery thrombosis after introducing microsurgery techniques. Among 12 viral, 5 bacterial, and 3 fungal postoperative infections, 1 Candida pneumonia and 1 EBV-associated lymphoma were lethal. Three patients with ABO-blood group compatible grafts and one with an incompatible graft developed acute rejection, which was controlled in evey case by steroid bolus and/or increasing the dose of FK506. There were no definite episodes of rejection in ABO-identical cases. Children with moderate growth retardation (&gt; or = -1.5 SD of normal growth) caught up in growth soon after LRLT, but those with severe retardation (&lt;-1.5 SD) were slow to attain age-normal height. Appropriate timing, meticulous surgical procedures, and comprehensive management of complications are crucial for successful outcome with LRLT. LRLT is a promising option for alleviating the shortage of livers for pediatric transplantation and may be regarded as an independent modality to supplement cadaver donation.
8037655##1994-7-1##Expression of the Wilson disease gene is deficient in the Long-Evans Cinnamon rat.##Long-Evans Cinnamon rats develop a necrotizing hepatitis characterized by excessive hepatic copper accumulation, defective holoceruloplasmin biosynthesis and impaired biliary copper excretion. To elucidate the molecular basis of this defect, a cDNA clone encoding the rat Wilson disease gene was isolated and used to examine gene expression in selected tissues from normal and Long-Evans Cinnamon rats. Although this cDNA readily detects Wilson transcripts in liver and other tissues from normal rats, such transcripts are entirely absent from tissues derived from the Long-Evans Cinnamon rat strain. These data therefore identify the Long-Evans Cinnamon rat as the first bona fide animal model of Wilson disease and suggest that this rat strain may be a valuable resource in the study of this genetic disorder.
8076990##1994-7-1##Wilson's disease: varied hepatic presentations.##
7991059##1994-7-1##[Diagnosis of Wilson disease by methods of molecular genetics].##Wilson's disease is an inborn error of cooper metabolism, inherited as an autosomal recessive gene. According to the variety of clinical features (most frequency hepatic, neurological, psychiatric and haematological) the clinical diagnostics often meets a number of difficulties. It is important to establish the diagnosis in the pre-symptomatic period, because treatment can prevent developing of the disease. The diagnosis is usually established after biochemical blood tests, that is the serum cooper and ceruloplasmin, 24-hour urinary cooper excretion and the functional test with radioactive cooper. However, all the methods quite frequently do not make it possible to confirm or exclude the diagnosis in sporadic cases. Sometimes, it is also impossible to distinguish between preclinical homozygotes and heterozygotes. Localizing of the pathogenic gene on the long arm of chromosome 13 opens new diagnostic prospects. Still, it is essential to find genetic markers situated next to the gene for applying the linkage analysis. It will also help to isolate the gene and to establish the primary biochemical defect of the disease.
8091505##1994-7-1##Wilson disease and Menkes disease: new handles on heavy-metal transport.##Little is known at the molecular level about the homeostatic control of heavy-metal concentrations in mammals. Recently, however, two human diseases that disrupt copper transport, Menkes disease and Wilson disease, were found to be caused by mutations in two closely related genes, MNK and WND, which encode proteins belonging to the P-type ATPase family of cation transporters. The MNK and WND proteins are unique in having at their amino termini six copies of a sequence that is remarkably similar to sequences previously found in bacterial heavy-metal-resistance proteins and in a P-type ATPase that appears to form part of a bacterial copper homeostatic system. These two human ATPases are the first putative heavy-metal transporters to be discovered in eukaryotes.
7911940##1994-6-25##Presymptomatic testing in families with Wilson's disease.##
7976229##1994-6-1##Motor impairment in Wilson's disease. 3: The clinical impact of pyramidal tract involvement.##Magnetic brain stimulation was performed on 24 patients with Wilson's disease (WD). Responses to the right and left first dorsal interosseus muscle (FDI) and to the right and left tibialis anterior muscle (TA) were analysed. In 45% of the patients prolonged central motor conduction times (CCTs) to the FDIs were found, whereas only 12% of the patients presented with prolonged CCTs to the TA muscles. No consistent significant correlations between copper metabolism and pyramidal tract function tested by magnetic brain stimulation were found. An improvement of CCTs and response amplitudes with copper elimination therapy was observed only at early phases of therapy. There was no correlation with duration of therapy or neurological symptoms. Thus magnetic brain stimulation turns out to be sensitive to detect subclinical pyramidal tract impairment in WD but seems to test a too specific aspect of motor impairment in WD to reflect the overall neurological status of the patients. Therefore, it has to be combined with other tests to be used for therapy control.
8198464##1994-6-1##Treatment of Wilson's disease with ammonium tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients.##
7922775##1994-6-1##Serum IgE levels in liver cirrhosis. Contrasting results in alcoholic and non-alcoholic patients.##Hypergammaglobulinemia is a well-known feature of liver cirrhosis, but studies on serum IgE in this setting are limited. The present study evaluates serum IgE concentration in a group of cirrhotic patients and examines their relationship with aetiological, clinical and analytical parameters (including liver function tests and hepatic phagocytic activity). The presence of specific IgE against common dietary antigens was also investigated. Total serum IgE was determined by enzyme immunoassay (EIA) in 52 cirrhotics (27 alcoholic and 25 non-alcoholic, including eight virus B and seven virus C-related cirrhosis, three primary biliary cirrhosis, three cryptogenic, three haemochromatosis and one Wilson's disease) and 34 healthy subjects (used as controls). Serum IgE (IU/ml) in controls was not significantly different from that of cirrhotic patients (median 42, range 2-726 vs median 86, range 2- &gt; 1000, respectively) (P = NS). However, serum IgE among alcoholics (median 199, range 19- &gt; 1000) was higher than that of controls (P &lt; 0.001), virus B-related cirrhotics (median 25, range 3- &gt; 1000) (P &lt; 0.05), virus C-related cirrhotics (median 47, range 2-170) (P &lt; 0.05), or non-alcoholic cirrhotics as a whole (median 23, range 2- &gt; 1000) (P &lt; 0.01). High IgE levels (&gt; or = 170 IU/ml) were detected in 55.5% of alcoholics compared with only 12% of non-alcoholic cirrhotics (P &lt; 0.01). Moreover, IgE levels were very high (&gt; 1000 IU/ml) in six patients of the alcoholic group (22.2%) compared with only one non-alcoholic patient (4%).(ABSTRACT TRUNCATED AT 250 WORDS)
8020819##1994-6-1##Fulminant hepatic failure resulting from coexistent Wilson's disease and hepatitis E.##Fulminant hepatic failure resulting from hepatitis E and coexistent Wilson's disease was diagnosed in a six year old girl six weeks after returning from a holiday in India. Wilson's disease was diagnosed on the basis of histological evidence of hepatocellular copper deposition, confirmed by biochemical estimation of liver copper concentration. Although severely damaged, the liver was non-cirrhotic. Hepatitis E virus (HEV) was diagnosed by nested polymerase chain reaction, the specificity of which was confirmed by direct sequencing of amplified DNA. Replication of HEV within the liver at the time of diagnosis was confirmed by selective amplification of the antigenomic strand of the virus obtained from total liver RNA. The patient had an orthotopic liver transplantation without recurrence of hepatitis and remains well at 19 months. Viral excretion, recorded by serial amplification of HEV RNA extracted from stool samples, persisted for 30 days after liver grafting. Severe vitiligo, present preoperatively, dramatically improved after liver grafting and institution of immunosuppressive treatment. This case suggests that viral infection may play a part in the acute decompensation seen in some cases of Wilson's disease.
8201263##1994-6-1##Treatment of Wilson's disease with zinc. XIII: Therapy with zinc in presymptomatic patients from the time of diagnosis.##The siblings of patients with newly diagnosed Wilson's disease are each at 25% risk of also having this autosomal recessive disease. Screening these siblings allows their detection and institution of prophylactic therapy before they become clinically ill. Herein we report the successful treatment of 13 presymptomatic patients with zinc acetate. These patients who received zinc have been followed for 3 to 9 years. In well-complying patients, 24-hour urine copper and non-ceruloplasmin plasma copper levels have decreased over years of follow-up, consistent with the elimination of the excess easily mobilized copper (the potentially toxic copper) of the body. Effect of therapy and compliance are easily monitored by following 24-hour urine zinc and copper levels. The urine copper level is a good reflection of the body's excess load of easily mobilizable copper. It will increase if control is not adequate. A decrease in urine zinc is an early signal that the patient's compliance is not optimal. The levels of hepatic copper in response to several years of zinc therapy may remain the same, go down, or go up temporarily. This is a reflection of zinc induction of hepatic metallothionein, which sequesters copper in a non-toxic pool. Hepatic copper levels should not be used to manage therapy. Liver function is well preserved by zinc therapy, and no zinc toxicity occurred in these 13 patients. No patient developed symptoms related to Wilson's disease. We conclude that zinc acetate is a fully effective and non-toxic therapy for the prophylactic treatment of the presymptomatic Wilson's disease patient.
8208404##1994-6-1##Treatment with D-penicillamine improves dopamine D2-receptor binding and T2-signal intensity in de novo Wilson's disease.##We report the results of in vivo striatal dopamine D2-receptor binding assessed by PET using 11C-raclopride (only one patient) and by single-photon emission computed tomography (SPECT) using 123I-iodobenzamide (123I-IBZM) and the findings of T2-weighted MRIs in two de novo Wilson's disease patients before and 4 months after initiation of D-penicillamine treatment. Before treatment, specific 11C-raclopride binding (only patient 1) was markedly reduced, with a putamen to cerebellum ratio of 1.99 (controls: 3.99 +/- 0.55, n = 15) and a caudate to cerebellum ratio of 2.52 (controls: 3.65 +/- 0.59, n = 15). Specific 123I-IBZM binding was reduced in both patients, with a basal ganglia to frontal cortex ratio of 1.25 (patient 1) and of 1.41 (patient 2) controls: 1.57 +/- 0.04, n = 5). After 4 months of therapy, 11C-raclopride-PET improved to a putamen to cerebellum ratio of 2.52 and a caudate to cerebellum ratio of 3.06 (patient 1). 123I-IBZM-SPECT revealed an increase of basal ganglia to frontal cortex ratios of 1.34 (patient 1) and 1.55 (patient 2). On heavily T2-weighted MRI sequences, hyperintense signal changes before therapy within the putamen (both patients), brainstem (only patient 1), and caudate (only patient 2) greatly diminished after treatment. Reduced striatal dopamine D2-receptor binding in these Wilson's disease patients improved under therapy, suggesting, in part, a reversible defect of striatal neurons.
8208401##1994-6-1##Initial and follow-up brain MRI findings and correlation with the clinical course in Wilson's disease.##We performed pretreatment brain MRIs in 25 patients with neurologically symptomatic Wilson's disease (WD) and clinical and MRI follow-up in 16 of them. All 25 pretreatment MRIs revealed abnormalities, with abnormal high-signal intensity (HSI) in bilateral thalami being the most common (92%). HSI lesions in the brainstem (84%) and the basal ganglia (72%) were also common. Brain atrophy was present in 88% of the 25 patients. In the follow-up period of 5 to 24 months, during which the patients were treated with D-penicillamine, both HSI lesions and neurologic symptoms improved in 88% of the 16 patients, but the brain atrophy did not change.
8202418##1994-6-1##Wilson's disease. Psychiatric manifestations may be the clinical presentation.##It is important to consider Wilson's disease in patients with psychiatric signs and symptoms who also have abnormal liver function test results or neurologic findings, or both. Thorough evaluation of emotionally disturbed persons, including complete history taking, careful physical examination, and appropriate laboratory profile, generally rules out or arouses suspicion of Wilson's disease during routine screening. Laboratory abnormalities necessitate repeated studies and additional family and personal history taking with emphasis on possible Wilson's disease. Further workup may then be indicated. Prompt recognition and vigorous, consistent treatment can minimize symptoms and tissue damage. Identifying a case of Wilson's disease and seeing clinical aspects improve with appropriate therapy is gratifying.
8197608##1994-5-27##Systemic chimerism in sex-mismatched liver transplant recipients detected by fluorescence in situ hybridization.##Fluorescent in situ hybridization (FISH) is a reliable, rapid, sensitive, and quantitative method for detection of residual host cells following sex-mismatched bone marrow transplantation. Recently, donor-derived long-term multilineage hematopoiesis was detected in a sex-mismatched liver transplant recipient. We therefore assessed chimeric status in 12 patients (F 9, M3), mean age 42.5 years (range 16-57), for a median period of 18 months (range 7-32) following sex-mismatched liver transplantation. Peripheral blood hematolymphoid cells were hybridized with Y- or X-chromosome fluorescently labeled specific probes, and the donor-typed hematopoietic cells were enumerated. In two F recipients 4-5% male hematolymphoid cells were detected in the peripheral blood at 15 and 22 months after sex-mismatched liver transplantation, respectively. These two patients with systemic chimerism suffered from primary biliary cirrhosis and fulminant Wilson's disease before transplantation. One of them had evidence of graft rejection only once during the posttransplant course and the other had no episode of graft rejection. Two other female patients who were found to have approximately 2% male hematolymphoid cells, which is considered to be in the false-positive range, also had no signs of graft rejection during the posttransplant follow-up period. Among the remaining eight patients, in whom systemic chimerism was undetectable, there was at least one episode of acute cellular rejection during the posttransplant period. In summary, the FISH technique enables us to detect systemic chimerism following sex-mismatched liver allografts. Inasmuch as balanced systemic chimerism after organ transplantation is of major importance for self tolerance, our findings may enable us to treat patients after liver transplantation without the need for immunosuppression.
8203535##1994-5-1##Pleiotropic effect of LEC mutation: a rodent model of Wilson's disease.##Metabolic studies with 67Cu were undertaken to identify the site of the cellular defect in copper metabolism in the Long-Evans Cinnamon (LEC) rat. The apparent rate of copper uptake by LEC primary hepatocytes was increased [maximal velocity (Vmax) = 259 pmol.min-1.mg protein-1] compared with controls (Vmax = 161 pmol.min-1.mg protein-1); however, Michaelis-Menten constant (Km) values were comparable (11.8 and 12.7 microM, LEC and control, respectively). Efflux of copper from LEC and control hepatocytes was similar from 0 to 15 min, but was reduced from 15 to 60 min in the former. Although hepatic copper contents were markedly elevated in LEC rats compared with controls (658 +/- 199 vs. 21.5 +/- 6.6 micrograms/g dry wt), biliary copper concentration was reduced in LEC rats compared with controls (0.187 vs. 1.39 +/- 0.66 microgram/ml). Subcellular fractionation of LEC liver homogenates revealed approximately 75% of copper to be present in cytosol, with gradients of copper concentration from cytosol to either lysosome or microsomal subcellular fractions. LEC rat bile and hepatic microsome and lysosome fractions contained smaller fractions of 67Cu administered intravenously as cupric acetate compared with control rats. However, recovery of 67Cu in bile and in lysosomal subcellular fractions were similar for LEC and controls following administration of 67Cu-labeled asialoceruloplasmin, which is targeted to lysosomes. This discordance suggests a possible defect in the entry of copper into lysosomes but normal delivery of lysosomal copper to bile. Based on these findings, we conclude that the mutation in LEC rats alters copper transport at more than one cellular site.
8017989##1994-5-1##Hepatic hypertrophic osteoarthropathy and liver transplantation.##
7958254##1994-5-1##Is copper incorporation to caeruloplasmin normal in Wilson's disease?##
8065844##1994-5-1##Impaired hepatic copper homeostasis in Long-Evans Cinnamon rats: reduced biliary excretion of copper.##To explain the pathogenesis of excessive copper accumulation in Long-Evans Cinnamon (LEC) rats, regarded as one of the animal models for hepatic-type Wilson's disease, we measured copper contents in liver tissue and bile, serum total copper concentration, and ceruloplamin oxidase activity in LEC rats before and after the onset of spontaneous hepatitis. The copper contents in liver tissue of both 11-wk-old and 18-mo-old LEC rats were about 60 times the amounts in age-matched Wistar and Long-Evans Agouti rats. The biliary copper excretion in 11-wk-old LEC rats was significantly lower than that of the Long-Evans Agouti and Wistar rats that were the same age (27.9 and 41.4%, respectively). In 18-mo-old LEC rats, biliary copper excretion was lower than that in the Long-Evans Agouti rats that were the same age, but the finding was statistically not significant. Serum copper and ceruloplasmin levels were markedly reduced in LEC rats of both ages. These findings suggest that LEC rats have similar defects of biliary copper excretion as observed in patients with Wilson's disease.
17977425##1994-5-1##[Wilson's disease].##A 17-year-old girl with haemolytic anaemia, parenchymal livel disease and gallbladder calculi, is reported. Kayser-Fleischer rings, transaminasaemia, deficiency of ceruloplasmin, increased cupriuria, and nodular cirrhosis of the liver, confirmed the diagnosis of Wilson's disease. Penicillamine therapy had to be interrupted a short time after it was started, because of penicillamine-induces acute psychotic episode. Zinc-sulphate has controlled Wilson's disease in the patient.
8042956##1994-4-1##Hepatic copper overload--is it Wilson's disease?##
8019018##1994-4-1##Orthotopic liver transplantation for familial amyloidotic polyneuropathy.##Orthotopic liver transplantation for inborn errors of metabolism has become a standard indication for transplantation in pediatric and adult patients with alpha-1 antitrypsin deficiency, Wilson's disease and tyrosinemia, amongst several less common diseases. Familial amyloidotic polyneuropathy (FAP) is a rare autosomal dominant disease whose metabolic origin lies in an abnormal protein synthesized primarily in the liver. FAP, also discussed as the autosomal dominant form of amyloidosis, is characterized as a hereditary form of amyloidosis. It is the rarest form of amyloidosis affecting kindreds of specific ethnic backgrounds. The true incidence of this disease in the United States is not known. The mutant protein, called transthyretin or prealbumin, forms amyloid fibrils which accumulate in vital tissues ultimately leading to the patient's death. Liver transplantation for this inherited disease leads to the production of normal transthyretin protein. This theoretically should arrest the disease process. The first 5 patients in the United States with FAP who have undergone transplantation are presented.
8045245##1994-4-1##The diagnostic value of multi-modality evoked potentials in Wilson's disease.##19 patients with a neurological manifestation of Wilson's disease (WD), most of them with long-term disease (&gt; 10 yr), underwent clinical, psychometrical and electrophysiological evaluation in order to test whether there is a correlation of psychometrical and evoked potential (EP) abnormalities with a semiquantitative clinical score ranging from no (0) to severe (3) symptoms. The following EPs were recorded: acoustically evoked event-related (ERPs), somato-sensory (SSEPs), visually (VEPs) and brainstem evoked potentials (BSEPs). Results were compared with the data of an age- and sex-matched control group. 89% of the patients revealed clinical signs of basal ganglia dysfunction, 11% oculomotor or cerebellar symptoms, but none of the individuals had any clinical hint for visual pathway affection. Psychometrically, 100% had mood disturbances without definite intellectual decline. In EP-recordings, 100% showed ERP, 58.0% SSEP and 53% VEP and BSEP abnormalities. VEP and BSEP measurements did not correlate with the clinical score. There was only a weak correlation of SSEP (right-side)- and ERP-amplitude reduction with the clinical total score. The only significant correlation was found between the clinical total score and the time dependent psychometrical tests. Thus, there is a fairly high percentage of subclinical cerebral impairment in Wilson patients with long-term disease detectable by ERP-recordings which do, however, not correlate with the clinical status of the patients.
7519580##1994-4-1##Monoclonal antibody against the active site of caeruloplasmin and the ELISA system detecting active caeruloplasmin.##Serum caeruloplasmin deficiency is a characteristic biochemical abnormality found in patients with Wilson's disease, but the mechanism of this disease is unknown. Although the phenylenediamine oxidase activity of serum caeruloplasmin is markedly low in patients with Wilson's disease, mRNA of caeruloplasmin exists to some extent. To investigate the deficiency of caeruloplasmin oxidase activity in Wilson's disease, we generated 14 monoclonal antibodies (MAbs) and selected ID1, which had the strongest reactivity, and ID2, which had neutralizing ability. We also established a system to measure active caeruloplasmin specifically using these MAbs. These MAbs and the system will be useful tools in analyzing the active site of caeruloplasmin in patients with Wilson's disease.
8014805##1994-4-1##Infectious complications in living related liver transplantation.##During the last 31 months, 50 children between 3 months and 15 years of age have undergone living related liver transplantation (LRLT) for end-stage liver diseases (39 biliary atresia, 2 Budd-Chiari syndrome, 2 progressive intrahepatic cholestasis, 3 liver cirrhosis, 1 Wilson disease, 1 protoporphyria, 1 tyrosinemia, and 1 fulminant hepatitis). Combined FK-506 and low-dose steroids were routinely used for immunosuppression. There were seven deaths, two of which were related to infection (Candida pneumonia and Epstein-Barr virus [EBV]-associated lymphoproliferative syndrome [LPS]). Five patients had a bacterial infection, all of which were associated with surgical complications. Three patients had Candida infection, all of which were malnourished, had biliary atresia, and had been managed with prolonged antibiotics against obstinate ascending cholangitis. There were 14 symptomatic viral infections (1 herpes simplex virus, 1 herpes zoster virus, 5 cytomegalovirus [CMV], 6 EBV, and 1 EBV-associated LPS). Three of the five CMV infections appeared in patients whose graft was ABO-incompatible, who were managed with prophylactic OKT-3. Most of the viral infections (except 1 EBV-associated LPS) were minor and were treated successfully. The low incidence and successful treatment of CMV infection are related to the high compatibility and low incidence of allograft rejection in LRLT. Bacterial and fungal infections can be decreased by greater refinement of surgical technique and more aggressive preoperative management. Treatment of EBV infection is still an unsolved problem.
7940525##1994-4-1##Impaired biliary excretion of copper and lysosomal enzymes in Long-Evans cinnamon.##Although impaired biliary excretion of copper through hepatocyte lysosomes has been postulated as a pathogenesis of Wilson's disease, direct evidence has been lacking. Our aim was to investigate the dynamics of biliary excretion of copper and lysosomal enzymes in the Long-Evans Cinnamon (LEC) rat, a recently established rodent model of Wilson's disease. Liver homogenate and bile were obtained from 12 week-old LEC rats (n = 7), Long-Evans Agouti rats (n = 3) and Sprague-Dawley rats (n = 8) and analyzed for copper and lysosomal enzymes. Structural integrity of hepatic lysosomes was assessed by the latency of N-acetyl-beta-glucosaminidase. Compared with the controls, LEC rats exhibited a 43-fold increase in hepatic copper concentration (p &lt; 0.001), a significant increase in hepatic activities of lysosomal enzymes (p &lt; 0.001) and reduction of lysosomal latency (p &lt; 0.05). In contrast, biliary excretion of copper and lysosomal enzymes were significantly impaired in LEC rats (p &lt; 0.05). These results suggest a coupled alteration between copper and lysosomal enzymes in both the liver and bile of LEC rats (i.e., increase in liver and decrease in bile). Defective biliary excretion of copper via hepatocyte lysosomes may play a role in part in spontaneous copper accumulation in LEC rats.
8122662##1994-3-1##Penicillamine hypersensitivity: successful desensitization of a patient with severe hepatic Wilson's disease.##We report a 16-yr-old patient who developed a severe allergic reaction to penicillamine which was prescribed for newly diagnosed hepatic Wilson's disease. The patient's name was placed on the liver transplant waiting list because of the severity of her liver disease. We describe successful desensitization to penicillamine, so that medical therapy alone was sufficient for management of her condition.
8129644##1994-3-1##Development of neurologic symptoms in a patient with asymptomatic Wilson's disease treated with penicillamine.##
8119682##1994-3-1##Liver transplantation for Wilson's disease: indications and outcome.##The objective of this study was to determine the indications for and results of liver transplantation in patients with Wilson's disease on the basis of results of a survey with retrospective review of data obtained on 55 transplants performed at centers in the United States and Europe. The study group comprised 32 females and 23 males, aged 8.5 to 51 yr, with features diagnostic of Wilson's disease. Indication for orthotopic liver transplantation included hepatic insufficiency (n = 32), wilsonian fulminant hepatitis (n = 21), intractable neurological Wilson's disease (n = 1) and gastrointestinal hemorrhage (n = 1). Forty-three patients have survived, at this writing, from 3 mo to 20 yr. Mean and median survival after orthotopic liver transplantation were 2.7 and 2.5 yr, respectively. Survival at 1 yr was 79%. Nonfatal complications occurred in five patients. Of the seven patients given transplants for hepatic insufficiency who manifested neurological and/or psychiatric manifestations at the time of orthotopic liver transplantation, four showed improvement of these symptoms. One patient given a transplant for intractable neurological disease improved but died of a vascular complication. Our data demonstrate that liver transplantation is life-saving but not without risk for patients with wilsonian fulminant hepatitis or chronic severe hepatic insufficiency unresponsive to medical therapy. Furthermore, neurological or psychiatric symptoms due to Wilson's disease may improve after liver transplantation; however, the role of this procedure in the management of patients with neurological Wilson's disease in the absence of hepatic insufficiency is still uncertain.
7860522##1994-3-1##Wilson's disease: unusual clinical and radiological features.##
8057991##1994-3-1##Wilson's disease--a review of cases at University Hospital, Kuala Lumpur.##The clinical course of 18 patients with Wilson's disease is reported. There were 13 males and five females of whom one is Malay. The prevalence of Wilson's disease in Malaysia is probably the same as elsewhere. Being a genetic syndrome, the genetic carrier rate for Wilson's disease is probably lower amongst the Malays. At diagnosis, the clinical signs were predominantly hepatic in 10 patients, neurological in five patients with three asymptomatic cases. All patients were commenced on penicillamine but poor compliance was observed in many patients. Two patients defaulted follow-up and seven patients died. Out of the nine surviving patients, only four are well with no clinical symptoms.
7817096##1994-3-1##[Acute hemolytic crisis followed by fulminant hepatic failure with fatal outcome, as a first clinical manifestation of Wilson's disease].##We describe in this work a clinical case of a female patient aged 21 years, bearer of Wilson's disease, a first clinical manifestation of the disease occurred as an acute hemolytic crisis followed by fulminant hepatic failure evolving to death after 26 days' internment. The definitive diagnosis was obtained only as a quantitative measurement of hepatic copper from the necropsy material. The search for Kayser-Fleischer ring was negative and the serum ceruloplasmin level was 9 mg/dl (15 to 60). No involvement of the central nervous system was noted from the pathologic analysis. The patient presented two Coombs negative hemolytic crises during the internment; the first on being admitted to hospital and the second after a transjugular hepatic biopsy carried out on the 16th day after internment. The last hemolytic crisis was accompanied by an increase of serum and urinary copper levels. On this occasion the patient evolved to a progressive hepatic failure with severe jaundice and hepatic encephalopathy. We are presenting the clinical-biochemical evolution of the patient and we shall discuss the existent hypotheses to the pathophysiology of this rare form for manifestation of the Wilson's disease as well the diagnostic difficulties.
8084826##1994-2-21##[Pregnancy and delivery in a woman with Wilson's disease (degeneratio hepatoleuticularis)].##The authors present the course of two gestations and labours in women with Wilson's disease. Both patients were treated with D-penicillamine during pregnancy. As a result of their observations, the authors suggest that Wilson's disease requires proper diagnosis and cure before pregnancy and adequate care during pregnancy. In such a situation Wilson's disease should not be a high risk factor for pregnant women and their babies. It should be pointed out that undiagnosed Wilson's disease can be a cause of habitual abortion and infertility.
8171374##1994-2-1##Severe spinal degeneration in Wilson's disease.##This case report is the first to report severe spinal degeneration and destruction in Wilson's disease. The presentation, assessment, and decision making for treatment are discussed. This condition should be considered in patients with Wilson's disease who present with back pain.
8109583##1994-1-17##Hepatic disease in pregnancy.##Liver disease occurring in pregnancy can be categorized into three groups. The first group includes diseases unique to pregnancy and caused by it. Among these are hyperemesis gravidarum, cholestasis of pregnancy, and disorders associated with preeclampsia. Liver involvement may be expected in 50% of patients with hyperemesis gravidarum. Preeclampsia has been associated with both the HELLP syndrome (hemolysis, elevated liver tests, and low platelets), which includes hepatic infarction and rupture, and with acute fatty liver of pregnancy (AFLP). In patients with HELLP syndrome, liver test abnormalities do not correlate with liver injury. Therefore, this and other disorders associated with preeclampsia require aggressive treatment, primarily with delivery. The second group of liver diseases are those exacerbated by pregnancy. Viral infections involving the liver that are usually benign, such as hepatitis E and herpes simplex, are more likely to be exacerbated in pregnant women and are more likely to lead to fulminant hepatic failure. Cholelithiasis and Budd-Chiari syndrome are more prevalent in pregnant women. The third group is comprised of liver diseases that are preexisting in the pregnant patient and includes autoimmune chronic active hepatitis and Wilson's disease. The number of patients in the last group is small, as chronic liver disease is rare in women who are able to bear children.
7818921##1994-1-1##Management options for primary hepatocellular carcinoma. An overview.##Hepatocellular carcinoma (HCC) is the seventh most common cancer in men and the ninth most common cancer in women with 500,000 to 1,000,000 new cases per year. Several risk factors (sex hormones, alcohol, thorotrast, aflatoxin B1, hepatitis B or C, haemochromatosis, alpha 1-antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, acute intermittent porphyria, Wilson's disease) associated with the development of HCC have been identified from epidemiological studies. The diagnosis is usually based on a combination of clinical and laboratory findings together with radiographic and histopathologic characteristics. HCC remains difficult to treat with a median survival of 3 to 6 months after the onset of symptoms. Surgical resection is the mainstay of treatment for HCC. Transcatheter arterial embolization and percutaneous ethanol injection have been used but neither therapy has been evaluated in a prospective randomized study. Combination treatment (e.g. chemotherapy and resection) may be of value but randomized controlled trials with long-term follow-up are still needed. Liver transplantation should be reserved for carefully selected patients.
8279473##1994-1-1##Refining the position of Wilson disease by linkage disequilibrium with polymorphic microsatellites.##Wilson disease (WND) is an autosomal recessive disorder that is due to an inability of the liver to eliminate copper. Copper buildup in the liver, brain, kidney, and other tissues can result in liver cirrhosis, neurologic and psychiatric defects, and other problems. We have localized the disease-containing region to between D13S31 and D13S59, with &gt; 70 multiply affected families, and have constructed a YAC contig of &gt; 4.5 Mb that spans these loci and orders nine highly polymorphic microsatellites. Here we present an analysis of disequilibrium with markers in this interval and provide evidence for strong allelic associations between AFM084xc5 alleles and WND alleles in European, Middle Eastern, and East Asian populations. Significant but weaker allelic associations were also observed between WND alleles and alleles at D13S137 and D13S169. The strength of the association between AFM084xc5 and WND in all non-Sardinian populations combined (linkage-disequilibrium coefficient [phi] = .61) suggests that the number of mutations accounting for WND is less than expected on the basis of the variety of clinical symptoms that are observed.
8279472##1994-1-1##Haplotype studies in Wilson disease.##In 51 families with Wilson disease, we have studied DNA haplotypes of dinucleotide repeat polymorphisms (CA repeats) in the 13q14.3 region, to examine these markers for association with the Wilson disease gene (WND). In addition to a marker (D13S133) described elsewhere, we have developed three new highly polymorphic markers (D13S314, D13S315, and D13S316) close to the WND locus. We have examined the distribution of marker alleles at the loci studied and have found that D13S314, D13S133, and D13S316 each show nonrandom distribution on chromosomes carrying the WND mutation. We have studied haplotypes of these three markers and have found that there are highly significant differences between WND and normal haplotypes in northern European families. These findings have important implications for mutation detection and molecular diagnosis in families with Wilson disease.
8291609##1994-1-1##The LEC rat: a model for human hepatitis, liver cancer, and much more.##The LEC rat is an inbred mutant strain with spontaneous hepatitis isolated from Long-Evans rats. Since approximately 40% of LEC rats die of fulminant hepatitis, the rat serves an animal model for studying the pathogenesis and treatment of human fulminant hepatitis. The remaining 60% of LEC rats survive and develop chronic (prolonged) hepatitis and subsequently develop liver cancer. Therefore, the LEC rat serves an important animal model for studying the significance of chronic hepatitis in the development of human liver cancer, which often develops in association with chronic hepatitis. The LEC rat can also be used as an animal model of Wilson's disease, since recent studies have disclosed high copper accumulation in the liver and low ceruloplasmin concentration in the serum of this mutant rat.
8186659##1994-1-1##Excessive iron storage in a patient with Wilson's disease.##We report on an otherwise healthy female, mother of two children, with severe decompensated liver cirrhosis due to an iron overload and Wilson's disease. The patient was considered heterozygote for hemochromatosis on the basis of the autosomal recessive inheritance for hemochromatosis, the frequency of the hemochromatosis gene, and the laboratory parameters defining her iron overload. The case is interesting because of the coincidence of Wilson's disease and excessive iron storage.
8003796##1994-1-1##Penicillamine-induced elastosis perforans serpiginosa treated successfully with isotretinoin.##Elastosis perforans serpiginosa (EPS) and the elastotic changes of pseudoxanthoma elasticum (PXE) are rare but well-recognized side-effects of long-term penicillamine therapy. A 42-year old female patient who developed both of these cutaneous side-effects following treatment with high-dose penicillamine for Wilson's disease is described; near-complete resolution of the EPS, but not the PXE was achieved by treatment with isotretinoin (0.5 mg/kg/day) for 6 weeks, despite continuation of the penicillamine.
7851456##1994-1-1##Pregnancy in a patient with Wilson's disease treated with D-penicillamine and zinc sulfate. A case report and review of the literature.##A case of successful pregnancy in a patient with Wilson's disease treated with D-penicillamine and zinc sulfate is presented. Experience with D-penicillamine, triethylene tetramine dihydrochloride (trien) and zinc salts during pregnancy is reviewed and discussed.
7915583##1994-1-1##Blink reflex in Wilson's disease.##Blink reflex and brainstem auditory evoked potential (BAEP) were studied in 10 patients with Wilson's disease (WD) and 10 family members. In blink reflex, R1 and R2 latencies as well as R2 duration were prolonged in the patient group, but not in the family group. In BAEP, latencies of peaks III and V and interpeaks I-III, III-V and I-V were also delayed only in the patient group. These data suggest that blink reflex abnormalities in WD are different from other movement disorders and are mainly due to brainstem dysfunction.
8201221##1994-1-1##Low vitamin E content in plasma of patients with alcoholic liver disease, hemochromatosis and Wilson's disease.##The RRR-alpha-tocopherol (vitamin E) content in plasma from 46 patients with liver diseases and 23 healthy controls was determined by high performance liquid chromatography and electrochemical detection. Patients were divided into three groups: alcoholic liver diseases (n = 17; group A), hemochromatosis (n = 17; group B) and Wilson's disease (n = 12; group C). Lipid-standardized alpha-tocopherol levels were determined to neutralize differences due to hyperlipemia. The ratio of serum vitamin E to serum lipids (cholesterol, triglycerides, phospholipids) was highest in healthy controls and in patients in group A with cirrhosis and normal transaminases and bilirubin. Patients in group A with acute or chronic ethanol intoxication and high bilirubin levels had a 37% lower lipid-standardized vitamin E level than controls. Patients in group B with hemochromatosis, showing high serum iron (&gt; 180 micrograms/dl), a low free iron binding capacity (&lt; 8 mumol/l) and high ferritin-levels (&lt; 450 micrograms/l), had a 34% lower vitamin E/lipid ratio than healthy controls. No significant lowering of the vitamin E/lipid ratio was observed in the other patients in group B. A significant decrease (37%) in the vitamin E/lipid ratio was only detectable in patients with Wilson's disease (group C) showing high free serum copper (&gt; 10 micrograms/dl). The data support a role for free radicals in the pathogenesis of active liver diseases.
7837770##1994-1-1##Measurement of blood holoceruloplasmin by EIA using a mouse monoclonal antibody directed to holoceruloplasmin. Implication for mass screening of Wilson disease.##
7853829##1994-1-1##Function of asialoglycoprotein receptor of hepatocytes in patients with Wilson's disease.##The function of hepatocyte asialoglycoprotein receptors was analyzed in normal subjects, in patients with Wilson's disease and in patients with chronic hepatitis C. A new radionuclide liver imaging, using Technetium-99m diethylenetriamine-pentaacetic acid-galactosyl human serum albumin, was applied to evaluate the function of the receptor, and a Receptor Index, LHL 15, which was calculated by dividing the radioactivity of the liver region-of-interest (ROI) by that of the liver plus heart ROI at 15 min after the radiolabeled ligand injection, was evaluated. The values were similar between the patients with Wilson's disease and patients with chronic hepatitis C. Hepatocyte receptors for asialoglycoproteins were not affected specifically in patients with Wilson's disease, suggesting that the defect in patients with Wilson's disease involves steps other than receptor-mediated endocytosis of asialoceruloplasmin via asialoglycoprotein receptor.
8183467##1994-1-1##Wilson's disease: MRI with clinical correlation.##We tried to establish possible correlations between clinical data and MRI in a group of patients with Wilson's disease. Eleven patients (6 male, 5 female), aged between 11 and 50 years old, with a duration of illness from 5 months to 32 years, were submitted to MRI on a 1.5 T System. Three patients were asymptomatic, two had mild neurological disturbances, two were moderately affected and the remaining four had a severe form of the disease. All were receiving D-penicillamine at the time of the study. In the most symptomatic patients there were abnormalities in five or more sites on MRI. The putamen was affected in all symptomatic patients, including five with dystonia. A striking feature was the peripheral location of high signal putaminal lesions on T2-weighted images. In five cases, lesions in the corpus striatum or substantia nigra explained the patient's Parkinsonian features. MRI is an efficient method for studying involvement of the central nervous system in Wilson's disease, and allows some interesting anatomoclinical correlations.
8114310##1994-1-1##[Liver cirrhosis, its definition and classification--from a morbid anatomical point of view].##Cirrhosis of the liver is a principally a morphological entity, and it has been assumed to be an end-stage condition of all chronic active liver diseases. Morphologically, liver cirrhosis can be defined briefly as &quot;a pathological condition characterized by diffuse pseudonodule formation throughout the entire liver&quot;. Fundamental pathogenetic changes in the cirrhotic process are hepatic necrosis, increase of connective tissue and regeneration of hepatocytes. For the sake of convenience, liver cirrhosis is classified into two groups; common and specific types. The former included postnecrotic, posthepatitic, alcoholic and mixed types of cirrhosis, and congestive, biliary, parasitic cirrhosis and Wilson disease were grouped into the latter. It should be mentioned that morphological diagnostic criteria is much more rigid for the common types than those of the specific type. Special stress has been laid on the importance of structural changes not only in the parenchymal disorganizations, but also in the stromal vascular changes in the cirrhotic process.
8114297##1994-1-1##[Liver cirrhosis in metabolic disorders].##The most early cirrhosis is observed in newborns with neonatal hemachromatosis. Early cirrhosis occurs in hereditary tyrosinemia type I, peroxisomal diseases and glycogen storage disease (type IV). In Wilson's disease, a case complicated with cirrhosis was reported in a 4-year-old patient. Slowly progressive cirrhosis is seen in patients with familial progressive intrahepatic cholestasis. Focal biliary cirrhosis is found in cystic fibrosis of the pancreas. Moreover, many other metabolic disorders, except for urea cycle disorders, are occasionally or rarely complicated with cirrhosis. Early diagnosis and proper management could prevent the development of cirrhosis in patients with galactosemia, hereditary fructose intolerance, etc. The occurrence of hepatoma must be monitored in these patients. Liver transplantation is indicated in a part of the patients with cirrhosis.
8114295##1994-1-1##[Liver cirrhosis in primary hemochromatosis and Wilson's disease].##Iron is an essential element in all living cells because it serves machineries for biological oxidation including hemoglobin, cytochrome c oxidase, etc. Copper is also essential for mammalian life since copper is the prosthetic element of several life-essential enzymes. Although intracellular excessive iron and copper were usually sequestrated in ferritin and metallothionein molecules, accumulation of excess iron and copper may also cause severe tissue injury by including oxyradicals and lipid peroxidation and eventually bring about tissue fibrosis such as liver cirrhosis. Hemochromatosis and Wilson's disease are known as iron and copper accumulation disorders, respectively. In this chapter, we review the cirrhosis in hemochromatosis and Wilson's disease.
7878329##1994-1-1##[Dermatomyositis and Wilson disease].##A 15 year-old girl developed both a dermatomyositis and a Wilson's disease. A clinical remission was obtained with steroids and D-penicillamine. The potential role of cupric intoxication in the pathogeny of the muscular syndrome is discussed.
8305691##1994-1-1##[MRT of the liver in Wilson's disease].##To show that Wilson's disease is one likely cause of multiple low-intensity nodules of the liver we obtained MR images in 16 patients with clinically and histopathologically confirmed Wilson's disease. Corresponding to morphological changes MRI enabled the subdivision of the patients into two groups. Using a T2-weighted spin-echo sequence (TR/TE = 2000/45-90) liver parenchyma showed multiple tiny low-intensity-nodules surrounded by high-intensity septa in 10 out of 16 patients. 5 patients had also low-intensity nodules in T1-weighted images (TR/TE = 600/20). In patients of this group histopathology revealed liver cirrhosis (n = 7) and fibrosis (n = 2). Common feature of this patient group was marked inflammatory cell infiltration into fibrous septa, increase of copper concentration in liver parenchyma and distinct pathological changes of laboratory data. In the remaining 6 patients no pathological change of liver morphology was demonstrated by MRI corresponding to slight histopathological changes of parenchyma and normal laboratory data. As low-intensity nodules surrounded by high intensity septa can be demonstrated in patients with marked inflammatory infiltration of liver parenchyma MRI may help to define Wilson patients with poorer prognosis. In patients with low-intensity nodules of the liver and unknown cause of liver cirrhosis laboratory data and histopathology should be checked when searching for disorders of copper metabolism.
11271177##1994-1-1##Living-related liver transplantation for fulminant hepatic failure in children.##Liver transplantation is increasingly accepted as a choice of treatment for fulminant hepatic failure (FHF) since it has been proved to significantly improve the survival rate in these patients compared with other therapeutic modalities. We have successfully performed a total of 76 living related liver transplantations (LRLT) three of which were for FHF. The first case was an 11-year-old boy with FHF due to an unidentified cause. He had required plasmapheresis a total of 24 times and haemofiltration to save his life before LRLT. He was transplanted with a left lobe (420 g) graft, calculated as 1.05% of his weight (40 kg). He recovered hepatic function uneventfully and was discharged from hospital after 7 weeks. The second case was a 13-year-old girl who developed FHF with grade III encephalopathy due to acute Wilson's disease, and was referred to us. She underwent LRLT with a left lobe graft (440 g), estimated as 0.95% of her weight (47 kg), which functioned well after surgery. The third case was a 13-year-old girl with grade II encephalopathy due to acute Wilson's disease. She was 27% obese with a body weight of 58 kg. She underwent LRLT with ABO blood group incompatibility with a left lobe (352 g), estimated as 0.80% of her weight (modified 44 kg). She was discharged with sensorimotor neuropathy due to vitamin B deficiency. The present results suggest that LRLT is feasible for FHF both clinically and ethically, and that a partial liver graft weighing around 1% of the recipient's weight can maintain the recipient's life. We limit the diagnostic indication for LRLT to chronic liver disease, since an urgent situation may affect a voluntary decision for the patient's parents to donate the partial liver. However, LRLT is thought to be an acceptable choice of treatment provided it is requested by the patient and family. Furthermore, it is a potential option for resolving the graft shortage in paediatric liver transplantation, being independent of cadaver donor availability.
11271176##1994-1-1##Orthotopic liver transplantation for acute hepatic failure in children.##Thirty children received 35 liver transplants for fulminant or late-onset liver failure between March 1988 and May 1993. Aetiology included non-A non-B hepatitis in 12, Wilson's disease in 8, drug-induced hepatic failure in 6, hepatitis B in 1, hepatitis A in 1, tyrosinaemia in 1 and congenital haemochromatosis in 1. Three patients were retransplanted, one each for hepatic artery thrombosis, non-A non-B graft reinfection, and chronic rejection. Two of these three patients received a third transplant for chronic rejection and hepatic artery thrombosis. One patient in the retransplant group survived. Overall, graft and patient survival at a mean follow-up of 17 months were 49% and 57%, respectively. Mortality was related to vascular complications in three patients (hepatic venous obstruction, portal vein thrombosis and hepatic artery thrombosis). Two patients died of primary sepsis (cerebral aspergillosis and cytomegalovirus (CMV) pneumonitis in association with graft-versus-host disease). Systemic sepsis and multiorgan failure was documented as a cause of death in four children and sepsis in association with chronic rejection in a further three patients. One child died of respiratory failure 4 weeks after transplantation. Mortality in eight children less than 2 years was 75% and this was significantly greater than for older children (P &lt; 0.003, Mantel Cox). Earlier referral, even in the absence of a definitive diagnosis and particularly in children under 2 years is advisable and may improve survival.
8280128##1993-12-30##Lack of copper binding sites in ceruloplasmin of LEC rats with abnormal copper metabolism.##Recently it was found that the clinical features of the LEC rat closely resemble those of human Wilson's disease. One of the characteristics of the animal is low levels of serum ceruloplasmin. Therefore, by using LEC rats, we attempted to define molecular basis of the deficiency in active site of ceruloplasmin in Wilson's disease patients. We made 3 monoclonal antibodies, ID2 against active site of ceruloplasmin, ID1 against inactive site of ceruloplasmin, and the remaining one against metallothionein. Using these monoclonal antibodies, we examined immunohistochemical stainings of LEC rat liver tissues, and compared them with those of LEA rats, as a control. ID1 stained the hepatocytes of both LEA and LEC rats, whereas ID2 stained LEA rat hepatocytes only. The results indicated that the ceruloplasmin secreted by LEC rat hepatocytes is mostly in inactive form. The antibody against metallothionein stained LEA rat hepatocytes only. This finding may also indicate that LEC rat hepatocytes express less amount of metallothionein than those of LEA rats.
8257436##1993-12-1##A mutant mouse (tx) with increased hepatic metallothionein stability and accumulation.##Metallothioneins (MTs) are low-molecular-mass cysteine-rich proteins implicated in metal homoeostasis and resistance to toxicity induced by heavy metals and alkylating agents. We report high hepatic MT protein accumulation (greater than 100-fold compared with wild-type mice) in toxic milk (tx) mice, along with markedly higher cytosol copper and zinc levels. Increased MT-gene transcription alone could not account for the high constitutive MT protein levels, since MT mRNA levels were not increased in tx mouse livers. However, hepatic MT was significantly more stable in adult tx mice: MT half-life (t1/2) was 79 or 77% greater than in wild-type mice before and after Cd induction respectively. Cd or Zn treatment increased MT mRNA, but not MT protein, accumulation in tx mouse livers: Cd displaced MT-bound Zn and Cu in preexisting MT. Thus tx mice appear to accumulate hepatic MT as a result of decreased protein degradation. These animals may provide a useful model to study the physiological role of MT, and human diseases (such as Wilson's disease) with abnormal copper metabolism.
8292651##1993-12-1##[Biosynthesis of two molecular forms of ceruloplasmin in rat liver and their polar secretion into the blood stream and bile].##Biosynthesis and secretion of ceruloplasmin (CP) in rat liver has been studied in order to elucidate its role in the distribution, transport and excretion of copper in the body. The kinetics and topography of CP synthesis, intracellular transport and secretion were followed using in vivo pulse-chase experiments. It was found that the newly formed CP was firmly bound to endoplasmic reticulum membranes in the hepatocytes. Liver slices incubated in vitro with [35S]methionine were characterized by a two-stage release of [35S]CP into the medium. After 30-min incubation the medium contained 200 kDa CP-like protein, while after 120 min the secretion of 130 kDa CP was demonstrated. The pulse-labelling experiments with [35S]methionine in rats with catheters inserted into the carotid artery and the common bile duct revealed the polar secretion of two distinct CP species differing in molecular structure and secretion rate. The slowly secreted CP isoform is the authentic serum CP, while the rapidly secreted CP is the specific biliary CP. The physiological function of biliary CP and its role in the pathogenesis of Wilson's disease are discussed.
8253357##1993-12-1##Alterations in hepatocyte lysosomes in experimental hepatic copper overload in rats.##
8138824##1993-12-1##Wilson's disease with cerebral manifestation: monitoring therapy by CSF copper concentration.##The clinical courses, cerebrospinal fluid (CSF) and serum copper concentrations and urinary copper excretions under different schemes of drug treatment in four patients with cerebral manifestations of Wilson's disease were monitored over 6-11 years. CSF copper concentration measurements were performed from the beginning of therapy onwards in three patients and from 16 months after initial treatment onwards in the fourth. CSF copper levels decreased slowly over the years in parallel with clinical improvements, and increased in one patient who interrupted therapy for 2 years. These findings confirm our hypothesis that the concentration of copper in the CSF is a valuable quantitative parameter reflecting the normalization of copper in the brain. Copper measurements during phases of initial neurological deterioration in two patients receiving D-penicillamine, and in one patient receiving D-penicillamine and zinc sulphate, revealed decreased free serum copper and CSF copper levels.
8298641##1993-12-1##The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.##Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium &amp; haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene.
8298640##1993-12-1##Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.##Wilson disease (WD) is an autosomal recessive disorder of copper transport which map to chromosome 13q14.3. In pursuit of the WD gene, we developed yeast artificial chromosome and cosmid contigs, and microsatellite markers which span the WD gene region. Linkage disequilibrium and haplotype analysis of 115 WD families confined the disease locus to a single marker interval. A candidate cDNA clone was mapped to this interval which, as shown in the accompanying paper, is very likely the WD gene. Our haplotype and mutation analyses predict that approximately half of all WD mutations will be rare in the American and Russian populations.
8298639##1993-12-1##The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.##Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P-type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.
8298634##1993-12-1##Cloning the Wilson disease gene.##
8250934##1993-11-30##Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease.##The putative copper and ATP-binding domains of the human Menkes disease gene were used as probes to screen a human liver cDNA library at reduced stringency. Sixty-five clones which remained positive after tertiary screening were subcloned and sequenced. One of these cDNA clones contains an open reading frame with 65% amino acid homology to the Menkes protein. Southern blot analysis localizes this cDNA to the region of the Wilson disease locus on chromosome 13. This cDNA detects a 7.5 kB transcript which is present in human liver and cell lines devoid of the Menkes transcript and which is absent in liver from a patient with Wilson disease. These data suggest that this cDNA is a candidate gene for Wilson disease and that the protein encoded at this locus is a member of the P-type ATPase family.
8151113##1993-11-1##Urinary copper excretion after penicillamine in the diagnosis of Wilson's disease in children.##
8138822##1993-11-1##Relationship between striatal glucose consumption and copper excretion in patients with Wilson's disease treated with D-penicillamine.##In 12 patients with Wilson's disease treated with D-penicillamine (DPA), the regional cerebral metabolic rate of glucose consumption of the lentiform and caudate nucleus was analysed using the 18Fluorodeoxyglucose method and correlated with the clinical symptoms of the patients, the ceruloplasmin level, the serum level of free copper and the 24-h copper excretion. The more copper was eliminated, the higher was the basal ganglia glucose consumption. On the other hand, in seven patients who had been treated for more than 7 years a significant decline of the basal ganglia glucose consumption was observed, suggesting too low a maintenance dose of DPA.
8277572##1993-11-1##[Movement disorders in miscellaneous disorders--inherited metabolic diseases].##A variety of inheritable metabolic disorders produce movement disorders. A lists of conditions associated with tremor, athetosis, chorea, dystonia and myoclonus are presented as a guide for the differential diagnosis of such abnormal involuntary movements. The list includes aminoacidopathies, lipidoses, mucopolysaccharidoses, mucolipidoses, organic acidemias, mitochondrial cytopathies and disorders of carbohydrate, purine, and metal metabolism. Clinical, pathological and biochemical features of movement disorders of three typical examples, Wilson's disease, Lesch-Nyhan syndrome and glutaric acidemia type 1, are described.
8277558##1993-11-1##[Dystonia].##Dystonia is a persistent attitude or posture in one or other of the extremes of athetoid movement. It may take the form of an over-extension or over-flexion of the hand, torsion of the spine, with arching and twisting of the back or forceful closure of the eyes and a fixed grimace. Dystonia is classified into idiopathic and symptomatic dystonia. Idiopathic dystonia is further divided into generalized, focal and segmental dystonia. Generalized dystonia covers classical torsion dystonia, paradoxical dystonia, myoclonic dystonia, dystonia with diurnal variation and Dopa-responsive dystonia. Dystonic tic, paroxysmal dystonia and hypnotic dystonia show a dystonic posture, although they are also accompanied by various other involuntary movements such as athetosis or chorea. Torticollis, writer's cramp or blepharospasm is assigned to the focal dystonia and Meige syndrome to the segmental dystonia. Symptomatic dystonia is observed in various neurological disorders, including cerebrovascular diseases, Parkinson's disease and Wilson's disease.
8234264##1993-11-1##A 4.5-megabase yeast artificial chromosome contig from human chromosome 13q14.3 ordering 9 polymorphic microsatellites (22 sequence-tagged sites) tightly linked to the Wilson disease locus.##We have previously performed a genetic analysis of multiply affected families to map a locus responsible for Wilson disease (WND) to a 0.3-centimorgan (cM) region within chromosome 13q14.3, between D13S31 and D13S59. Here we describe the construction of a contig of approximately 4.5 Mb, which spans this region and extends from D13S25 to D13S59. This contig consists of 28 genomic yeast artificial chromosome (YAC) clones. Five critical crossover events have been defined in this interval in two unaffected (Centre d'Etudes du Polymorphisme Humain) and three WND families. The combination of sequence tagged site content mapping of YACs with both polymorphic and nonpolymorphic markers and recombination breakpoint mapping resulted in the following order of polymorphic markers: centromere-RB1-D13S25-AFM205vh2-D13S31-D13S22 7-D13S228-AFM238vc3-D13S133- AFM084xc5-D13S137-D13S169, D13S155-D13S59-telomere. The recombination/physical distance ratio varies from approximately 3000 kb per cM in the region between D13S31 and D13S25 to 6000 kb per cM in the region between D13S31 and D13S59. Three WND families exhibiting recombination between the disease locus and D13S31 or D13S59 were genotyped for additional markers in this region and further refined the location of the WND gene to between D13S155 and D13S133. Nine of the markers in this region of &lt; 1 cM are polymorphic microsatellites (seven have observed heterozygosities of 70% or above) that will be extremely useful in prenatal and preclinical diagnosis of this disease. This physical map is an essential step in the isolation of the WND gene and is a framework for the identification of candidate genes.
8140327##1993-11-1##Disease recurrence after orthotopic liver transplantation.##With the advent of cyclosporine immunosuppression in the late 1970s, liver transplantation became a widespread modality for the treatment of end-stage liver disease. Several metabolic disorders that produce liver injury, such as Wilson's disease and alpha-1-antitrypsin deficiency, are cured by liver transplantation. However, many other diseases for which transplantation is undertaken may recur in the allograft. As follow-up increases and newer diagnostic modalities become available, those diseases that recur, and their natural histories, are becoming better understood. This new information may lead to a reevaluation of the suitability of some conditions for transplantation. This article briefly reviews disease recurrence in orthotopic liver transplants.
8213814##1993-10-1##Polymorphic microsatellites and Wilson disease (WD).##Wilson disease (WD), an autosomal recessive disorder of copper metabolism, has been previously mapped to chromosome 13q. Highly informative PCR-based polymorphic microsatellites closely linked to the WD locus (WND) at 13q14.3, as well as sequence-tagged sites for closely linked loci, are described. Two polymorphic microsatellite markers at D13S118 and D13S119 lie within 3 cM of WND. Two others (D13S227 and D13S228) were derived from a yeast artificial chromosome containing D13S31. These were placed on a genetic linkage map of chromosome 13 and were typed in 74 multiplex WD families from a variety of geographic origins (166 affected members). Multipoint analysis provides very high odds that the location of WND is between D13S31/D13S227/D13S228 and D13S59. Previous odds with RFLP-based markers were only 7:1 more likely than any other location. Current odds are 5,000:1. Preclinical testing of three cases of WD by using the highly informative polymorphic microsatellite markers is described. The markers described here ensure that 95% of predictive tests using DNA from both parents and from at least one affected sib will have an accuracy &gt; 99%.
8251685##1993-10-1##Endstage liver disease associated with nitrofurantoin requiring liver transplantation.##
8280286##1993-10-1##Fatal deterioration of Wilson's disease after institution of oral zinc therapy.##
8244665##1993-10-1##Hemolytic episode in a patient with Wilson's disease treated with zinc.##
8263268##1993-10-1##Does a vegetarian diet control Wilson's disease?##The literature indicates that copper (Cu) is less bioavailable from a vegetarian as compared to mixed diet. Further, several groups, including ours, find rather marginal average Cu intake in the typical American diet. For example, our data indicate that Wilson's disease patients on a typical American diet ingest only about 25% more Cu than is required. This suggests that a vegetarian diet, if it reduced bioavailability by about 25% or more, would be an adequate maintenance therapy for Wilson's disease. Observations in two of our patients, who were on lactovegetarian diets by choice, and who were almost totally noncompliant with anti-Cu therapy, support this view. These observations suggest that vegetarian diets may be a management tool for Wilson's disease. They also further emphasize the marginal Cu intake in American diets, and suggest that some seemingly healthy people, particularly vegetarians, may be at risk for mild Cu deficiency.
12318529##1993-10-1##The intrauterine device today.##The intrauterine contraceptive device (IUD) is effective and reversible and has a high continuation rate. It can also be used within 7 days postcoitus. Developed separately by Richter, Grafenberg, and Ota between 1909 and 1934, the IUD gained popularity in the 1960s and 1970s with the introduction of the Margulies Spiral, the Lippes Loop, the Birnberg Bow, and the Dalkon Shield. The last proved dangerous, and the IUD became unpopular. The 4 IUDs which are available in Canada include the TCu-380S (GYNE T Slimline), the TCu-200, the NOVA-T, and the Progestasert. All are T shaped and medicated (copper or progesterone). The 1st and 3rd can be left in situ for 10 years; the 2nd, for 4 years; and the 4th, for 1 year. The NOVA-T has a copper wire with a silver core and is inserted with a unique pull-push technique. The Progestasert, which contains 38 mg of progesterone, releases 65 mcg of the hormone daily. The best candidate for IUD use is parous, but not pregnant, is in a stable monogamous relationship, and has a healthy reproductive tract and no history of ectopic pregnancy, sexually transmitted disease, pelvic inflammatory disease, undiagnosed genital bleeding, endometrial or cervical neoplasia, abnormal endometrial anatomy, compromised immune system, allergy to copper, or Wilson's Disease. The only infection related to the IUD is that associated with insertion. Such an infection is polymicrobial and involves the endogenous, cervicovaginal flora (primarily anaerobes). It is usually asymptomatic and contained by the immune system. 200 mg of Doxycycline can be given orally as a prophylactic 1 hour prior to insertion. A nonprescription, nonsteroidal, anti-inflammatory drug, also taken 1 hour before the procedure, will prevent pain and a vasovagal reaction. Paracervical anesthesia should be used. If the depth of the uterus is less than 6 cm or greater than 10 cm, another form of contraception should be used. Although little research is being done in Canada on new IUDs, the Levonorgestrel IUD from Europe and the CuFix-360 (Flexigard) offer promise. The former, which is T shaped, contains polydimethylsiloxane and levonorgestrel (52 mg, total; releases 20 mcg daily) and can be used for 7 years. The latter IUD is shapeless and consists of 6 copper sleeves strung on surgical nylon thread knotted at 1 end. The knot is inserted, using a needle, into the fundal myometrium. The truth and falsehood of several myths about IUDs are noted with supporting citations.
8226276##1993-10-1##Absence of linkage between the retinoblastoma gene and hts gene in the LEC rat: a model of human Wilson's disease.##The LEC rat is an authentic model of human Wilson's disease (WD) with an autosomal recessively inherited hepatitis. We investigated linkage between the hepatitis gene (hts) and the rat retinoblastoma gene (RB), that is closely linked to the WD gene in humans, to see whether or not the hts gene is located on the syntenic region of WD and is the counterpart of the WD gene. Polymerase chain reaction-single strand conformation polymorphism analysis with backcross progenies from LEC and TM strains showed that the recombination rate between these two loci was 55.6%, demonstrating that the hts and RB genes are not linked to each other. These data indicate that the hts gene is not the counterpart of the WD gene and that the human syntenic region on which the WD locus and human RB gene are located, is not conserved in the rat genome.
8264372##1993-10-1##Wilson's disease and offending behaviour--a case report.##
8413967##1993-10-1##Correlation of evoked potential and MRI findings in Wilson's disease.##We recorded brainstem auditory evoked potentials (BAEPs) and somatosensory evoked potentials to median nerve stimulation (MSEPs) within 10 days of brain MRI in 20 patients with Wilson's disease (WD). MRI was abnormal in 90% of patients, demonstrating symmetric striatum and brainstem lesions with or without thalamic lesions. MSEPs were abnormal in 65% of patients, usually showing bilaterally prolonged N/P13-N20 latencies. BAEPs were abnormal in 40%, most often with bilateral prolongation of the III-V latency. The III-V and N/P13-N20 interpeak latencies correlated significantly with the severity of MRI lesions in the caudal pons, rostral pons, and caudal midbrain. Our results indicate that subclinical sensory dysfunction is common in WD, and that auditory and somatosensory pathways are most severely affected at the brainstem level. Both the localization and severity of evoked potential abnormalities correspond closely to the morphologic changes in the pons and caudal midbrain shown by MRI.
8259463##1993-10-1##[Nephrotic syndrome secondary to d-penicillamine in a patient with Wilson's disease].##
8293612##1993-10-1##[Study of diffusion weighted magnetic resonance imaging in Wilson's disease].##We analyzed diffusion weighted magnetic resonance images (diffusion MRI) of the basal ganglia, which were obtained from four patients with Wilson's disease, and compared them with the images from ten age-matched normal individuals. In all patients, T2-MRI of the basal ganglia disclosed low or iso-signals, but diffusion MRI revealed abnormal high signals in some areas of the basal ganglia in each case. Pathological changes except for copper and/or iron deposits are difficult to estimate by T2-MRI because the low signal on T2-MRI emphatically reflects the deposits, while the abnormal high signal on diffusion MRI is thought to reflect parenchymal lesions such as cell loss, demyelination and/or increase of the extracellular fluid. From our results, we confirmed that diffusion MRI was very useful for estimating parenchymal lesions with metal deposits.
8293604##1993-10-1##[Cranial MRI in hepatic disease--relationship between MR imaging and clinical symptoms and laboratory analysis of liver function].##Magnetic resonance imaging studies on 12 cases with hepatic disease were performed. In 11 adult patients with chronic hepatic failure, T1-weighted images demonstrated increased signal in the globus pallidus in 7 patients (63.6%) and in some parts of the cerebral peduncles in 6 patients (54.5%), in the substantia innominata in 4 patients (36.3%). There might be some correlation between the abnormality of MR imaging and clinical symptoms of hepatic encephalopathy. There was a significant correlation between the intensity of the signal and Fischer's ratio of amino acid analysis. In one patient with Wilson's disease, who developed symptoms of central nervous system, T1-weighted images demonstrated increased signal in the globus pallidus. After treatment of D-penicillamine, the signal of the globus pallidus decreased.
8212292##1993-10-1##Metabolic effects of liver transplantation in Wilson's disease.##
8219405##1993-9-1##Investigation of alcoholic liver disease.##In heavy drinkers with clinical evidence of liver disease, routine investigations should exclude the possibility of other chronic liver diseases of non-alcoholic aetiology requiring specific therapy--these include chronic viral hepatitis, autoimmune diseases of the liver, Wilson's disease and genetic haemochromatosis. If abnormalities in liver biochemistry persist despite abstinence, or if the diagnosis of alcoholic liver disease is in doubt, a liver biopsy should be carried out. Studies evaluating the role of liver biopsy in alcoholic liver disease suggest that without histological confirmation the diagnosis will be inaccurate in 10-20% of patients. Serum biochemistry and the currently available imaging modalities have severe limitations in determining the relative contributions of fatty liver, alcoholic hepatitis and cirrhosis to the overall picture in alcoholic liver disease. Histological examination is therefore of additional value in determining the prognosis, which is worst in patients with a combination of alcoholic hepatitis and cirrhosis. There are a number of indices available, based on clinical and laboratory information, for evaluating the short-term prognosis, but these can only be used with accuracy if the histological pattern of damage has initially been evaluated.
8359089##1993-9-1##Intractable neurological Wilson's disease treated with orthotopic liver transplantation.##
7902160##1993-9-1##Allelic association and linkage studies in Wilson disease.##We have studied 21 families with Wilson disease (WND), using restriction fragment length polymorphisms (RFLPs) in the 13q14.3 region, to measure linkage of these markers to the disease locus. In addition to previously described markers, we include linkage data for a newly isolated marker (D13S86) and an established marker (D13S56), which were previously not placed on the genetic map in the region of the WND locus. Our data, including those from two recombinant families, support the location of WND between the markers D13S31 and D13S59. We have examined the distribution of marker alleles at the loci studied and have found that D13S31 and D13S228, and associated microsatellite marker, show a non-random distribution on chromosomes carrying the WND mutation. The significant linkage disequilibrium indicates that these two markers must be close to the WND locus.
8229372##1993-9-1##Wilson's disease: a diagnosis made in two individuals greater than 40 years of age.##Wilson's disease is an autosomal recessive disease of copper metabolism which is widely recognized as a disease occurring clinically in children, adolescents, and young adults. Unrecognized and therefore untreated Wilson's disease in patients over age 40 is thought to occur either rarely or not at all. Two cases of Wilson's disease presenting at an age greater than 40 years are presented. The first is a 42-year-old Israeli women who presented with fulminant hepatic failure. The serologic and biochemical investigations obtained at the time of her fulminant hepatic failure included copper studies which suggested the diagnosis of Wilson's disease, which was confirmed by an examination of the native liver following successful orthotopic liver transplantation. The second case is that of a 56-year-old white male who presented to the hospital with a three-year history of neurological dysfunction, pancytopenia, and mild splenomegaly. A battery of serologic and biochemical investigations suggested a diagnosis of Wilson's disease. The diagnosis was confirmed by quantitative hepatic copper estimation and the demonstration of Wilson's disease in three of his siblings, all of whom were diagnosed after the proband case had been identified. This man and his siblings have been treated with d-penicillamine, with remarkable improvement in their neurologic and hepatic function. The proband is currently well 11 years after his diagnosis was established. These two cases demonstrate that a diagnosis of Wilson's disease should be considered as part of the differential diagnosis of individuals in the fourth and fifth decades of life who present with unexplained liver disease.
8398232##1993-9-1##[A study of trientine therapy in Wilson's disease with neurological symptoms].##D-penicillamine, an orally-administered chelating agent, is effective for Wilson's disease (WD). However 25% of WD patients showed serious adverse reactions to D-penicillamine cause this drug to be discontinued after months or years of treatment. For these cases, trientine-2HCl and trientine-4HCl, less toxic agents, are investigated. Three patients with WD, associated with neurological symptoms, were given either trientine-2HCl or trientine-4HCl. These patients had been on therapy with D-penicillamine. Severe adverse reactions had developed during the course of therapy, and D-penicillamine was discontinued, pancytopenia in case 1, nephrotic syndrome in case 2, and myasthenia gravis in case 3. Trientine-2HCl for case 1, and trientine-4HCl for cases 2 and 3 were instituted and continued. The neurological findings in all patients were extremely improved without side effects by trientine therapy. Though the chelating action on copper is weaker than that of D-penicillamine, it is efficient in improvement of the clinical neurological symptoms.
8212149##1993-9-1##An analysis of liver transplant experience from 37 transplant centers as reported to Medicare.##Analysis of 5180 liver transplant cases from 37 liver transplant centers in the United States (1982-1991) shows an overall one-year survival rate of 79.4 +/- 0.6% and a five-year survival rate of 69.2 +/- 0.9%. There was marked improvement in the one-year survival rate after liver transplantation from 36.0 +/- 9.6% in 1982 to 85.0 +/- 1.8% in 1991. One-year survival rates after liver transplantation for postnecrotic cirrhosis, primary biliary cirrhosis, alcoholic cirrhosis, primary sclerosing cholangitis, alpha-1-antitrypsin deficiency, and Wilson's disease ranged from 78.4 +/- 1.0% to 84.2 +/- 1.5% and five-year survival rates from 68.6 +/- 3.8% to 79.2 +/- 5.3%. Survival rates after liver transplantation for hemochromatosis were poor--a one-year survival rate of 53.8 +/- 6.8% and a five year survival rate of 43.1 +/- 11%. One- and five-year survival rates for the 0-13 years age group were 74.6 +/- 2.8% and 66.7 +/- 3.4%; for the 14-37 years age group, 83.3 +/- 1.2% and 73.8 +/- 1.8%; for the 38-54 years age group, 79.6 +/- 0.8% and 69.7 +/- 1.3%; for the 55-63 years age group, 76.0 +/- 1.4% and 63.0 +/- 3.1%; and for the 64-77 years age group, 76.5 +/- 3.0% and 65.4 +/- 4.6%.
8351148##1993-8-15##[Genetic counseling and successful pregnancy in patient with Wilson disease].##The principles of genetic counselling are summarized in a female with Wilson's disease. Pregnancy after appropriate treatment during gestation had a successful outcome: a healthy boy.
8232692##1993-8-1##Wilson disease.##
8100330##1993-7-3##Early diagnosis of Wilson's disease.##
8333453##1993-7-1##Copper disposition of the fetus and placenta in a patient with untreated Wilson's disease.##A patient with untreated Wilson's disease showed the possibility of fetal liver damage and copper accumulation in the placenta by this disease. This is the first report of copper disposition on the fetus and placenta in a patient with untreated Wilson's disease.
8369935##1993-7-1##Orthotopic liver transplantation for hepatic complications of Wilson's disease.##Thirteen orthotopic liver transplantations were performed in 12 patients for hepatic complications of Wilson's disease between May 1988 and July 1992. Ten patients had fulminant hepatic failure and two chronic liver disease. One patient underwent retransplantation for liver abscess secondary to hepatic artery thrombosis. Nine patients survive at a median follow-up of 18 (range 6-31) months. Three patients have died: two from multiple organ failure and sepsis, one from B cell lymphoma. Postoperative complications included bleeding requiring laparotomy in two patients, renal impairment in five, bacterial septicaemia in three, fungal sepsis in two and acute cellular rejection in six. The nine surviving patients are well with normal liver function test results.
8410043##1993-7-1##Geographic variations in Wilson's disease.##Certain features of Wilson's disease (WD) in Asia have been found to be different from those in other continents. The higher prevalence rate in Japan is presumably due to a higher consanguinity rate. In Chinese there is a tight linkage between WD and two gene loci for esterase D and retinoblastoma in the long arm of chromosome 13. The high proportion of patients with hepatic presentation accounts for early onset of WD in the Japanese and Chinese series. Skeletal involvement, leg hyperpigmentation, dark complexion, amenorrhea, epileptic seizures, and cerebral white matter degeneration are relatively more common among WD patients in Asia. Excessive copper in the liver appears to have a protective effect against hepatocellular carcinoma and type B hepatitis. Electrophysiological studies suggest widespread functional disturbances of the CNS in WD. Side-effects from penicillamine are rather frequent and often lead to interruption of the therapy. Trien is found to be effective without adverse reactions. Oral zinc therapy may be a suitable alternative for long-term management of WD patients in developing Asian countries.
8350202##1993-7-1##DNA-based diagnosis of Wilson disease.##
8234006##1993-7-1##[Liver in Wilson's disease].##
8378798##1993-7-1##Brain single-photon emission computed tomography for behavior disorders in children.##Single-photon emission computed tomography (SPECT) of the brain has been used to define functional abnormalities in two groups of childhood behavior disorders: (1) a &quot;primary&quot; category in which there is exclusive or predominant presentation with cognitive and/or behavioral dysfunction and (2) encephalopathies, often defined etiologically at the biochemical or molecular level, in which clinical expression includes, but is not confined to, neural dysfunction. Radiopharmaceuticals available for such studies are manifold, but those used to date have been predominantly perfusion agents, eg, Xenon-133 (133Xe) and technetium-99m (99mTc) hexamethylpropylene amine oxime, and studies with [99mTc]bicisate are eagerly awaited. Xenon-133 studies require that the patient be in the field of view of the detector while the tracer is administered. This renders it difficult for a subject to perform cognitive and other exercises while being imaged, because the environment is quite foreign. On the other hand, the 99mTc-labeled perfusion agents permit a scintigraphic &quot;snapshot&quot; of regional cerebral blood flow during a behavioral event without having to have the patient under the imaging instrument. Thus, one can separate the administration of the radiotracer, which can be done under more controlled and physiological conditions, from the actual imaging. In addition, greater spatial resolution is achieved with the technetium-based agents. Currently, multidetector or dedicated annular crystal-type cameras are the preferred brain SPECT devices, and they are essential to applications such as cortical &quot;activation mapping&quot; or tomographic detection of receptor systems. Close attention to technical detail and standardization of the child's behavioral environment during the investigation are critical to a successful study. The relative advantages and disadvantages of qualitative versus semiquantitative analysis of imaging date are reviewed. Among primary behavioral disorders, 133Xe SPECT studies in attention deficit disorder-hyperactivity (ADHD) have suggested a pattern of hypoperfusion of striatal and periventricular structures with sensorimotor cortical hyperperfusion. This pattern is consistent with some neurophysiological models of the disorder. In cerebral palsy, perfusional abnormalities have paralleled clinical deficits and may offer information to help predict outcome. The important field of childhood affective disorders (schizophrenia, juvenile autism, depression, etc) remains largely unstudied with SPECT. Finally, representative examples of the use of SPECT to study perfusion in encephalopathies with behavioral expression (phenylketonuria, MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome, Wilson's disease, etc) are given.
8109051##1993-7-1##Hepatic manifestations of Wilson's disease: frequency and pattern in Saudi patients.##Seven symptomatic patients with Wilson's disease have so far been diagnosed at King Khalid University Hospital (KKUH), Riyadh, over the last six years. On family screening, another three asymptomatic patients were found to be affected. Five of the symptomatic patients had clinical features of liver disease on initial presentation and was preceded by renal dysfunction in another patient. The remaining patient presented with neurological features. Six patients had Kayser-Fleisher ring. Abnormal liver function tests were found in half of the patients. Ceruloplasmin was reduced in 7 of 10 patients. Serum copper and urinary copper estimations were most useful diagnostic laboratory tests. Morphological alteration was found in all 9 patients who had a percutaneous liver biopsy. All patients were treated initially with D-penicillamine and clinical response was noted in seven, of whom one developed neurological manifestations while receiving the treatment. D-penicillamine was replaced by zinc sulfate in 3 patients who developed thrombocytopenia. The data suggest that Wilson's disease may not be rare in Saudi Arabia. For early detection and prompt treatment, the disease should be suspected under appropriate clinical circumstances especially in young patients with liver diseases. Close relatives of such index patients should be routinely screened.
8135612##1993-6-1##[Wilson disease, IgA glomerulonephritis and vascular purpura: an incidental association?].##
8325631##1993-6-1##Long range restriction mapping of 13q14.3 focused on the Wilson disease region.##The Wilson disease locus (WND) has been mapped by multipoint linkage analysis to a region within 13q14.3 that is flanked proximally by marker D13S31 and distally by marker D13S59 at distances of 0.4 and 1.2 cM, respectively. Long range restriction maps were constructed around these two markers to provide a framework for the detailed physical analysis that will be necessary for the cloning of the gene. The maps, together spanning over 4 Mb, include five newly isolated markers (D13S110, D13S113, D13S194, D13F71S1, and D13S196) and two established markers (D13S56 and D13S25) that were previously localized to 13q14.2-q14.3 using a hybrid panel. Markers D13F71S1 and D13S196 map to the region between D13S31 and D13S59 and will therefore be useful for the isolation of YACs for further molecular studies on Wilson disease.
8314565##1993-6-1##Physical localisation of the chromosomal marker D13S31 places the Wilson disease locus at the junction of bands q14.3 and q21.1 of chromosome 13.##D13S31 is the marker closest to the Wilson disease locus according to genetic analysis. Its physical localisation was refined by fluorescent in situ hybridisation to the junction to chromosomal bands 13q14.3 and 13q21.1. Using polymerase chain reaction analysis, D13S31 and D13S59 (the closest proximal and distal marker, respectively) were found to be located on the end of the der(13) consisting of 13pter-13q14.3: in the somatic cell hybrid ICD, and to be absent from the cell lines WC-H38B3B6 containing a del(13) (13pter-q13::13q21.1-qter) and KSF39 containing a del(13) (13pter-q14.1:).
8102988##1993-6-1##Pregnancy after liver transplantation.##Two patients who became pregnant after liver transplantation for end-stage liver disease were carefully monitored using pulsed Doppler waveform measurements. One patient with Wilson's disease, on triple immunosuppressive therapy including prednisone, azathioprine and low-dose cyclosporin A, delivered a healthy girl weighing 2650 g after 38 weeks' gestation. The other patient, with HBV-related postnecrotic cirrhosis, became pregnant less than 3 months postoperatively, under triple therapy, after being amenorrheic for 6 years. Episodes of elevation in liver enzymes were noted, and severe osteoporosis with low back pain developed. A healthy boy weighing 2975 g was born at 35 weeks' gestation. Our cases add to previous reports of successful pregnancies under cyclosporin A immunosuppression.
8357929##1993-6-1##Biochemical polymorphisms in Long-Evans Cinnamon (LEC) inbred strain of rat.##Long-Evans Cinnamon (LEC) rat is an inbred strain of mutant rat which has been proposed to be an animal model for human Wilson's disease. In the present study, 28 genetic marker proteins were analyzed by electrophoresis in sublines of LEC inbred strain held separately by four facilities. As expected, the 27 markers were homozygous and identical in all of examined animals. We further found a novel variant of esterase-2 (ES-2) showing an intermediate mobility between profiles of ES-2A and ES-2C types.
8403687##1993-6-1##[Slow eye movements (slow saccades) in Wilson's disease].##Slow eye movements or slow saccades are relatively rare conditions in Wilson's disease where selective impairments of saccades are observed. The authors have a case of Wilson's disease showing a defect of saccades in all directions, with the complete preservation of smooth pursuit eye movements. T2-weighted images revealed abnormalities of signal intensity in bilateral pontine tegmentum, besides putaminal and thalamic lesions commonly seen in the previous reports. A rather selective disturbance of saccade eye movements due to the pontine tegmentum is consistent with the concept, as yet mainly based on experimental work on animals, of an anatomical segregation of the brainstem pathways for smooth pursuit eye movements, saccades, and vestibular and optokinetic patterns. Whereas the basal brainstem, especially basal pons, subserves smooth pursuit eye movements, saccades and reflex-like eye movements are mediated by the pontine tegmentum. The authors' case offers a support that dissociating eye movement disorders are due to the restricted lesions mentioned above.
8482474##1993-5-1##Zinc in the treatment of Wilson's disease: how it works.##
8314575##1993-5-1##Regional localization of 32 NotI-HindIII fragments from a human chromosome 13 library by a somatic cell hybrid panel and in situ hybridization.##Relatively few DNA probes have been regionally assigned to chromosome 13 bands, and these tend to be clustered in the proximal end of the chromosome in the regions where intensive mapping efforts have been focused because of the retinoblastoma and Wilson disease genes. We have developed a chromosome 13-specific half-linking library of NotI-HindIII fragments and regionally mapped 32 of these on chromosome 13, using a somatic cell hybrid panel that subdivides chromosome 13 into 11 regions and nonisotopic in situ hybridization with silver amplification of a digoxigenin-labeled probe.
8327653##1993-5-1##Neurological Wilson's disease.##
8108634##1993-5-1##Wilson's disease: magnetic resonance imaging (MRI) with clinical correlations in 16 cases.##The purpose of this study was to evaluate MRI findings in a group of patients with Wilson's disease, trying to establish possible correlations between clinical and image data. Sixteen patients (8 males and 8 females), with ages ranging from 11 to 50 years, and duration of illness ranging from 5 months to 32 years, were submitted to MRI in a 1.5T System. Four patients were asymptomatic, 4 had mild neurological findings, 2 were moderately affected and the remaining 6 had a severe form of the disease. All patients were receiving D-penicillamine by the time of the study. The most symptomatic patients presented five or more sites of abnormalities on MRI. The putamen was affected in all symptomatic individuals and one asymptomatic and 11 of them presented dystonia on neurological examination. A striking feature was the peripheral localization of putaminal hyperintense lesions on T2 weighted images. In eight cases, striatum or &quot;substantia nigra&quot; lesions explained parkinsonism observed on neurological examination. MRI seems to be an efficient method to study neurological involvement of Wilson's disease allowing some interesting anatomo-clinical correlations.
8475943##1993-4-1##Treatment of Wilson's disease with zinc XII: dose regimen requirements.##A considerable body of data is now available indicating the efficacy and lack of toxicity of zinc treatment of Wilson's disease. Dose-response studies have shown that regimens of 50 mg of elemental zinc 3 times a day (50 mg x 3), 25 mg x 3, and 50 mg x 2 are effective, but 25 mg x 2 and 50 mg x 1 are not adequately effective. These studies indicate that 75 mg a day is close to the minimally effective dose, but do not address the question of necessary dose frequency. In the current study, the authors have used the minimally effective daily dose, 75 mg, and studied this daily dose in regimens of 25 mg x 3, 37.5 mg x 2, and 75 mg x 1 in treatment of four patients with Wilson's disease. These data have been supplemented with additional data from 11 patients treated with 25 mg 3 times a day and with data from 2 patients treated with 75 mg once a day. Efficacy was evaluated by 10-day copper balance and absorption of orally administered 64copper. The findings indicate that a daily dose of 75 mg must be divided into at least two doses to be effective, and that the 64copper procedure is more sensitive to zinc dose than copper balance.
8409480##1993-4-1##Wilson's disease with neurologic manifestation.##
8347336##1993-1-1##Metabolic and degenerative diseases of childhood.##The metabolic and degenerative diseases of childhood are a diverse group of disorders with varied imaging features. Some of the disease processes have characteristic findings and some have no findings at all, but most present with nonspecific abnormalities in white matter. These patchy lesions, seen best on magnetic resonance scanning with T2 weighting, require a good history and a dialogue with the referring physicians to help in narrowing the differential possibilities. The major disease processes involving white matter are the dysmyelinating diseases, in which the abnormal white matter is the result of an inherited enzyme deficiency, and the demyelinating diseases, in which an acquired process such as infection destroys white matter. Several diseases result in gray matter abnormalities, including central pontine myelinolysis, MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like symptoms), Batten's disease, Leigh disease, and Wilson's disease.
8465128##1993-3-23##[What is your diagnosis? Wilson's disease (hepatolenticular degeneration)].##
8477294##1993-3-1##Case report of anorexia nervosa associated with Wilson's disease.##Wilson's disease is a recessively inherited disorder of copper metabolism with prominent hepatic, hematopoietic, central nervous system (CNS), and ocular involvement. Psychiatric manifestations are notoriously variable. The following case history of a patient with both anorexia nervosa and Wilson's disease is presented and discussed in the context of organic CNS lesions associated with anorexia nervosa-like syndromes.
8315256##1993-3-1##The outlook for the diagnosis of Wilson's disease.##
8100247##1993-3-1##DNA markers for the diagnosis of Wilson disease.##Wilson disease is an autosomal recessive disorder of copper transport for which the basic defect is unknown. Laboratory diagnosis of Wilson disease is usually made by measuring serum ceruloplasmin concentration, urinary copper excretion, and liver copper concentration. However, discrimination between heterozygotes and patients is sometimes difficult. The gene for Wilson disease has been assigned to chromosome-13 at q14-q21. In this study, 10 markers from the 13q14-13q21 region were investigated in 12 families with a well-established diagnosis, to confirm reported linkage results. Markers from the same region were tested in two additional families, in which a sib of each index case had unclear results with conventional biochemical assays. The linkage results in this study are similar to those of Middle Eastern families, and support the hypothesis of a single disease locus. In the two families studied for diagnostic purposes, the status of 2 presymptomatic sibs was established as affected and 1 as unaffected. This study therefore shows that DNA markers can be used to discriminate between presymptomatic patients and non-affected individuals when biochemical results are equivocal, as long as an index case with Wilson disease of known status is available and markers are informative.
8459248##1993-3-1##An epidemiological study of Wilson's disease in the Republic of Ireland.##In a population based study of the prevalence of Wilson's disease in the Republic of Ireland from 1970-89, 26 definite and probable cases were ascertained. The adjusted birth incidence rate was 17.0 per million live births (95% (confidence interval 9.9 to 27.2)) for the 20 year period 1950-69. The gene frequency was 0.41% (95% (confidence interval 0.31% to 0.52%) indicating that one in 122 of the population was a gene carrier. Allowing for a maximal degree of consanguinity, the gene frequency is reduced to 0.36% and the proportion of heterozygotes to one in 139 of the population. The consistency of the adjusted birth incidence rates over the decades 1950-59 and 1960-69 suggests a high degree of ascertainment of diagnosed cases of Wilson's disease.
8387476##1993-3-1##Abnormal hepatic iron accumulation in LEC rats.##The LEC (Long-Evans cinnamon) rat is a mutant strain displaying hereditary hepatitis and spontaneous hepatocellular carcinoma, and shows abnormal hepatic copper accumulation similar to that occurring in Wilson's disease. We evaluated the iron metabolism of LEC rats compared to LEA (Long-Evans agouti) rats. Hepatic iron and ferritin concentrations were remarkably increased depending on age in LEC rats but not in LEA rats. Increased hepatic iron is normally associated with decreased serum transferrin and total iron binding capacity in hepatic iron overload. In LEC rats, however, both serum transferrin and total iron binding capacity increased with increasing hepatic iron. This increase of serum transferrin and hepatic iron may be an additional important factor contributing to liver injury in LEC rats.
8247102##1993-3-1##Intrahepatocellular localization of copper in Wilson's disease.##It is well known that excess copper plays a role in the pathogenesis of Wilson's disease; however, the hepatic copper contents, determined either histochemically or biochemically, are not always correlated with the activity of Wilson's disease. To better understand copper-induced cytotoxicity, intrahepatocellular localization of copper was studied in five patients with Wilson's disease. The liver specimens were obtained by biopsy to confirm the clinical diagnosis of Wilson's disease before treatment. Neither hepatic copper content nor histochemical copper deposits were correlated with any of the biochemical indices studied. Energy-dispersion X-ray microanalysis was done on the nuclei, lysosomes and lysosome-free cytoplasm of hepatocytes. Lysosomes had the highest Cu X-ray intensity but no correlation was shown between the lysosomal copper content and biochemical indices. The nucleus/lysosome-free cytoplasm ratio of the copper content was correlated with the serum levels of aminotransferases. These results suggest that the copper increasing gradient from the lysosome-free cytoplasm to the nucleus is associated with hepatocyte necrosis, and probably causes irreversible nuclear damage.
8369040##1993-3-1##Chelation treatment of neurological Wilson's disease.##The results of chelation treatment of 137 patients presenting with neurological Wilson's disease are described, together with the more commonly observed toxic reactions to the various drugs employed. Fifty-seven patients made an excellent response to treatment and became symptom free. Thirty-six patients made a good recovery, but were left with some minor neurological deficit. Twenty-four patients had a poor response: although the disease process was arrested they were left more or less disabled. Twenty patients died: nine had little or no treatment, but 11 died despite apparently adequate chelation therapy. There was no obvious reason for this failure. The liver copper level was estimated in six of these patients: it was still significantly elevated in only one, but in all four in whom it was possible to make the determination, the concentration of copper in the basal ganglia was in excess of 45 micrograms/g wet weight. It was not apparent why adequate therapy failed to remove copper from the brains of these patients. There was no obvious clinical, histological or biochemical indicator of failure to respond to treatment. Initial deterioration before improvement was seen in 30 patients: the prognosis for a useful recovery was not necessarily worse than that in patients who did not show this phenomenon.
8511806##1993-3-1##IUD protocols for international training.##A review of 9 reference protocols for IUD training in the US and in developing countries revealed conflicting instructions on antibiotic prophylaxis, postpartum insertion of IUDs, management of complications, and sterilization and disinfection procedures. The protocols only agreed on the contraindication status of pregnancy and active gynecological or chlamydial infections (all listed as absolute contraindications) which were just 2 of 32 different contraindications. US physicians considered some conditions to be contraindications to IUD use, but they usually are not applicable to women in developing countries. In developing countries with maternal mortality rates 2 times greater than those in developed countries, 8 contraindications may be inappropriate: prior expulsion of or perforation by an IUD, IUD insertion during the postpartum period, prior pregnancy with and IUD in place, prior ectopic pregnancy, copper allergy, coagulopathy, valvular heart disease, and Wilson's disease. The only inappropriate contraindication addressing infection (1 of 8) was a distant history of pelvic inflammatory disease. This history should not exclude IUD use in a woman not at risk of sexually transmitted diseases. Contraindications referring to cancer of the reproductive tract should be consolidated in a statement warning against hormonal contraceptive and IUD use in women, especially those over 35, who have recent, undiagnosed, irregular vaginal bleeding, until the cause has been determined. The reviewers also discussed justifications for other contraindications, including those related to menstrual blood loss, small uterus, structural abnormality of the uterus, severe vasovagal reactivity or fainting and severe cervical stenosis, no access to services, and future fertility. THis analysis indicated a need to simplify, rationalize, and update current IUD protocols as well as make them consistent. This will improve service quality and reduce unnecessary medical obstacles to contraception.
8442397##1993-2-1##Motor impairment in Wilson's disease, II: Slowness of speech.##The maximal syllable production rate (MSPR) and the ability to reproduce a given target frequency in the 1 to 8 Hz range by repeating the short syllable &quot;ta&quot; was tested in 20 patients with Wilson's disease (WD) and 20 normal subjects. MSPR was significantly reduced in the WD-patients. In the 1 to 5 Hz range normal subjects as well as WD-patients tended to produce slightly higher frequencies than the target frequencies. This hastening was maximal in normals between 4 to 5 Hz whereas in the WD-patients hastening mainly occurred between 3 to 4 Hz. The test results showed a considerable variation across the patients. This variation can be interpreted on the basis of the theory of coupled oscillators. Comparison of speech and finger movements revealed a highly significant correlation between MSPR and the highest possible frequency of voluntary alternating index finger movements. As an application of the presented test treatment effects on speech movements were demonstrated.
8442396##1993-2-1##Motor impairment in Wilson's disease, I: Slowness of voluntary limb movements.##Twenty-three patients with Wilson's disease (WD) treated with D-penicillamine underwent clinical examination, as well as laboratory and motor testing. The clinical findings were scored. Laboratory tests included determination of the caeruloplasmin level, the free serum copper level, 24 h urinary copper excretion, liver enzymes and in 10 patients liver copper content of a liver biopsy. Laboratory tests and clinical scores were correlated. To quantify impairment of voluntary movements in WD fastest possible isometric index finger extensions and fastest alternating finger movements were analysed. Eleven patients presented with abnormally slow and 15 with abnormally irregular voluntary movements. Slowness of alternating movements correlated with the clinical score. The clinical score also correlated with the duration of symptoms prior to onset of therapy. Motor testing turned out to be sensitive enough to monitor improvement of neurological symptoms after onset of therapy. Comparison with motor testing in other basal ganglia diseases and cerebellar patients showed differences to patients with Parkinson's and Huntington's disease and similarities to patients suffering from AIDS-related dementia. In a small number of WD-patients similar results as in patients with a degenerative cerebellar disease were found.
8435699##1993-2-1##Wilson's disease and catatonia.##A 12-year-old Indian boy presented to a psychiatric unit with catatonia. He was subsequently diagnosed to have Wilson's disease. Symptoms improved on treatment with penicillamine, zinc sulphate, and benzodiazepines.
8472614##1993-2-1##Chronic hepatitis.##Evaluation, management and treatment of patients with chronic inflammation of the liver is an important task for the clinician. Almost every ongoing liver injury has an element of inflammation. In those disorders grouped as chronic hepatitis, the brunt of the liver injury is borne by the hepatocyte and continues until either the stimulus is removed or the inflammatory response is blunted. Chronic viral infection is by far the most important cause of chronic hepatitis. Hepatitis B and hepatitis C infections are both frequent causes and may result in cirrhosis. Interferon therapy has proven useful in the treatment of some patients with bone disorders. Idiopathic autoimmune chronic hepatitis is an important contributor to the diagnosis of chronic hepatitis and usually responds to corticosteroid therapy. Because of the availability of effective therapy, Wilson's disease, which is a quite rare but important cause of chronic hepatitis, should be considered. Even more rarely, an ongoing reaction to the continued administration of a therapeutic drug leads to chronic hepatitis. Advances in diagnosis, increased understanding of the courses followed by each of the major disorders, and the availability of effective treatment for many patients has heightened interest in the syndrome of chronic hepatitis.
8440814##1993-2-1##Treatment of Wilson's disease with zinc: XI. Interaction with other anticopper agents.##Zinc (Zn) is increasingly being used as a treatment for Wilson's disease. Some physicians have been prescribing Zn in conjunction with other anticopper agents, such as penicillamine or trien, although theoretically these drugs might be antagonistic in their effects. In addition, Wilson's disease patients quite often take vitamin C in high doses in conjunction with Zn therapy, and there are indications of possible interactions among vitamin C, Zn and copper (Cu). Interactions of penicillamine, trien, and vitamin C with Zn have not been previously studied in terms of the potential effects of these agents on Zn efficacy in Wilson's disease. Here we have studied these interactions in the maintenance phase of therapy, using Cu balance and absorption of orally administered 64Cu as endpoints. We find evidence for probable interactions of both penicillamine and trien with Zn; however, the end result on Cu balance is about the same with Zn alone as it is with Zn plus one of the other agents. Thus, there appear to be no advantages to concomitant administration. We find no detectable interaction of Zn and vitamin C on Cu balance, when vitamin C is taken in daily doses of 1000 mg.
8487473##1993-2-1##[Treatable diseases of the nervous system with cataract formation].##The detection of a cataract in combination with a neurological deficit may provide the physician with important diagnostic help. But a minority of underlying diseases (angiokeratoma corporis diffusum, cerebrotendinous xanthomatosis, diabetes mellitus, galactosemia, hypocalcemia, Refsum's disease, Wilson's disease; Charles Bonnet syndrome; relapsing Perichondritis; adverse effects of medication and intoxications) can be treated causally. Therefore they are summed up and discussed in this paper.
8459679##1993-2-1##Effects of dietary vitamin E on clinical course and plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activities in hereditary hepatitis of LEC rats.##Long-Evans Cinnamon (LEC) rats are autosomal recessive mutants that develop hepatitis and hepatocellular carcinoma. Because copper accumulates in the livers of these rats, and some of their clinical and pathological features are similar to those of patients with Wilson's disease, LEC rats are proposed as an animal model of Wilson's disease. It has been thought that unbound copper generates free radicals, which act as hemolytic and hepatocytotoxic agents. To examine the effects of vitamin E as an antioxidant on hereditary hepatitis in LEC rats, we fed 3-week-old rats for 25 weeks either vitamin E-deficient, control, or vitamin E-supplemented diets which contained &lt; 0.01 mg of total tocopherols, 2 mg of d,l-alpha-tocopheryl acetate (2 I.U.), and 58.5 mg of d,l-alpha-tocopheryl nicotinate (50 I.U.), respectively, per 100 mg of feed. In males, body weight loss was first observed in the vitamin E-deficient group, and mean ages at which jaundice occurred were in the order: deficient younger than control younger than supplemented groups. The ages when plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activities began to increase sharply and peaked followed the same order. Thus, it is likely that free radicals are involved in jaundice and hepatitis in LEC male rats, and they are a model for studying the relationship of copper, free radicals, and hepatitis. Conversely, in females, no apparent differences in clinical and biochemical changes were observed among the three groups. Causes for the discrepancy between the sexes remain to be clarified.
8436325##1993-1-15##[Psychiatric manifestations in Wilson's disease].##Wilson's disease is an inherited, autosomal recessive disease characterized by progressive hepatic and neurological symptoms. Clinical features usually start between the ages of 10 and 40. Psychiatric disturbances are present in almost all patients. In about a third of them psychiatric symptoms are present early in the disease and in almost 20% they precede hepatic and neurological dysfunction. In these cases the diagnosis of Wilson's disease is often difficult, as a result of which treatment is begun when the illness is already advanced. We report 3 patients with Wilson's disease in whom the psychiatric manifestations preceded neurological symptoms and necessitated admission for psychiatric treatment.
7681616##1993-1-1##Further observations on Tau-positive glia in the brains with progressive supranuclear palsy.##The previously reported unusual, Tau-positive glia with astrocytic morphology seen in brain tissues from cases of progressive supranuclear palsy (PSP) were re-examined immunohistochemically using antibodies to CD44 and vimentin, as well as Alz-50. Four brains of PSP cases, one of whom had atypical clinical features, were examined. All four cases showed the unusual glia which were positive to Alz-50 and anti-CD44 antibodies, but negative to anti-vimentin antibody. Ultrastructurally, they had either paired nucleated or lobulated nuclei and the cytoplasm frequently contained lipofuscin pigment. The CD44 was located on the surface of the cell bodies and their processes. Such glia were most numerous in the striatum in all cases. They also appeared in the cortex and some subcortical nuclei in the three typical cases. They were not seen in the lower brain stem or cerebellum. In their morphological characteristics and regionally specific appearance, these unusual glia seemed similar to the Alzheimer type I glia which are commonly seen in hepatic encephalopathy or Wilson's disease.
8494330##1993-1-1##Cyclosporine-induced chorea after liver transplantation for Wilson's disease.##
17587981##1993-1-1##Reply: Wilson disease in Saudi Arabia.##
17587979##1993-1-1##Wilson disease in Saudi Arabia.##
7687112##1993-1-1##The pattern of liver disease in Indian children: a review of 128 biopsied cases.##We report the pattern of childhood liver disease revealed by a study of 134 biopsies obtained from 128 infants and children below the age of 16 years seen in this hospital during a 3-year period. The most common histological diagnoses were neonatal hepatitis syndrome in 23, storage disorders in 11, and cirrhosis in 26 children. Less common diagnoses included Reye's syndrome in four, fatty liver in seven, granulomas in four, and chronic active hepatitis, fulminant hepatitis, congenital hepatic fibrosis and neoplasms in two children each. Miscellaneous specific diagnoses were made in 16 cases. Twenty-three per cent of the liver biopsies were non-diagnostic. The study has provided background information on the occurrence of specific histological diagnoses in liver biopsies in infants and children in this tropical region and identifies a group with cirrhosis and copper deposition which was not typical of either Indian childhood cirrhosis or Wilson's disease.
8435326##1993-1-1##Acquired sideroblastic anaemia during treatment of Wilson's disease with triethylene tetramine dihydrochloride.##We report one case of acquired sideroblastic anaemia in a patient treated for Wilson's disease with triethylene tetramine dihydrochloride (TTH). No other cause of acquired sideroblastic anaemia was found, and neither iron nor pyridoxine therapy could correct this anaemia. In contrast, decreasing the dose of TTH led to disappearance of ringed sideroblasts. Thus TTH should be added as a further cause of secondary acquired sideroblastic anaemia. The pathophysiology of this finding, probably linked to an abnormality of mitochondrial iron metabolism, is briefly discussed.
8443556##1993-1-1##Synovial copper deposition as a possible explanation of arthropathy in Wilson's disease.##A patient with longstanding Wilson's disease and arthritis is presented. Synovial biopsy disclosed thickening of the membrane, intimal histiocytes, and lymphocyte infiltration without pigmentation. X-ray energy spectroscopy demonstrated copper and iron in high concentrations. These findings may contribute to our understanding of the development of the arthropathy in patients with Wilson's disease.
8467638##1993-1-1##Computer simulation of normal and pathological copper metabolism in man.##A digital computer simulation of copper metabolism was used to simulate human copper metabolism. The simulation agrees well with the normal data extant. Wilson's disease (hepatolenticular degeneration) and Menkes' disease (steely-hair syndrome) were simulated. Simulation of the unavailability of accumulated liver copper simulated Wilson's disease if it was assumed that the increased urinary excretion was due to induction of an enzymic mechanism for enhanced excretion. This would be consistent with the genetic defect causing only the sequestering of unavailable copper in the liver. Other genetic defects need not be present. Menkes' disease is also a genetic disease affecting the newborn. It was simulated successfully as a defect in absorption of copper from the gastrointestinal tract.
8458236##1993-1-1##Pseudo-Kayser-Fleischer ring of the cornea associated with non-Wilsonian liver disease. A case report and literature review.##The Kayser-Fleischer ring of the cornea is usually considered a pathognomonic finding of Wilson's disease. A case of a Kayser-Fleischer ring associated with non-Wilsonian liver disease is presented. The pathophysiology of copper deposition in the cornea and the differential diagnosis of this rare finding are discussed.
8508673##1993-1-1##Isolation of new probes in the region of the Wilson disease locus, 13q14.2--&gt;q14.3.##A hybrid panel was used to refine the localizations of eight established markers useful for the diagnosis of Wilson disease. Two of the markers, D13S59 and D13S31, that map very close to the Wilson disease locus (WND) were localized to the region 13q14.2--&gt;q14.3. We report the isolation of seven new probes from this region, using two different approaches. First, 16 clones from a chromosome 13-specific library were mapped using the hybrid panel. Three of the clones mapped to 13q14.2--&gt;q14.3. As a second approach, Alu element-mediated PCR (Alu-PCR) was used to generate clones from a hybrid (ICD) that contains the proximal half of chromosome 13 as the only human component. To select for those that potentially mapped within the region 13q14.2--&gt;q14.3, the clones were screened by differential hybridization using the labeled Alu-PCR products from a hybrid (KSF39) that is similar to ICD but has a deletion in the region 13q14.2--&gt;q14.3. The procedure was successful even though KSF39 contains five additional human chromosomes. Six independent clones were selected. Five of these were found to be nonrepetitive, and four were found to map correctly to 13q14.2--&gt;q14.3 when localized using the hybrid panel.
8432555##1993-1-1##Evidence for locus heterogeneity in autosomal dominant torsion dystonia.##Idiopathic torsion dystonia (ITD) is most commonly an autosomal dominant disorder with reduced penetrance and variable expression. A locus on the distal long arm of chromosome 9 has been identified in one large non-Jewish and several Jewish families in the United States. Linkage analysis in a large Australian kindred with ITD, also containing two patients with Wilson's disease, excludes a locus for ITD in chromosome 9q34 or the region of chromosome 13 containing the Wilson disease gene. This study provides evidence for locus heterogeneity in autosomal dominant ITD and also gives additional information on gene order in chromosome 9q.
8432554##1993-1-1##Linkage studies of the esterase D and retinoblastoma genes to canine copper toxicosis: a model for Wilson disease.##Canine copper toxicosis, an autosomal recessive disorder, is prevalent among certain dog breeds. It results in liver disease from copper accumulation and toxicity similar to the human autosomal recessive disorder, Wilson disease. The Wilson disease locus has been mapped to 13q and is closely linked to the esterase D and retinoblastoma genes. We developed informative polymorphic systems in the dog using the human cDNA clones of the esterase D and retinoblastoma loci as probes. We investigated the linkage relationship of these two loci to the copper toxicosis locus, and to each other in the dog. Our results indicate that none of the loci are closely linked in the dog. Linkage of copper toxicosis to the retinoblastoma locus can be excluded up to 13% recombination, and to esterase D up to 5% recombination. Furthermore, esterase D and retinoblastoma, tightly linked in the mouse and human genomes, are not found to be closely linked in the canine genome.
8445321##1993-1-1##Penicillamine-induced changes in elastic tissue of the upper respiratory tract.##We describe a patient who developed upper respiratory tract symptoms following long-term treatment of Wilson's disease with penicillamine. These symptoms were attributed to areas of pharyngeal thickening and were treated with a laser. Histological examination of the lesions showed proliferations of abnormal elastic fibres similar to those previously described at other sites, especially the skin, in patients receiving penicillamine. This drug impairs the maturation and reduces the stability of elastic fibres and although elastic tissue throughout the body is affected, we are aware of no previous reports of penicillamine-induced changes presenting with upper respiratory tract symptoms.
8290000##1993-1-1##Hypercalciuria and nephrocalcinosis, a feature of Wilson's disease.##Hypercalciuria and nephrocalcinosis are not uncommon in patients with Wilson's disease but have only once been reported as the presenting sign. We diagnosed Wilson's disease in a 17-year-old male patient 6 years after his first episode of gross hematuria and 2 years after detection of hypercalciuria and nephrocalcinosis. Therapy with penicillamine resulted only in a moderate reduction of urinary calcium excretion but oxalate excretion increased.
8423874##1993-1-1##Wilson's disease: evidence of subgroups derived from clinical findings and brain lesions.##Using exploratory factor analysis, we prospectively investigated neuropsychiatric symptoms and structural brain lesions of 47 patients with proven Wilson's disease and identified three subgroups. The first subgroup clinically exhibited bradykinesia, rigidity, cognitive impairment, and an organic mood syndrome and by MRI showed a dilatation of the third ventricle. The second subgroup was characterized by ataxia, tremor, reduced functional capacity, and focal thalamic lesions. The third subgroup showed dyskinesia, dysarthria, an organic personality syndrome, and focal lesions in the putamen and in the pallidum.
8433797##1993-1-1##Decreased signal intensity of the putamen and the caudate nucleus in Wilson disease of the brain.##
8433789##1993-1-1##Magnetic resonance imaging of the brain in Wilson's disease.##Fifteen patients with Wilson's disease were examined, using spin-echo (SE) and gradient-echo (GE) sequences with 0.5 T and 1.5 T magnetic resonance (MR) imagers. They fell into three groups: groups 1 and 2 were examined retrospectively after 3-18 years of treatment, while group 3 was examined prospectively from the start of treatment, after recommencement of treatment, or inadequate treatment. MRI was sensitive to changes in the basal ganglia at sites typical of Wilson's disease and was useful for documenting the effects of treatment. It was found necessary to estimate the relaxation times T1 and T2, to better assess improvement or transient worsening of the disease in the prospective group. Residual cavitation and gliosis could be distinguished in the retrospective group using a subtraction technique.
8433788##1993-1-1##Magnetic resonance imaging of the brain in Wilson's disease.##Eight patients with Wilson's disease (WD) were studied by magnetic resonance imaging (MRI) of the brain; seven also underwent X-ray computed tomography (CT) of the brain. We describe the changes in the brain and try to correlate them with the clinical manifestations and progress of the disease. Six patients were symptomatic, with predominantly neurological problems. Two were asymptomatic, diagnosed upon screening siblings of index cases. Of the six symptomatic patients, five had basal ganglia lesions, combined in four with brain stem changes; in one with only brain stem abnormalities, clinical findings were minimal despite pronounced MRI changes. In three patients MRI abnormalities regressed following chelating therapy. MRI can contribute to documentation of early neurological involvement in WD, especially in patients with no abnormalities on CT. However, MRI changes may not correlate with clinical presentation or response to therapy.
8516046##1993-1-1##Wilson's disease: MRI demonstration of cavitations in basal ganglia and thalami.##An MRI study of a patient with Wilson's disease is described, showing bilateral hyperintensity of the basal ganglia and thalami on T2-weighted images. Multiple, small nodular hyperintensities were superimposed on these hyperintense regions which presumably represented cavitations secondary to the spongy degeneration that is one of the histopathological features of cerebral Wilson's disease.
8152872##1993-1-1##The claustrum on MRI: normal anatomy, and the bright claustrum as a new sign in Wilson's disease.##One hundred MRI examinations of normal subjects obtained at 0.5 T were studied in an effort to evaluate the claustrum and to establish a control group for patients with Wilson's disease. The claustrum was detectable unilaterally or bilaterally in 40 out of 100 subjects (40%) on spin-echo long TR (proton density and T2-weighted) MR images as a thin sheet of grey matter enclosed by low signal white matter of the external and extreme capsules. Spin-echo T1-weighted images were negative for the claustrum, however, it was identifiable in 12 out of 25 subjects (48%) studied utilizing the inversion recovery pulse sequence. In addition, eight patients with clinically established diagnoses of Wilson's disease were evaluated. The claustrum was normal (invisible) in four neurologically asymptomatic Wilson's disease patients, however, in 75% (n = 3) of the four neurologically symptomatic patients it was bilaterally thickened and bright on long-TR MR images. The bright claustrum appears to be a new sign in Wilson's disease.
8456122##1993-1-1##Molecular genetics and zinc-copper interactions in human Wilson's disease and canine copper toxicosis.##
8303158##1993-1-1##[Treatment of Wilson's disease with zinc. 5 cases].##Zinc treatment of Wilson's disease was introduced by Schouwink en 1961 and is still uncommon in France. We evaluated the effectiveness and safety of zinc in 5 patients with Wilson's disease aged from 19 to 40 years. There were three neurological, one hepatic and one asymptomatic cases. Zinc was administered in doses of 120 to 272 mg/day, alone in 3 cases and combined with D-penicillamine in 2 cases. After 1 to 7 years of zinc therapy, our experience is consistent with data from recent literature and provides further evidence of zinc effectiveness. Zinc may be prescribed as first treatment in most patients, including asymptomatic cases. The only exception concerns patients with severe symptoms in whom it is recommended to combine zinc with D-penicillamine during the early phase of treatment for more rapid effectiveness. Because of its safety, zinc is particularly indicated in cases of intolerance to D-penicillamine and trien.
8211970##1993-1-1##Fate of orally administered triethylenetetramine dihydrochloride: a therapeutic drug for Wilson's disease.##Triethylenetetramine dihydrochloride (TETA) is a therapeutic drug for Wilson's disease. We developed a simple fluorometric method for detection of TETA in biological fluids by using high-performance liquid chromatography (HPLC), and examined TETA concentrations in the serum and urine of two healthy adults who were given TETA orally. No TETA peak was detected in the serum. The amount of TETA in the urine of the two adults was only 1.6 and 1.7% of the dose administered. However, a large unidentified peak appeared in the urine after oral administration. This peak was not observed in a mixture of TETA and control urine or in urine before TETA administration. When the urine after TETA administration was analyzed after hydrolysis with HCl, the unidentified peak disappeared, while the TETA peak increased. These findings indicate that the substance which yielded the unidentified peak is a metabolite of TETA, suggesting that most of the TETA administered is metabolized and then excreted in the urine.
8333287##1993-1-1##[Lowe syndrome: report of one case].##The Lowe syndrome, or oculocerebrorenal syndrome, is a rare X-linked recessive hereditary disease which typically involves three major systems including ocular defects (congenital cataracts, glaucoma, searching nystagmus), central nervous system defects (generalized hypotonia with decreased or absent deep tendon reflex and severe mental retardation), and renal dysfunction (progressive renal tubular dysfunction with acidosis and hyperaminoaciduria). Less than 200 cases have been reported in the English literatures since 1952. This article presents the first case of Lowe syndrome in Taiwan. Patient was a newborn who was born with congenital cataracts, glaucoma, generalized hypotonia with areflexia. In following laboratory studies showed early manifestations of renal tubular dysfunction with metabolic acidosis, proteinuria, glycosuria, phosphaturia and generalized hyperaminoaciduria (19 types). CT of brain showed an arachnoid cyst about 4.5 x 5 cm in size below the cerebellar tentorium. Large amount of copper, about 20-30 times above normal range, was detected in the urine. To our knowledge, Lowe syndrome associated with hypercupriuria and arachnoid cyst has not been reported in the past. Whether hypercupriuria is a part of the entity of this disease or prodromal stage of Wilson's disease is obscure. Further investigation and long-term observation are necessary to draw any conclusion.
1471864##1992-12-1##Decrease of D2 receptors indicated by 123I-iodobenzamide single-photon emission computed tomography relates to neurological deficit in treated Wilson's disease.##Single-photon emission computed tomography with 123I-iodobenzamide, a dopamine D2 receptor antagonist, was employed to study dopamine D2 receptor densities in 17 patients with biochemically proved Wilson's disease and stable neurological status with therapy and in 5 age-matched control subjects. Of the 17 patients with Wilson's disease, 5 were neurologically asymptomatic, 3 had cerebellar signs, 1 exhibited a mild parkinsonian syndrome, 7 showed a parkinsonian syndrome and cerebellar signs, and 1 had generalized dystonia and a parkinsonian syndrome. In 5 age-matched control subjects specific isotope binding as calculated by the basal ganglia to frontal cortex ratio was 1.57 +/- 0.04 (mean +/- standard deviation). The ratio in patients with Wilson's disease ranged from 1.56 +/- 0.05 (n = 5, asymptomatic patients) to 1.17 +/- 0.02 (n = 4, marked neurological impairment). We observed an almost linear correlation between the reduction of 123I-iodobenzamide (IBZM) binding and the severity of neurological signs at the time of IBZM-SPECT (correlation coefficient, -0.84; p &lt; 0.01). We suggest that the reduction of postsynaptic striatal dopamine D2 receptors as detected by IBZM-SPECT reflects striatal neuronal damage in Wilson's disease.
1489223##1992-12-1##Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis.##The portal tract mononuclear cell infiltrate has been characterised in 28 liver biopsy samples showing features of chronic aggressive hepatitis from 12 patients with autoimmune chronic active hepatitis, 12 with primary sclerosing cholangitis, and four with other chronic liver diseases (two with alpha 1-antitrypsin deficiency, one with Wilson's disease, and one with chronic hepatitis B infection). In all patients liver disease had started in childhood. The mononuclear cell infiltrate was investigated by a two step immunoperoxidase technique using monoclonal antibodies to: total, alpha/beta T cell receptor positive, helper/inducer, suppressor/cytotoxic T lymphocytes; B lymphocytes; killer/natural killer cells; monocyte/macrophages; and to the activation markers HLA-DR antigens, interleukin 2 receptor (IL-2R), transferrin receptor, and 4F2Ag. In all samples the infiltrate consisted of mainly alpha/beta T cell receptor T lymphocytes. Although T helper/inducer cells predominated in patients with autoimmune chronic active hepatitis, T suppressor/cytotoxic lymphocytes were preponderant in patients with primary sclerosing cholangitis and the other chronic liver diseases. Killer/natural killer cells accounted for up to 25% of the mononuclear cell infiltrate in patients with autoimmune chronic active hepatitis, being rare or absent in the other diseases. Monocytes/macrophages were always found, but they were more numerous in primary sclerosing cholangitis than in the other chronic liver diseases. B lymphocytes were rare or absent in all subjects. Activated mononuclear cells were present in all subjects, but although in patients with autoimmune chronic active hepatitis and primary sclerosing cholangitis most cells of the infiltrate expressed HLA-DR antigens and up to 75% IL-2R, in other forms of chronic liver diseases HLA-DR positive cells were less common and IL-2R positive cells ere rare or absent. These results show that the cells responsible for the histological characteristics of chronic aggressive hepatitis vary in their functional phenotype and state of activation according to the type of underlying liver disorder, confirming the involvement of different pathogenetic mechanisms.
1363748##1992-12-1##[Tightly linked DNA probe for presymptomatic diagnosis and carrier detection of Wilson disease].##Haplotype analysis of the polymorphic loci, D13S26 and retinoblastoma (RB) gene which were closely linked to the gene responsible for Wilson disease (WD), was carried out to predict the presymptomatic stage or to detect carrier status in phenotypically normal sibs in 9 Chinese families with WD syndrome. By analysis of D13S26/HphI and RB/XbaI sites, 72% parents in these families were haplotypically heterozygote and therefore informative for linkage study. In 9 phenotypically normal sibs in these families, presymptomatic status was predicted with 99.2% confidence in 1 and excluded in 4. In the other 4 cases, 2 were unpredictable and 2 were at least heterozygote and had 50% chance of being WD homozygote, depending on which chromosome they have got from their fathers.
1423047##1992-11-1##Symptomatic dystonia: clinical profile of 46 Brazilian patients.##Dystonia is a syndrome characterized by sustained muscle contraction, provoking twisting and repetitive movements or abnormal postures. It may be classified according to etiology, as idiopathic or symptomatic. We studied 122 Brazilian patients with a dystonic syndrome. Of these, 46 (37.7%) had symptomatic dystonia. The most frequent cause was tardive dystonia (34.8%) followed by perinatal cerebral injury (30.4%). Other causes were stroke (13.0%), encephalitis (6.5%) and Wilson's disease (4.3%). Cranial trauma, mitochondrial cytopathy and psychogenic, were the least frequent causes with one patient in each category. The etiology in two patients could not be established. Perinatal cerebral injury and postencephalitic dystonia were seen in the younger age group, while post-stroke and tardive dystonia were seen in the older age group.
1427659##1992-11-1##Failure of simple biochemical indexes to reliably differentiate fulminant Wilson's disease from other causes of fulminant liver failure.##Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (&lt; 0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (chi 2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)
1427654##1992-11-1##Emergency liver transplantation for fulminant liver failure in infants and children.##We report our results with orthotopic liver transplantation in children with fulminant liver failure. Thirty-five children with fulminant liver failure were evaluated for liver transplantation. The main causes of liver failure were viral hepatitis (54.2%), drug-induced liver injury (14.2%) and Wilson's disease (11.4%). Children were considered as candidates for liver transplantation only if hepatic encephalopathy was associated with a decrease in the level of factor V to below 25%. Seven children (20%) did not meet this criterion and recovered spontaneously. Six children (17.1%) had contraindications for liver transplantation and died. In three of these six children, contraindications included irreversible brain damage at the time of admission. Twenty-two children (62.8%) met the criteria for liver transplantation and were placed on the emergency transplant list. Three of them died awaiting grafts. Nineteen children underwent liver transplantation; 13 of them (68.4%) are alive without sequelae, after 6 mo to 4 yr of follow-up, at this writing. Four of the children who died after surgery had severe encephalopathy on admission that did not improve after liver transplantation. In conclusion, emergency liver transplantation appears to be an effective treatment for children with fulminant liver failure. Nevertheless, irreversible brain damage developed in 10 patients, and they died before or after surgery. We postulate that many of these deaths could have been avoided if children had been transferred to a liver transplantation facility and had undergone transplantation earlier. We emphasize that children with acute liver failure should be transferred to a center that performs liver transplantation before the development of hepatic encephalopathy.
1487612##1992-11-1##Metallothionein concentration in the liver of patients with Wilson's disease, primary biliary cirrhosis, and liver metastasis of colorectal cancer.##In patients with primary biliary cirrhosis and Wilson's disease liver copper concentrations become elevated during the evolution of the disorder. The accumulated copper is thought to be detoxified by metallothionein, a protein which binds copper and zinc. In liver metastasis of colorectal cancer, copper and zinc concentrations are usually decreased compared to normal liver tissue, but little is known about the concomitant metallothionein levels. In the present study metallothionein concentrations were determined in archival liver samples from patients with primary biliary cirrhosis and Wilson's disease, and in both normal and malignancy-containing liver samples from patients with metastasis from a colorectal adenocarcinoma. Twenty-seven control liver samples contained 3.98 +/- 1.55 mg metallothionein/g protein. From the 21 liver samples of patients with primary biliary cirrhosis, which had a mean metallothionein concentration of 6.06 +/- 5.03 mg/g protein, 6 were above the highest control level. Liver metallothionein concentrations for the 8 patients with Wilson's disease were significantly elevated (10.98 +/- 6.93 mg/g protein, p &lt; 0.005 vs. controls and p &lt; 0.05 vs. primary biliary cirrhosis). In the 11 liver metastases from colorectal adenocarcinomas metallothionein concentrations (1.17 +/- 0.90 mg/g protein) were significantly (p &lt; 0.005) lower than surrounding normal liver tissue (4.25 +/- 1.75 mg/g protein). We conclude that in primary biliary cirrhosis and Wilson's disease increased liver metallothionein concentrations may detoxify the accumulated copper. Furthermore, liver metastasis of colorectal cancer contains less metallothionein than the surrounding normal liver tissue.
1298933##1992-11-1##[Liver transplant in childhood: our experience].##From december 1984 to december of 1991, 12 children underwent on orthotopic liver transplantation (OLT): 6 had extrahepatic biliary atresia (EHBA), 2 had Byler disease, 2 hepatocellular carcinoma (HCC), 1 Alagille Syndrome and 1 had a hyperacute Wilson disease. The children, transplanted for the most part a broad, return for observation 3 months after OLT. A patient with hyperacute Wilson's Disease had 2 emergency OLTs and died of sepsis (due to Aspergillus); another with EHBA, operated for hepatoportoenterostomy, without result, died after OLT because of a ruptured aortic aneurysm. The other 10 are living with a variable follow-up between 8 months and 7 years. The post-operatory complications were present in 4 cases: in the same patient (15 months old) a hepatic artery thrombosis and then a portal vein thrombosis were observed; 3 patients had to have their biliary-digestive anastomosis redone. 7 of 10 patients had acute rejection. During the first month after OLT infection episodes were mostly due to bacteria (G-), Candida and Pneumocystis carinii (blood and intraabdominal sepsis). In the second period (1-3 months) there were viral infections, in particular CMV. An emergency transplanted patient, incompletely vaccinated, developed HBV infection. During long term follow-up (after the 3rd months from OLT) the children usually have mild infections of the respiratory and urinary tracts. After 1 year, they have a mean annual growth velocity that is between the 50th and 90th percentile. They showed a good rehabilitation. Their hospitalizations rate was reduced if compared with the period before OLT. Health, motor function and general behavior improved significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
1466536##1992-10-11##Penicillamine-induced pseudoxanthoma elasticum-like skin changes requiring rhytidectomy.##A 42-year-old woman with pronounced skin laxity of her neck underwent a rhytidectomy and was found to have pseudoxanthoma elasticum-like changes of her skin. Her medical history was significant for Wilson's disease, requiring that she take penicillamine for 26 years. In patients on long-term penicillamine therapy, 20% to 33% will develop a dermatopathy. The drug has been used to alter scar formation in various surgical conditions. Penicillamine is known to alter cross-linking of elastin and collagen fibers. A review of the literature reveals other penicillamine-related dermatopathies that may present to the surgeon.
1446209##1992-10-1##Impairment of temporal organization of speech in basal ganglia diseases.##Absolute and relative speech timing were examined in patients suffering from Parkinson's, Huntington's, and Wilson's disease. The task was to speak a standard sentence 10 times, first slowly, and then successively faster up to maximum rate. All patient groups had low maximal speech rates and showed decreased variability of speech rate. The duration of pauses between words was the same as in normals and the relative time structure of the test sentence was basically preserved. For comparison, two cases with nonfluent aphasia had even slower speech rates, large increases in pause duration, and major changes in relative speech timing. The results show the same type of alterations of the temporal organization of speech as those characteristic for rapid alternating limb movements in such patients. They support the view that the speech and skeletomotor systems share common neural control modes despite fundamental biomechanical differences. The common denominator between the speech and the skeletomotor disturbances in basal ganglia diseases may be the undamping and slowing of a fast central oscillator.
1307367##1992-10-1##Extensive CT scan abnormality in Wilson's disease.##
1505917##1992-9-1##Fraternal concordance of types of abnormal hepatocellular mitochondria in Wilson's disease.##Three distinct patterns of structural abnormalities of mitochondria, indicated as types I, II and III and associated with steatosis, were identified in the hepatocytes of 40 of 42 asymptomatic and 8 of 22 symptomatic patients with documented Wilson's disease before treatment. No correlation was seen between the type of mitochondrial abnormality and the patient's age, hepatic copper concentration, degree of hepatic steatosis or serum aminotransferase level. However, comparison of the types of abnormal hepatocellular mitochondria displayed by five pairs and one trio of asymptomatic siblings revealed remarkably similar types of abnormalities in each family. The variety of mitochondrial types encountered in different families and the high degree of type identity in sibling relationships indicate that the structural changes are genetically determined.
1517684##1992-9-1##Treatment of Wilson's disease with zinc: X. Intestinal metallothionein induction.##Oral zinc therapy is effective in controlling copper balance in patients with Wilson's disease and blocks the intestinal absorption of copper, as demonstrated by uptake of copper 64 and copper balance measurements. In this study, 64Cu uptake measurements were concomitantly carried out with intestinal biopsies to investigate the relationship of reduced copper absorption to the levels of intestinal metallothionein in patients with Wilson's disease at different stages of zinc therapy. A pronounced increase in intestinal metallothionein levels and a sharp drop in 64Cu absorption were found 4 to 5 days after the initiation of zinc treatment. Conversely, metallothionein levels decreased and 64Cu uptake increased on the discontinuation of zinc therapy. The data indicate that 64Cu absorption varies as a function of intestinal metallothionein level. Intestinal metallothionein levels were found to correlate linearly with urinary zinc levels, which reflect body zinc status. These findings support our hypothesis that intestinal metallothionein induction mediates decreased copper absorption observed during zinc therapy. The suppressive effect of zinc on copper absorption appears to have a half-life of about 11 days.
1306026##1992-9-1##[Wilson's disease and pregnancy].##Wilson's disease is rare autosomal-recessive disorder originated on the basis of metabolic copper over-storage. This is the case report of patient aged 28, who suffers Wilson's disease during last ten years. She has been treated by penicillamine unregularly from the beginning of her disease. She reported three spontaneous abortions in her previous history. She was treated by penicillamin and bedoxin in current pregnancy. Vaginal delivery was completed using oxytocin stimulation. Newborn was male, alive, with body weight of 2900 grams. Apgar score was 8. During puerperal period normal uterine involution was estimated, but lactation was ceased.
1524511##1992-8-1##Wilson's disease: hypothesis of a deficiency of copper excretion via the endosome to the bile.##
1511977##1992-8-1##Identification of crossovers in Wilson disease families as reference points for a genetic localization of the gene.##Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. A minimum recombinant analysis using D13S22, ESD, RB1, D13S31, D13S55, D13S26, D13S39, and D13S12, all localized at 13q14-q22, has been carried out in 20 WD families of Northwest-European origin. No inconsistencies have been observed with respect to locus order or location of the WD locus (WND) compared with previous linkage studies. D13S31 was mapped as the closest marker proximal to WND, whereas D13S55 and D13S26 were mapped as the closest markers distal to WND. We have identified a crossover between WND and D13S31 in one family and a crossover between WND and D13S55 in another. These crossover sites can be used as reference points for new chromosome 13q14-q21 markers, and are therefore important for a more accurate mapping of the WD locus.
1527540##1992-8-1##Wilson's disease: the problem of delayed diagnosis.##To discover the earliest symptoms and signs of neurological Wilson's disease we analysed the case histories of 136 patients who were seen between 1955-87: patients with hepatic or presymptomatic Wilson's disease were excluded from this series. Thirty one patients (23%) gave a history of an episode of liver damage. The onset of symptoms ranged from nine to 40 years with a median of 16.2 years. The correct diagnosis was made at presentation in only 43 patients. The mean delay before diagnosis was 12.8 months for the others. The earliest symptoms were dysarthria or difficulty with the hands, or often both. There was often an associated change in personality or deteriorating performance at school. The four common clinical pictures were Parkinsonian (61 cases), &quot;pseudosclerotic&quot; (33 cases), dystonic (21 cases) and choreic (15 cases): six cases were unclassified. Parkinsonian symptoms were equally common in children (under 17 years) and adults, a &quot;pseudosclerotic&quot; picture was much more common in adults but dystonic and choreic symptoms were seen more often in children. Experience suggests that no two patients are ever the same, even in a sibship.
1434496##1992-8-1##Effects of sex hormones on fulminant hepatitis in LEC rats: a model of Wilson's disease.##LEC rats, which have hereditary hepatitis and have recently been proposed as an animal model for Wilson's disease, were examined to determine the effects of sex hormones on fulminant hepatitis. After the rats had undergone ovariectomies or orchidectomies (castration) and were compared with intact rats, the age at the onset of fulminant hepatitis was not substantially altered but the survival rates decreased from 50% to 12.5% for females and 75% to 14.3% for males, indicating that sex hormones did not influence the occurrence of fulminant hepatitis but influenced mortality due to fulminant hepatitis. When testosterone was administered to the ovariectomized or orchidectomized rats, the survival rate increased to over 90% in both sexes. In contrast, estradiol did not affect the survival rate of either sex but affected the onset of fulminant hepatitis. That is, with the administration of estradiol, the age at which serum GPT activity reached its maximum was delayed 4 weeks in ovariectomized rats and 6 weeks in orchidectomized rats as compared with intact rats. A similar but somewhat weaker tendency appeared in rats given progesterone. The results of our study indicate that sex hormones have no effect on the rate of occurrence of hepatitis but affect the progression of hepatitis. In particular, testosterone increased the survival rate of rats with fulminant hepatitis, and exogenous estradiol delayed the onset of hepatitis for several weeks.
1353866##1992-8-1##[Tardive dystonia].##Two patients with tardive dystonia are presented. Tardive dystonia is a late-onset side effect of dopamine antagonist, which occurs in approximately 2% of the patients in the course of treatment with neuroleptic medication. The dystonia usually starts by affecting the musculature of face and (or) neck and is often progressive to a segmental localization. Of differential diagnostic importance are: conversion disorder, acute dystonia, Wilson's disease, idiopathic dystonia and dystonia triggered by other agents. Treatment starts with reevaluation of the need for ongoing neuroleptic treatment. Investigation of the pharmacotherapy of the dystonia concerns mostly treatment with dopamine depletors or with high doses of anticholinergic agents. Improvement of 50% of the patients is reported, although total recovery is rare. Many other substances and also some physical methods (ECT and surgery) have been used with varying results.
1496628##1992-8-1##Disappearance of Kayser-Fleischer rings following liver transplantation.##1. Four cases of Kayser-Fleischer rings of Wilson's disease were observed to disappear after liver transplantation. 2. The disappearance of Kayser-Fleischer rings was in reverse order from that in which they appear. 3. The duration of disappearance was variable. 4. The density of Kayser-Fleischer rings correlated with the duration of clinical symptoms.
1496621##1992-8-1##Abatement of secondary amenorrhea in Wilson's disease following liver transplantation.##
1350853##1992-7-2##Prenatal diagnosis of Wilson's disease by analysis of DNA polymorphism.##
1596056##1992-7-1##Diagnosing Wilson disease.##
1596055##1992-7-1##Diagnosing Wilson disease.##
1428152##1992-7-1##Wilson's disease: initial worsening of neurologic syndrome with penicillamine therapy.##
1515566##1992-7-1##Striking variability of hepatic copper levels in fulminant hepatic failure.##Two cases of acute hepatic failure are reported in which the diagnosis of Wilson's disease was considered because of low serum ceruloplasmin, low serum copper levels and high 24 h urinary copper. Case 1 had Kayser-Fleischer rings, haemolysis and a high 24 h urinary copper, and so Wilson's disease was confidently diagnosed. Case 2 had high urinary copper excretion, but [64Cu] study indicated a 24:2 h ratio of 0.7 and made the diagnosis of Wilson's disease uncertain. Both patients underwent orthotopic hepatic transplantation, and multiple biopsies were taken from the resected specimen in order to estimate hepatic copper levels. In both cases, hepatic copper levels revealed considerable variation: 0.8-5.2 mumol/g dry wt (case 1) vs 0.02-12.65 mumol/g dry wt (case 2). In case 1, only two of 14 levels were within the diagnostic range for Wilson's disease (greater than 4 mumol/g dry wt), whereas hepatic copper levels in case 2 were in the Wilsonian disease range in three of 16 specimens. These results were in contrast to uniformly high hepatic copper levels in one patient with established cirrhosis secondary to Wilson's disease and two cases of primary biliary cirrhosis. This report indicates that hepatic copper levels vary greatly in acute liver failure, and that estimates from a single biopsy specimen may be misleading as to the cause of the underlying liver disease.
1515561##1992-7-1##Fulminant hepatic failure and acute intravascular haemolysis as presenting manifestations of Wilson's disease in young children.##The cases of three young children (mean age 5.8 years) in whom fulminant hepatic failure and acute intravascular haemolysis were the presenting manifestations of Wilson's disease are reported. Although diagnosis was made ante-mortem and chelation therapy instituted, the course was relentlessly fatal in all three cases. This presentation of Wilson's disease at such a young age is noteworthy.
1498590##1992-1-1##Cognitive impairment in Wilson's disease.##
1631398##1992-7-1##Restoring childhood through rehabilitation.##Nine-year-old Alesha's symptoms began with tingling in her hands, and within a few months she could neither walk nor talk. Alesha has Wilson's disease, a rare genetic condition that results in a progressive buildup of copper in the body. Alesha lost 2 years of her life to Wilson's disease. This article focuses on the clinical and rehabilitation aspects of Wilson's disease and on the efforts to restore to Alesha the childhood the disease cost her. Nursing care for Alesha involved physiological, developmental, and restorative components, with special attention to the home pediatric rehabilitation program.
1605146##1992-6-1##Wilson's disease: current status.##
1352099##1992-6-1##Expression of sialylated Lewis(x) antigen in chronic and neoplastic liver diseases.##Phenotypic expression of sialylated Lewis(x) antigen by means of the monoclonal antiserum SNH3 was studied in 87 livers, which included normal and steatotic livers and livers with chronic persistent and chronic active hepatitis, alcoholic hepatitis, allograft rejection, focal nodular hyperplasia, hepatocellular carcinoma, cholangiocarcinoma, metastatic carcinoma, cirrhosis of various causes (autoimmune, alcoholic, viral, drug induced, Wilson's disease, and primary biliary cirrhosis). The biotin-streptavidin-peroxidase method was used on formaldehyde-fixed, paraffin-embedded sections. Sialylated Lewis(x) antigen was not demonstrated in normal livers. Hepatocellular expression in a diffuse or perinodular honeycomb pattern was seen in cirrhosis, irrespective of cause. Sialylated Lewis(x) antigen was also observed in hepatocytes around metastatic carcinoma in the absence of inflammation, cirrhosis, or regeneration. Some bile ductules, most likely ductular hepatocytes, but not bile ducts, expressed sialylated Lewis(x) antigen. Sialylated Lewis(x) antigen was seen diffusely in fibrolamellar hepatocellular carcinoma, focally in other hepatocellular carcinomas, and either focally or diffusely in cholangiocarcinomas.
1353405##1992-6-1##[Schizophrenia and Wilson's disease].##An 18 year-old male first presented a clinical picture of acute psychosis with two recurrences at ages 22 and 23. The diagnosis made at that time was paranoid schizophrenia. Twelve years after his first psychiatric hospitalization, it was discovered that he was suffering from Wilson's disease. In retrospect, the clinical picture was atypical, notably with an important neurologic involvement mainly parkinsonism almost uncontrollable and aggravated with neuroleptics. The chelating treatment with d-penicillamine resulted in partial improvement of the neurological involvement because the extrapyramidal and neurovegetative symptoms persisted. The psychiatric symptoms improved with fewer neuroleptics than during the 12 previous years. However, neuroleptics had to be continued because of the delay in diagnosing the illness, which diminished the efficiency of the single chelating treatment. The clinical presentation and therapeutic response of this patient strongly suggest a link between the cerebral intoxication by copper and the psychiatric symptoms.
1644402##1992-6-1##[Wilson's disease with primary CNS manifestation--current status in diagnosis and therapy].##Five cases studied at our clinic are discussed and the literature reviewed with the aim of assessing the diagnostic value of various examination methods used for Wilson's disease and a modified diagnostic approach is suggested. CT and MRI are compared with regard to sensitivity, specificity and prognostic value. Almost regularly, MRI showed bilateral lesions in the basal ganglia in combination with structural changes in the brain stem. A pattern consisting of symmetrical lesions of the red nuclei, the periaqueductal grey region and, facultatively, the substantia nigra and the dentate nuclei was discovered and appeared almost pathognomonic. Follow-up studies revealed excellent reversibility of MRI changes by both penicillamine and trientine. Auditory evoked potentials showed the highest sensitivity and the best correlation with structural findings. Kayser-Fleischer corneal rings--a diagnostic requirement in the literature--were not found in all patients. The current state of therapy and therapy management is discussed on the basis of pathophysiological considerations. As possible complications of penicillamine administration the deterioration of the clinical condition after initiating therapy, and the risks associated with an abrupt termination of therapy are discussed in detail.
1607275##1992-6-1##Screening for Wilson's disease in the investigation of hematuria.##
1358351##1992-6-1##Resolution of cerebral white matter lesions following long-term penicillamine therapy for Wilson's disease: report of a case.##Although lenticular gray matter lesions in Wilson's disease (WD) may resolve following long-term decoppering therapy, response of cerebral white matter lesions to such a treatment has not been reported. A patient with WD developed dystonia of the left hand and focal seizures involving the left upper limb with occasional generalization. CT disclosed a low density area in the right frontal white matter. Initiation of penicillamine therapy resulted in worsening of clinical manifestations, further extension of the right frontal lesion, and development of a new left parietal lesion. However, after five years of continued penicillamine therapy, clinical improvements were noted, including disappearance of the left parietal lesion and almost complete resolution of the right frontal lesion. The present case suggests that cerebral white matter lesions in WD may also respond to long-term chelating therapy.
1593220##1992-6-1##The interactions of penicillamine with copper in vivo and the effect on hepatic metallothionein levels and copper/zinc distribution: the implications for Wilson's disease and arthritis therapy.##D-penicillamine does not remove copper from metallothionein, but it has been suggested that it may increase hepatic metallothionein levels. D-penicillamine was shown to increase rat hepatic metallothionein levels; however, the effect was dependent on an interaction with copper. The drug accelerated the excretion of exogenous copper but increased the amount retained on metallothionein. This interaction of penicillamine and copper also provoked changes in the distribution of zinc and in particular an increase in the heat-stable cytosol zinc fraction. In contrast, thiomolybdates were much more effective in eliminating exogenous copper and even removed copper that was already bound to metallothionein; thus, the copper level in the heat-stable cytosol fraction decreased. The observations support the view that patients with Wilson's disease may not be truly &quot;decoppered&quot; but that treatment with d-penicillamine is effective because the accumulated copper in the liver is bound in a nontoxic form by the increased metallothionein. The results explain why cessation of treatment is dangerous. The results may also partially explain the effectiveness of D-penicillamine copper chelates as antiinflammatory drugs.
1603726##1992-6-1##Neurologic conditions presenting as psychiatric disorders.##Neurologic disease can present as a psychiatric disorder. Understanding underlying neuroanatomic function helps physicians to localize defects and search for treatable neurologic conditions. Neurologic conditions such as Huntington's chorea, Wilson's disease, Gille de la Tourette syndrome, brain tumors, encephalitis and meningitis, neurodegenerative conditions and metabolic or toxic conditions can have psychiatric manifestations.
1633017##1992-6-1##[Wilson's disease].##
1356645##1992-6-1##[Polymorphisms of the D13S26 locus in Chinese and its application to linkage analysis of Wilson disease].##The D13S26 locus has been mapped to 13q21.1-q21.2 and is linked with Wilson disease gene at a distance of 3.8 centimorgans. The polymorphic alleles detected by HphI, EcoRI and BclI at the D13S26 locus are the same in Chinese as in Caucasians, but the allele frequencies are quite different. As calculated from 30 unrelated Chinese individuals, the allele frequencies were as follows: HphI 2.8 kb(0.47)/2.0kb(0.53); EcoRI 9.0 kb (0.02)/8.0 kb (0.98); BclI 6.3 kb (0.02)/5.6 kb (0.98). Cosegregation analysis of the D13S26 locus and Wilson disease locus was carried out in 3 families with the disease. In one of these families, the proband and his younger sister (7-years-old and phenotypically normal) were both heterozygous for this site. We predict with 85.6% confidence that the younger sister is in the presymptomatic stage of Wilson disease.
1437767##1992-5-18##[Results of the treatment of Wilson's disease with zinc sulfate and d-penicillamine].##Nine patients with newly diagnosed Wilson's disease were treated with zinc sulphate for 12 months. Polish preparation Zincteral was administered in doses of 200 mg 4 times daily. The neurological status has improved in five cases. No adverse reactions of zinc sulphate were observed. The results were compared with the therapeutic effect, obtained in the group of 10 patients who received d-penicillamine (Cuprenil-Polfa) 1.0-1.5 g daily from the very beginning. In three cases drug was discontinued due to adverse reactions. In remaining seven cases, in five evidence of the clinical improvement of the neurological status was observed, but in one case during 12 months of observation progressing deterioration was noticed. Neurological state of one patient remained unchanged.
1589371##1992-5-15##Chronic liver disease. The scope of causes and treatments.##Evaluation of chronic liver disease begins with a carefully taken history, thorough physical examination, and standard laboratory tests. Often, however, other studies are required, such as a viral hepatitis panel, serologic tests for autoimmune markers, tests for antimitochondrial antibodies, measurement of serum iron and ceruloplasmin levels, liver biopsy, and imaging studies of the extra-hepatic bile ducts. Medical treatment of chronic active hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis remains unsatisfactory. Early treatment of hemochromatosis and Wilson's disease can prevent cirrhosis and liver failure. Liver transplantation is now a viable procedure for patients with end-stage chronic liver disease.
1590176##1992-5-1##MR of the base of the pons in Wilson disease.##The authors describe unusual MR findings in three patients with Wilson disease, eg, white matter changes in the base of the pons, and speculate whether the changes are caused by Wilson disease or by concomitant disease, and whether the pontine lesions they observed are primary or related to lesions located more rostrally.
1600113##1992-5-1##Comparison of disposition behavior and de-coppering effect of triethylenetetramine in animal model for Wilson's disease (Long-Evans Cinnamon rat) with normal Wistar rat.##The disposition behaviors and de-coppering effect of triethylenetetramine dihydrochloride (trientine), a selective chelating agent for copper and an 'orphan drug' for Wilson's disease, have been evaluated in an animal model, Long-Evans Cinnamon (LEC) rats, and normal rats (Wistar). In LEC rats, urinary excretion of trientine was remarkably lower than that of Wistar rats. The absorption rates from the jejunal loop and in vitro metabolism in the liver S9 fraction (supernatant of 9000 x g) were approximately the same for both strains. The decline of urinary excretion of trientine in LEC rats is thought to be due mainly to the lowering of the functional activity of the kidney, because urinary excretion of creatinine and phenolsulfonphthalein were significantly lower in LEC rats than those in Wistar rats. Both acceleration of urinary excretion of copper and reduction of hepatic copper levels were observed with treatment of trientine in LEC rats aged 6 weeks. In LEC rats aged 13 weeks, however, no de-coppering effect from the liver was observed, though urinary excretion of copper was increased. These results suggest that trientine has a pharmacological effect in disease state, especially in the early stages of hepatitis.
1358328##1992-5-1##Wilson's disease: clinical analysis of 71 cases and comparison with previous Chinese series.##We analyzed 71 patients (45 males and 26 females) with Wilson's disease (WD) who were seen at our hospital from 1979 through 1990. The mean age at onset was 18.1 +/- 6.5 years, with 17.0 +/- 6.6 years for males and 20.2 +/- 5.7 years for females. The mean age at the time of diagnosis was 21.0 +/- 6.3 years. Hepatic WD was the most frequent mode of presentation in childhood with a mean age of 15.5 +/- 6.0 years, while neurologic WD tended to occur in adolescence with a mean age of 21.0 +/- 8.9 years. The ages of onset were 12.5 +/- 0.5 years for renal WD and 25.3 +/- 2.4 years for psychiatric WD. The common initial symptoms were neurologic and hepatobiliary. In addition, hematologic and renal disorders were also common during evaluation. The neurologic findings at the time of diagnosis were tremors (66.2%), dysarthria (56.3%), gait disturbances (46.5%), dystonia (42.3%) and decreased facial expressions (40.8%). Less frequent but notable neurologic presentations were psychosis (11.3%), epileptic seizures (5.6%) and hypokalemic periodic paralysis (1.4%). When compared with two previous large Chinese series, the present data show a male preponderance, an earlier age of onset for males and higher incidences of hepatic, hematologic and renal involvement. The possible reasons for the discrepancies between the present study and previous Chinese series are discussed.
1506662##1992-5-1##Copper metabolism in hypercupremic human livers. Studies of its subcellular distribution, association with binding proteins and expression of mRNAs.##In the present study we have used differential centrifugation, size exclusion chromatography, Western and Northern blotting to investigate the subcellular distribution of hepatic copper, the association of the metal with hepatic copper binding proteins and the expression of specific mRNAs for copper binding proteins in liver tissue from two patients with Wilson's disease, two patients with chronic liver disease and two patients with normal hepatic copper levels. Unlike previous studies the present results fail to show any gross differences in subcellular distribution of copper between the livers, with most of the copper being found in the soluble supernatant where it is associated with metallothionein. Caeruloplasmin mRNA levels were reduced in the two patients with Wilson's disease and also in a patient with fulminant hepatic failure. It remains to be confirmed if the reduction of caeruloplasmin mRNA is specific for Wilson's disease. Levels of mRNAs for copper zinc superoxide dismutase and metallothionein were variable and not related to liver copper.
1635439##1992-5-1##Wilson disease.##Wilson disease is an inherited disorder of copper metabolism. Progress has been made in establishing the location of the gene on the long arm of chromosome 13, and in finding nearby probes that can be used to identify affected sibs of newly diagnosed patients. However, the gene has not been cloned, and the molecular nature of the defect remains unknown. The cause of the disease is a failure to excrete unneeded and excessive copper in the bile for loss in the stool. This may be due to a failure to excrete copper packaged in ceruloplasmin into the bile. Clinically, patients usually present during the second to fourth decades of life with liver, neurologic, or psychiatric disease, but the diagnosis is often missed or delayed. Once a diagnosis of Wilson disease is considered, reliable studies of copper variables can be carried out. After diagnosis, patients must receive anticopper treatment for the rest of their lives, to reduce copper levels and prevent copper reaccumulation. For life-long maintenance therapy, we recommend zinc acetate because of its complete efficacy and lack of toxicity; it acts by blocking copper absorption. For initial therapy of the acutely ill patient, no currently available therapy has proven to be ideal. A chelator-type drug, either penicillamine or trien, can be used for the initial therapy of patients who present with liver disease; transition to zinc acetate can then be made after a few months. For the initial therapy of acutely ill patients who present with neurologic disease, chelation should be avoided because neurologic worsening frequently occurs, probably due to redistribution of copper which temporarily raises the levels of copper in the brain. For initial treatment, zinc therapy is also not ideal because it is relatively slow-acting. A new experimental drug, tetrathiomolybdate, shows promise in the initial treatment of patients with Wilson disease. The major challenges ahead include closing the remaining therapeutic hiatuses, cloning and expressing the gene to understand its function, and improving clinical diagnosis so that therapy can be instituted as quickly as possible.
1439104##1992-5-1##[Wilson's disease].##Wilson's disease, also called hepatolenticular degeneration, is a serious inherited disorder of copper metabolism. The disease needs a particular attention because it is estimated that about half of the patients are never diagnosed. Beside, once the diagnosis is made, Wilson's disease can be effectively treated. After the epidemiological, pathogenetical and clinical data, authors present the diagnostical aspects of the disease, and the various approaches to the treatment of the symptomatic or presymptomatic patients and of the pregnant patients. Also reported are two cases of Wilson's disease.
1458725##1992-5-1##[A case of ceruloplasmin deficiency which showed dementia, ataxia and iron deposition in the brain].##A 55-year-old female with progressed dementia, cerebellar ataxia was reported. There was no family history of the same symptoms although her brothers, sisters and a son showed hypoceruloplasminemia and decrease of the serum copper content. On physical examination, anemia, dementia, dysarthria, torticollis, choreic involuntary movement of respiratory muscles, hyperreflexia in extremities and cerebellar ataxia were noted. Blood analysis revealed microcytic hypochromic anemia, diabetes mellitus, decrease of copper content of the serum and urine. Serum ferritin concentration was increased. Serum ceruloplasmin could not be detected. Biopsy of the liver showed that copper content in the liver was slightly increased and iron content was remarkably increased. On MRI study, dentate nucleus of the cerebellum, the thalamus, the putamen and the caudate nucleus and the liver showed low intensity in both T1 and T2 weighted images. Based on increased iron content in the liver, the radiological findings of the brain suggested deposition of iron in the brain. This deposition was considered as caused by deficiency of function of ceruloplasmin as ferroxidase. This disorder is suggested as a new disease due to ceruloplasmin deficiency different from Wilson's disease.
1643196##1992-4-15##The interaction of motor, memory, and emotional dysfunction in Wilson's disease.##Measures of the degree of motor, psychiatric, and declarative memory disability were made in neurologically impaired and neurologically asymptomatic patients with Wilson's disease. All three types of disability were significantly greater in the neurologically impaired than in the asymptomatic patients. There was no significant interaction between these disabilities in the impaired patients suggesting that motor, psychiatric, and memory symptoms are three relatively independent sequelae of the copper-induced central nervous system (CNS) damage that underlies Wilson's disease.
1499587##1992-4-1##Plasma exchange for fulminant Wilson disease.##
1551638##1992-4-1##Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease.##To investigate the diagnostic value of 24-hr urinary copper excretion testing after penicillamine challenge in the diagnosis of Wilson's disease, 75 consecutive children referred for a variety of liver problems and in whom parameters of copper metabolism had been investigated were analyzed retrospectively. Seventeen had Wilson's disease, 22 had autoimmune chronic active hepatitis, 6 had primary sclerosing cholangitis, 12 had chronic liver disease of various etiologies, 4 had cryptogenic acute liver failure, 6 had acute hepatitic illnesses and 8 had a variety of disorders featuring normal liver histological appearance. Serum ceruloplasmin and total copper levels were significantly lower in Wilson's disease patients compared with all other groups, but three children with Wilson's disease had normal ceruloplasmin levels and seven had normal total copper levels. No significant difference was found for free serum copper levels and liver copper content between Wilson's disease patients and the other groups. Baseline 24-hr urinary copper excretion was significantly higher in Wilson's disease patients compared with that of the other patients, but six children with Wilson's disease had levels just above the upper limit of normal, overlapping with values obtained in three children with liver failure, two with acute hepatitis, two with autoimmune chronic active hepatitis and three with primary sclerosing cholangitis. The 24-hr urinary copper excretion after penicillamine challenge proved the most accurate single diagnostic test; levels more than 25 mumol/24 hr were present in 15 of 17 patients with Wilson's disease, but in only 1 child with liver failure of the 58 with other disorders.(ABSTRACT TRUNCATED AT 250 WORDS)
1618601##1992-4-1##Strategies for the development of new antiarthritic agents.##Therapeutic advances in rheumatoid arthritis (RA) have largely focused on the development of non-steroidal antiinflammatory drugs (NSAIDs) with improved characteristics compared with aspirin [Brooks &amp; Day, New Engl. J. Med., 324, 1716-1725 (1991)]. For example, greater potency, safety, improved tolerance in the elderly and reduced frequency of dosing have been achieved. However, these agents are generally considered to be palliative treating of the symptoms of the disease. The development of disease modifying drugs (DMD), also known as second line drugs, for RA has not been very successful. Most of the agents that are currently used in this category were originally used to treat other diseases such as malignancy (cyclophosphamide, methotrexate), Wilson's disease (d-penicillamine) and tuberculosis (gold salts) [Pullar, Br. J. clin. Pharmac., 30, 501-510 (1990)]. Unfortunately, none of the agents is ideal and each has potentially serious side-effects. There have been several attempts to develop agents with new mechanisms of action that hopefully will greatly improve these current therapies.
1573328##1992-4-1##Wilson's disease: a need for early diagnosis and referral.##
1619543##1992-4-1##Penicillamine hepatotoxicity in the treatment of Wilson's disease.##
1518956##1992-4-1##Correlation between a hepatic copper accumulation and an altered expression of glutathione S-transferase Ya/Yc subunits in LEC mutant rat.##Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, that develops a necrotizing hepatic injury with an abnormally high hepatic copper accumulation exhibits an altered expression of glutathione S-transferase (GST) subunits, that is, a low percentage of the Ya and a high percentage of the Yc subunit expression in males. The altered expression of GST subunits and the abnormal copper accumulation in liver were found to be completely correlated in male LEC mutant rat liver, suggesting that the copper toxicity caused by the anomaly of copper metabolism in LEC rat liver leads to the altered expression of GST subunits.
1736780##1992-3-1##Wilson disease--penicillamine therapy and late presentation.##
1736779##1992-3-1##Wilson disease--penicillamine therapy and late presentation.##
1621928##1992-3-1##Tongue dyskinesia in Wilson disease.##
1315164##1992-3-1##Prevalence of anti-HCV among Chinese patients with acute and chronic liver disease.##To assess whether the hepatitis C virus plays an important role in Chinese patients with acute and chronic liver disease, antibodies to HCV (anti-HCV) were measured by enzyme immunoassay in 67 patients with type A and B acute viral hepatitis, 165 patients with non-A, non-B (NANB) hepatitis, 438 patients with chronic hepatitis, 200 patients with postnecrotic liver cirrhosis, 72 patients with alcoholic liver disease, 55 patients with non-alcoholic fatty liver, 24 patients with toxic and drug-induced hepatitis, and 20 patients with other chronic liver diseases. Anti-HCV was not detected in sera from patients with type A and B acute viral hepatitis, toxic and drug-induced hepatitis, primary biliary cirrhosis, Wilson's disease, or lupoid hepatitis. The anti-HCV prevalence was found to be highest in patients with NANB hepatitis (59% in sporadic and 73.2% in transfusion-associated), 16.4% in non-alcoholic fatty liver, 5.6% in alcoholic liver disease, 6.8% in chronic hepatitis, and 16% in postnecrotic liver cirrhosis. In patients with chronic hepatitis, the anti-HCV prevalence was significantly higher in HBsAg-negative (15/34, 44.1%) than in HBsAg-positive cases (15/404, 3.7%; P less than 0.0001). The results indicate that HCV is a major agent of NANB hepatitis and plays an important role in HBsAg-negative chronic liver disease in Taiwan.
1506790##1992-3-1##Wilson's disease.##Fourteen cases of Wilson's disease in Thais were studied retrospectively. Most were in the second and third decades. The hepatic form occurs in all age groups and the most common presentation was cirrhosis and complications. Neurological complications were observed during the second decade and consisted of Parkinsonism, dystonic and pseudosclerotic forms. A Keyser-Fleisher ring was detected in 2/3 of the cases. D-penicillamine was the mainstay of our therapy. Death in this series was related to crisis such as acute hemolysis, hepatitis as well as septic complications of cirrhosis. Since Wilson's disease is a treatable and preventable disorder, early clinical diagnosis and screening of asymptomatic siblings is mandatory.
1561010##1992-3-1##Inherited copper toxicity in Long-Evans cinnamon rats exhibiting spontaneous hepatitis: a model of Wilson's disease.##The copper concentrations in organs of developing Long-Evans Cinnamon (LEC) rats (2 d to 13 mo) were measured to elucidate the pathogenesis of their hereditary hepatitis. Hepatic copper contents of LEC rats were significantly higher than those of control rats (26 to 92 times higher). The subcellular distribution of hepatic copper indicated that the nuclear and large granular fractions had been saturated and the cytosol fraction contained about 70% of all the hepatic copper in LEC rats. The serum concentrations of copper and ceruloplasmin were significantly lower than those of control rats from the 4th wk (10-12% and 5-19%, respectively). Copper contents in kidney of LEC rats did not exhibit an increase over those of control rats until 12 wk, but then increased to nearly 40 times higher during fulminant hepatic failure. Accumulation of copper was not detected in the brain or small intestines of LEC rats until 13 mo. The hepatic copper concentration, its subcellular distribution, and serum copper concentration of F1 rats (LEC x Long-Evans Agouti) exhibited the same levels as those of Long-Evans Agouti rats. In addition to their similarity concerning inheritance of autosomal recessive means and clinical course, we found causality relating copper accumulation to the pathogenesis of the disease. We propose that LEC rats will be the most promising animal model for the study of Wilson's disease.
1579693##1992-3-1##[Wilson's disease. A retrospective analysis of 12 cases].##We reviewed retrospectively 12 patients with Wilson's disease diagnosed during a 16-year period (1974-1989). The prevalence rate was 0.6 per 100,000 individuals. Clinical onset was hepatic (50%) or neurologic (50%), but at diagnosis (6.4 years later) 67% of patients showed several clinical manifestations: hepatic, neurologic, renal and haematologic. Among the essential diagnostic indices we find false negative results for Kayser-Fleischer ring (25%), serum ceruloplasmin (8%) and total serum copper (34%). Ten patients were treated with penicillamine. This drug was effective and well tolerated, although one patient (10%) developed membranous nephritis and required to change successively to BAL and trien. In a 61 months follow-up 5 patients (42%) died from severe liver failure. Patients with poor prognosis had a diagnostic delay and a liver failure degree significantly greater than patients with good prognosis. Our results suggest the following conclusions: a) in Spain the prevalence rate of Wilson's disease is near the lower reported rate; b) the early diagnosis of Wilson's disease is rare; c) diagnosis should be made only when several essential indices are positive; d) early hepatic transplantation showed carried out in patients with acute or chronic severe liver failure.
1595220##1992-3-1##[Wilson's disease and pregnancy].##The authors describe the case of a 27-year-old female patient with Wilson's disease who during penicillinamine treatment became pregnant and was delivered of a healthy infant. The diagnosis of Wilson's disease was confirmed by the finding of a Kayser-Fleischer ring in the cornea and a concurrent serum ceruloplasmin concentration lower than 0.20 g/l. Unrecognized and untreated, the disease is associated with the development of organ complications which in the end prove fatal. On the other hand, early diagnosis and effective treatment throughout life can prevent liver and brain damage and thus enable the patient to live a normal life and women can have a healthy child.
1590017##1992-3-1##[Pathogenesis of Wilson's disease].##Wilson disease is due to a genetically determined impairment of copper excretion from liver into bile resulting in copper overload of the organism. The chromosomal defect and the primary defect of copper metabolism is not yet defined. When during the course of the disease the cytoplasmatic copper binding sites of hepatocytes are saturated, excess of &quot;free&quot; copper is accumulating. It induces liver cell damage and necrosis followed by the development of fibrosis and cirrhosis. The accumulation process of excess free copper in hepatocytes is accompanied by a redistribution into the lysosomal compartment of the cells as well as by release of free copper into blood. This increase of the free serum copper concentration leads during the course of the disease to an elevated copper burden of other organs. This results in a variety of symptoms, of which liver disease and neurologic disturbances are of major significance in regard to clinical presentation and prognosis of the patients.
1373211##1992-2-15##[Wilson's disease. A histological review of 7 patients and the value of histological copper positivity in relation to other hepatopathies].##
1574992##1992-2-1##Treatment of Wilson's disease: penicillamine or triene?##
1515762##1992-2-1##Oral zinc as initial therapy in Wilson's disease: two years of continuous treatment in a 10-year-old child.##Two years of continuous therapy promoted a significant overall amelioration in a 10-year-old boy affected by an hepatic form of Wilson's disease in which zinc sulphate was the sole therapy. In particular, liver function returned to normal and hepatic histology also improved. The parameters characterizing copper metabolism were kept under good control, and a decrease in copper concentration was found in both erythrocytes and liver. The copper balance study performed during the 25th month of treatment showed that oral zinc was still efficiently inhibiting the intestinal absorption of copper. No side effects have been reported so far.
1599534##1992-2-1##Thiomolybdates in the treatment of Wilson's disease.##
1370780##1992-2-1##Detailed evaluation of evoked potentials in Wilson's disease.##Detailed evoked potentials (EPs) were studied in 52 patients (28.7 +/- 11.9 years) with Wilson's disease (WD). Various peak latencies, interpeak latencies and amplitudes of somatosensory, auditory brain-stem and visual EPs were significantly abnormal in the group of 28 neurologically symptomatic patients as compared to controls. Interhemisphere latency and amplitude differences tended to be increased without reaching significance, indicating a symmetrical rather than focal subclinical brain involvement. Selected conduction times of at least 1 EP modality were prolonged in all 4 patients with severe, in 16 of 18 with moderate, in 4 of 6 with mild, and in 4 of 24 patients without neurological symptoms. Auditory brain-stem and somatosensory EPs were more frequently prolonged than visual EPs (more abnormalities with check sizes of 13 than 54 min of arc). Cortical somatosensory EPs correlated well (P much less than 0.01) with either Fz or earlobe reference.
1552305##1992-2-1##Evoked potentials in patients with non-neurological Wilson's disease.##In Wilson's disease neurological manifestations result from the damage in the basal ganglia, even if a widespread degeneration of the brain occurs. The few studies performed using evoked potentials with the aim of identifying subclinical dysfunction in the three major sensory pathways have never shown abnormalities in patients without neurological manifestations. To verify this observation we studied 12 patients suffering from Wilson's disease in a pre-neurological stage by using pattern visual evoked potentials (VEPs), somatosensory evoked potentials (SEPs) to median nerve stimulation and brainstem auditory evoked potentials (BAEPs). Four of these patients had not yet been treated with penicillamine or trientine (triethylenetetramine dihydrochloride), while the remaining 8 patients were on treatment for at least 1 year. In 3 patients of this second group and in 1 patient of the first group we observed a significant (3 SD over the mean) increase in P100 wave latency, while SEPs and BAEPs were found to be abnormal in only 1 patient, respectively.
1314321##1992-2-1##Hepatocellular carcinoma in a case of Wilson's disease.##Hepatocellular carcinoma has rarely been reported in Wilson's disease, particularly in women. We describe the case of a female patient who was diagnosed with Wilson's disease at the age of 39 years, after presenting with severe neurological symptoms. She had significant neurological improvement following penicillamine therapy and succumbed to hepatocellular carcinoma at the age of 72 years, following 33 years of penicillamine therapy. The patient described here was the oldest and only the third female patient with hepatocellular carcinoma complicating Wilson's disease to be reported in the literature.
1545578##1992-2-1##Kayser-Fleischer rings in a patient with basal cell carcinoma: fortuitous diagnosis of presymptomatic Wilson's disease.##Kayser-Fleischer rings were detected during a routine ophthalmologic workup in a 25-year-old man with basal cell carcinoma of the eyelid. Although the importance of this association is uncertain, the routine preoperative evaluation of basal cell carcinoma led to the presymptomatic diagnosis of Wilson's disease. These disorders are discussed, as are the benefits of a multidisciplinary approach for the diagnosis and management of medical problems.
1625648##1992-2-1##Anesthetic management for cesarean section in a patient with Wilson's disease.##We describe the successful management of a 28-year-old female with Wilson's disease who developed gestational pre-eclamptic hypertension (GPH) during pregnancy and who required an urgent cesarean delivery. We discuss the rationale of using magnesium sulphate prior to induction and the importance of adequate monitoring is selecting an anesthetic technique based on the pathophysiology of the disease.
1553834##1992-2-1##[Diagnostic characteristics of acute hepatic failure in fulminant Wilson's disease].##
1736635##1992-1-1##Pathological case of the month. Wilson's disease (hepatolenticular degeneration).##
1458566##1992-1-1##Liver transplantation in Taiwan: the Chang Gung experience.##Between March 1984 and February 1991, six orthotopic liver transplantations were performed at the Chang Gung Memorial Hospital in Taiwan. The indications for transplantation were Wilson's disease (5 patients) and biliary atresia (1 patient). Donors and recipients were matched only for size and ABO blood group compatibility, and the recipient operations were performed without the use of a venovenous bypass. Arterial reconstruction was carried out by end-to-end hepatic artery anastomosis (4), thoracic aortic conduit (1), or interposition of an iliac artery graft (1), whereas biliary reconstruction was accomplished by a choledochocholedochostomy using a T-tube stent (4) or a choledochocholedochostomy using an external cholecystostomy without stenting (2). Biliary complications occurred in three patients, and all required additional surgery. The average duration of donor-liver cold ischemia, operating time, and blood loss during surgery were 7 h and 50 min (range, 4.5-9 h), 13.5 h (range, 11.8-17 h), and 4,385 ml (range, 750-12,000 ml), respectively. The immunosuppressive regimens included a cyclosporin-steroid combination (n = 2) and a triple-drug combination (n = 4). All except one of the surviving patients experienced at least one rejection episode that was reversed by a methyl-prednisolone bolus and/or recycle. One patient developed a primary cytomegalovirus (CMV) infection that responded well to Ganciclovir treatment. Two of the patients died, one of injuries sustained in a traffic accident 3 years after transplantation, and the other of massive upper gastrointestinal bleeding. The overall survival value at 3 months was 83%, and the follow-up period ranged from 3 months to 7 years. All of the survivors have achieved complete rehabilitation and currently enjoy an excellent quality of life with normal liver function. Although the present study involved a small number of cases, our results indicate that liver transplantation can be successfully achieved in a high proportion of patients with acceptable morbidity, mortality, and cost in an Asian setting. The extreme shortage of donor organs is currently the most important obstacle limiting the application of liver transplantation in Taiwan.
1576875##1992-1-1##Magnetic resonance imaging in hepatolenticular degeneration. Analysis of 9 cases.##Nine patients with biochemically proved Wilson's disease underwent magnetic resonance imaging (MRI) of the brain. Areas of abnormal signal, long T1 and long T2, caused by gliosis and edema were seen in the lenticula, thalami, caudatum, brain stem as well as in the dentate nuclei. The abnormalities were bilateral and symmetric. Asymmetric focal white matter lesions were noted in a few patients. Focal atrophies were seen in the head of caudatum. Symmetric cavitations were only seen in the lenticular nuclei. Acute progressive type (2 patients) was characterized by cavity formation, and chronic progressive type (7 patients) by gliosis, edema and focal atrophy.
1558988##1992-1-1##Pseudoxanthoma-elasticum-like skin changes induced by penicillamine.##The interference of penicillamine with collagen and elastin cross-linking can lead to wrinkling and anetoderma-like lesions in flexural areas as well as fragility and hemorrhagic blisters in pressure areas. These changes are seen primarily in patients with Wilson's disease or cystinuria who are on long-term therapy. This is a report of a patient with cystinuria on long-term, high-dose penicillamine who developed pseudoxanthoma-elasticum-like lesions. Coalescent yellow papules with a 'plucked-chicken skin' appearance were seen in the axillae and on the neck while redundant skin folds were noted in the anterior axillary line and lower buttocks. By light and electron microscopy, involved and uninvolved skin demonstrated 'lumpy-bumpy' dermal elastic fibers with no calcium deposition. These histologic changes are similar to those previously described in patients with penicillamine-induced skin lesions.
1307347##1992-1-1##Wilson's disease treatment by triethylene tetramine dihydrochloride (trientine, 2HCl): long-term observations.##Wilson's disease is an autosomal recessive disorder characterized by an accumulation of a toxic amount of copper in the body. Triethylene tetramine dihydrochloride (trientine, 2HCl) is a new chelating agent that may be effective in the removal of excess copper but long-term efficacy has not yet been investigated. Here we report the use of trientine over more than 8 years in 2 patients with Wilson's disease who could not tolerate D-penicillamine. We found no significant side effect, except a decreased serum iron concentration without clinical symptoms of anemia. In annual examinations at a steady state, the serum copper levels remained below 20 micrograms/100 ml. The 24-hour urinary copper excretion was less than that found using D-penicillamine, while the basal copper excretion, after 5 days abstinence from trientine, was maintained below 100 micrograms/day. Both hepatic and neurological manifestations except bulbar symptoms were recovered without any initial deterioration.
1563446##1992-1-1##Regional cerebral glucose consumption measured by positron emission tomography in patients with Wilson's disease.##Using positron emission tomography (PET), the regional cerebral metabolic rate of glucose consumption (rCMRGlc) was measured in 14 patients with Wilson's disease (WD) and 23 normal subjects. In WD patients, cerebellar, striatal and--to a lesser extent--cortical and thalamic rCMRGlc were significantly decreased compared with controls. Striatal rCMRGlc was significantly reduced in those 4 patients who had recently started decoppering therapy as compared with striatal rCMRGlc measured in those 10 patients with longer duration of medication. Caudate rCMRGlc correlated significantly with various signs of extrapyramidal dysfunction. Cerebellar, thalamic and cortical rCMRGlc correlated significantly with the severity of pyramidal signs. These data indicate that the PET measurement of rCMRGlc may be a useful tool to evaluate cerebral involvement in WD and to monitor the response to treatment.
1345101##1992-1-1##Orthotopic liver transplantation in liver-based metabolic disorders.##The efficacy of orthotopic liver transplantation (OLT) in the management of more common liver-based metabolic disorders associated with severe liver damage, alpha-1-antitrypsin deficiency (PIZZ), Wilson disease and tyrosinaemia has been demonstrated and indications defined. An early mortality in excess of 15% and finite resources limit its use. Phenotypic heterogeneity make the precise indication in other disorders less certain. In disorders in which endstage liver disease is less frequent such as cystic fibrosis, haemochromatosis and galacosaemia it has been a very effective therapy. It has been used with encouraging results in disorders in which the liver is structurally normal such as Crigler-Najjar type I, primary hyperoxaluria type I and primary hypercholesterolaemia. In these it should be performed before there is permanent damage to brain, kidneys or heart. OLT in the short term prevents hyperammonaemic coma in urea cycle defects and may prevent extrahepatic disease in glycogen storage disease type IV. Its limitation in reversing all metabolic effects in these and other disorders is discussed. It is ineffective in protoporphyria or Niemann Pick disease type II (Sea Blue Histiocyte syndrome) in which the transplanted liver acquires the lesions of the initial disorder and extrahepatic features progress. Early referral provides optimum circumstances to assess the benefits of OLT as compared with those of other forms of management and to achieve transplantation at the ideal time. The place of OLT in management will require constant review as metabolic disorders are better defined, new forms of therapy evolve and as techniques of liver transplantation and modes of immunosuppression improve.
1612893##1992-1-1##Who should log SHIPS? The accuracy of Scottish Hospital Morbidity Data for Wilson's disease.##We have studied the accuracy of the hospital diagnostic data for Wilson's disease (WD) in Scotland. The computerised records of the Scottish Hospital In-Patient Statistics provided information on 41 patients, coded as having been discharged from hospital with a diagnosis of WD. Review of the patients' case notes revealed that 12 (29.6%) did not have WD, although half of these cases had 'query Wilson's disease' on the discharge summary or letter. In the other six cases, errors arose due to miscoding by the medical records staff.
1370162##1992-1-1##D-penicillamine prevents the development of hepatitis in Long-Evans Cinnamon rats with abnormal copper metabolism.##The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatocellular carcinoma. Because we found a corresponding gross copper accumulation in the liver of the rats, we examined whether the development of hepatitis in our rat system could be prevented by administration of D-penicillamine. D-Penicillamine is a copper-chelating agent and one of the drugs effective for human Wilson's disease, in which abnormal copper metabolism is also observed. The results show that D-penicillamine treatment inhibited the elevation of serum transaminases, suppressed abnormal histological changes in the liver and completely prevented the onset of hepatitis in the Long-Evans Cinnamon rats. We further found that the copper concentration in the liver and serum copper and ceruloplasmin levels were decreased, whereas the urinary copper level was increased in the D-penicillamine-treated Long-Evans Cinnamon rats. These findings demonstrate that the pathogenesis of hereditary hepatitis in Long-Evans Cinnamon rats is due to abnormal copper accumulation in the liver.
1356168##1992-1-1##DNA-based presymptomatic diagnosis of Wilson disease.##Investigation using DNA markers in a family with Wilson disease revealed that an apparently normal child of 10 years of age with non-diagnostic copper biochemistry had the disease. The procedure used linked restriction fragment length polymorphic markers. Demonstration of increased liver copper concentration from a liver biopsy confirmed the diagnosis and the child was started on chelation therapy. Two other asymptomatic siblings were shown, using the same techniques, not to have the disease. Similar analysis was carried out on another family with just one index case.
1548626##1992-1-1##Use of 64copper measurements to diagnose canine copper toxicosis.##Inherited canine copper toxicosis is a serious problem in Bedlington terriers and West Highland White terriers, and may also be a problem in other less-studied breeds. Affected dogs become ill at midlife with progressive and ultimately fatal liver disease. Treatments for removal of copper and prevention of copper accumulation are available, but are most effective if begun before the dog becomes ill. Until recently diagnosis has not been available until the dog is 1 year of age, and then only by an invasive liver biopsy with determination of liver copper concentration. The authors studied the use of 64copper for early diagnosis of canine copper toxicosis. Two procedures were evaluated. The first involved measuring the concentration of 64copper in blood 24 hours after oral administration of the radioisotope. At this time, 64copper was associated primarily with ceruloplasmin secreted into the blood by the liver. This procedure is useful in the diagnosis of the human counterpart, Wilson's disease. However, the authors found it to be nondiscriminatory between affected and unaffected dogs. In contrast, the second procedure, which involved measuring 64copper excreted in stool during 48 hours after an intravenous dose of radioisotope, yielded results that differentiated most affected and unaffected dogs.
1532631##1992-1-1##Marked reduction of striatal dopamine D2 receptors as detected by 123IBZM-SPECT in a Wilson's disease patient with generalized dystonia.##[123I]iodobenzamide-single photon emission computed tomography (IBZM-SPECT) was employed to study the distribution of dopamine D2 receptors in a patient with biochemically proven Wilson's disease presenting with generalized dystonia. IBZM is a dopamine D2 receptor antagonist with high affinity and specific binding to basal ganglia detectable by SPECT. IBZM-SPECT in this patient (age, 20 years) displayed a striatum to frontal cortex ratio of 1.2 compared to 1.55 +/- 0.05 (mean +/- SD) in normal controls (n = 7; mean age, 53.3 years). In parallel with this finding, MRI with heavily T2-weighted sequences showed atrophy and low signal intensity changes of the basal ganglia. There was no improvement of dystonia after a subcutaneous injection of apomorphine. In contrast, IBZM-SPECT of a neurologically asymptomatic Wilson's disease patient (age, 21 years) displayed a striatum to frontal cortex ratio of 1.6. The MRI scan of this patient was normal. It is suggested that the observed apomorphine-unresponsive generalized dystonia in this Wilson's disease patient is related to striatal lesions proven by IBZM-SPECT and MRI.
1630615##1992-1-1##Atypical MR presentation of Wilson disease: a possible consequence of paramagnetic effect of copper?##A 53-year-old patient with Wilsons's disease and without autonomic dysfunction presented on T2-weighted MR study an atypical decreased signal intensity of the putamina and the caudate nuclei. Possible explanations of such a signal abnormalities are discussed.
1331967##1992-1-1##[Cirrhosis and cirrhogenic diseases in Tunisian children. Multicenter study of 65 cases].##Over a period of 10 years, 65 cases of hepatic cirrhosis and cirrhogenic disease have been observed in five Pediatric Centers in mid Tunisia. The age of the patients ranged from 30 days to 14 years. The main etiology was biliary cirrhosis (24 cases) followed by post-hepatic cirrhosis (15 cases). Eight cases had a metabolic origin, which was Wilson's diseases in five cases. Three children had cirrhosis of a pre-hepatic origin. In 15 children, the liver biopsy showed the presence of cirrhosis but the etiology could not be found. Preventive measures are needed in order to reduce the frequency of cirrhosis among Tunisian children: 1) early recognition of biliary atresia, 2) vaccination against hepatitis B virus of at risk neonates and children, 3) Genetic counselling and search for familial cases when cirrhosis of metabolic origin is identified, particularly Wilson's disease.
1666959##1991-12-1##[Interaction of molecular forms of ceruloplasmin with specific membrane receptors from healthy persons and patients with hepatolenticular degeneration].##The ceruloplasmin (CP) interaction with the specific receptor localized on the erythrocyte membrane of healthy donors and of patients with hepatolenticular degeneration (HLD) was studied by using Scatchard analysis. It was found that in patients with the Wilson's disease the CP receptor is unaffected by the pathological process. The molecular mass of the erythrocyte receptor of CP is about 130 kDa. The CP binding to the specific receptor is followed by limited proteolysis of the latter. No CP binding to the receptor occurs in the presence of serine protease inhibitors. The CP-like protein previously detected in the sera of Wilson gene carriers can specifically interact with the CP receptor.
1773964##1991-12-1##Wilson's disease in Scotland.##The prevalence and clinical features of Wilson's disease in Scotland were investigated. Thirty three cases were identified but adequate information was available on only 28. In 1989, the prevalence rate was 4 per million. Ten patients with a mean (SEM) age of 18 (1.9) years presented with neurological symptoms, 12 patients aged 14 (1.7) years presented with hepatic symptoms, and six patients aged 12 (0.9) years were asymptomatic siblings of patients with Wilson's disease. Nine (56%) of the 16 patients who underwent liver biopsy on presentation were found to have cirrhosis. Penicillamine treatment was stopped in nine patients because of: abnormal peripheral blood count (6), rash (2), and patient's own choice (1). Nineteen patients were alive in 1989 -12 were well, one had chronic liver failure, four chronic neurological disabilities, and two had both chronic liver failure and neurological disabilities. Twelve patients died from: complications of chronic liver failure (2), acute liver failure (4), pneumonia associated with immobility (4), and other causes (2). Several patients who died had received incomplete medical supervision.
1929042##1991-11-1##Wilson disease: clinical presentation, treatment, and survival.##
17590808##1991-11-1##Wilson's disease in Saudi Arabia: Report of a Saudi Arab family.##A Saudi family with Wilson's disease (hepatolenticular degeneration) is described. The index case presented with anicteric hepatitis and hydrops of the gallbladder. Neurological involvement appeared later. The diagnosis of Wilson's disease was based on the presence of Kayser-Fleischer rings, a low serum ceruloplasmin level, and an elevated urinary copper concentration. Histological examination of the liver biopsy specimen revealed active cirrhosis. Acute hepatic failure developed during D-penicillamine therapy. Continuation of the drug at a lower dose, along with other supporitve measures, was successful in reversing this. After three years of therapy, the index patient's neurological signs disappeared, and liver function and gallbladder size and function returned to normal. Family screening revealed that three other siblings have the disease, and all have been treated with D-penicillamine. The parents are related but are asymptomatic. An unusual feature of the index case was the presence of a distended nonfunctioning gallbladder that reverted to normal with decoppering. Although D-penicillamine treatment possibly precipitated the acute hepatic failure, paradoxically it was also successful in treating it.
17590807##1991-11-1##Wilson's Disease.##
1810163##1991-11-1##Tongue dyskinesia as an early manifestation of Wilson disease.##A 15-year-old boy was diagnosed as having Wilson disease. He perceived involuntary tongue movement and speech disorder since March 1990. The tongue movements presented in the resting state and during action. It contracted transversely and bilaterally with an irregular frequency about 1 Hz. As a result, the sides of the tongue moved to form a narrow central groove. This was quite different from the tongue protrusion of tardive dyskinesia. His speech had imprecise consonants, monopitch, low pitch, low volume, harsh voice, and hyponasality. These suggested that tongue dyskinesia could be an early sign of Wilson disease and was not the main cause of his dysarthria.
1794220##1991-11-1##Pathophysiology and treatment of Wilson's disease.##The pathophysiology, symptomatology, and treatment of Wilson's disease are reviewed, and new approaches to drug management are discussed. Wilson's disease is a rare, autosomal recessive disorder that occurs between the ages of 6 and 60 years. Disturbances in copper metabolism may result in the accumulation of excess copper in the liver, the basal ganglia of the brain (lenticular degeneration), the kidneys, the cornea (Kayser-Fleischer rings), and other tissues. The diagnosis of Wilson's disease is frequently overlooked; nonspecific symptoms and multisystem involvement may mimic other disease states, such as neurologic and psychiatric disorders, and hemolytic anemia. Screening tests for Wilson's disease include 24-hour urinary copper levels, serum ceruloplasmin and copper assays, radioactive uptake of 64Cu, and liver biopsy. Current methods of therapy include the use of a chelating agent--penicillamine or trientine--for initial rapid decoppering. Penicillamine therapy has been associated with many adverse reactions, including worsening of the neurologic symptoms of the patient. Zinc is a useful agent for maintenance therapy. Investigational studies exploring the use of ammonium tetrathiomolybdate for initial rapid decoppering have shown promising results. Unless it is recognized and treated, Wilson's disease can cause severe symptoms and, ultimately, death. Initial rapid decoppering with chelating agents, such as penicillamine and trientine, followed by lifelong maintenance therapy with zinc is the current method of treatment.
1940587##1991-11-1##Treatment of Wilson's disease with zinc. IX: Response of serum lipids.##Zinc therapy in Wilson's disease is a lifelong treatment to prevent reaccumulation of copper. Previous reports have shown that in normal male subjects, zinc ingestion has reduced high-density lipoprotein cholesterol level. This finding raises the possibility that lifelong zinc therapy could be atherogenic. In the present work, the effects of zinc therapy on serum lipids over a period of years is evaluated in patients with Wilson's disease. Zinc therapy reduces total cholesterol level by about 10% in both sexes and reduces high-density lipoprotein cholesterol level by about 20% in male patients. The mechanisms of these interesting effects of zinc on cholesterol metabolism are unknown. The coronary heart disease risk factor is not changed significantly by zinc therapy in either sex, and further, it remains below average in these patients after zinc therapy. We conclude that zinc therapy in Wilson's disease is not atherogenic.
1940586##1991-11-1##Diagnosis and characterization of presymptomatic patients with Wilson's disease and the use of molecular genetics to aid in the diagnosis.##Wilson's disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. Although fatal if untreated, the condition can be treated effectively. Autosomal recessive inheritance indicates that siblings of affected patients are at 25% risk of having the disease. If they are diagnosed prior to becoming symptomatic, affected siblings can be kept free of symptoms by prophylactic therapy. In this paper we have examined the utility of copper-related variables, along with other clinical and molecular findings, in identifying those siblings of affected patients who should be further evaluated with a liver biopsy. Data are presented on a series of 13 presymptomatic patients in whom we have made the diagnosis of WD based on liver biopsy findings. Signs of liver disease were present in 12 out of 13 cases. The classic, noninvasive, screening approaches that we evaluated were not adequate to identify all cases of WD in this group of patients. These included positive Kayser-Fleischer (KF) rings, elevated liver serum alanine transferase, elevated urine copper, or elevated plasma nonceruloplasmin copper. We have introduced the use of molecular genetics for screening siblings of affected patients for WD. We show that a probe from the linked retinoblastoma (RB) gene can be very helpful in problem cases. However, at this time, the quantitative determination of liver copper concentration remains as the definitive diagnostic criterion.
1779232##1991-11-1##EEG spectral analysis and topographic mapping in Wilson's disease.##Computerized EEG spectral analysis and topographic mapping were performed on 14 patients with Wilson's disease (WD) and 10 normal subjects of comparable ages. The predominant EEG changes in WD were diffuse but uneven topographic abnormalities with a decrease in alpha activity, an increase in theta and delta activities, and a low voltage background mainly in the alpha frequency band. Eleven patients (80%) had at least one of the above EEG changes. Furthermore, topographic mapping provided more clearly defined foci of slowing and epileptiform activity. Patients with cerebral white matter involvement, akinetic-rigid syndrome, dystonia, or psychiatric symptoms tended to have more abnormal EEGs. It is concluded that EEG changes in WD are common and the quantitative EEG analysis can increase the likelihood of detecting mild or even subtle EEG abnormalities in individual patients as well as in the patient group.
1913431##1991-10-15##Wilson's disease presenting as Heinz-body hemolytic anemia.##
1752285##1991-10-1##Copper metallothionein in patients with hepatic copper overload.##We studied the Cu-MT present in the hepatic cytosol obtained from 7 patients suffering from conditions associated with hepatic Cu overload (Wilson's disease, biliary atresia, familial cholestatic cirrhosis). Since chromatographic methods appropriate for the isolation of Zn- and Cd-MT were unsuitable for Cu-MT, we developed an indirect procedure for the estimation and resolution of the latter. This procedure involved the preparation of apo-MT and its reconstitution to holo-MT with Zn or Cd. Three predominant isoforms of MT were present in all specimens. Our results indicate that at most 36 +/- 5% of the Cu present in the 10 kDa fraction of cytosol is bound to MT in the liver of patients with hepatic copper overload.
1821256##1991-1-1##The psychiatric presentations of Wilson's disease.##We reviewed the records of 42 patients with Wilson's disease participating in a zinc acetate treatment protocol and interviewed 17 of them. Five of the patients studied were asymptomatic. A significant number of symptomatic patients (64.8%) reported psychiatric symptoms at the time of initial presentation. These symptoms were severe enough to warrant psychiatric intervention in almost half of all symptomatic patients before the diagnosis of Wilson's disease was made. Personality changes, particularly irritability and aggression, were most commonly described (45.9%), followed by depression (27%). Cognitive changes, anxiety, psychosis, and catatonia, while less frequent, also occurred. These data underscore the need to include Wilson's disease in the differential diagnosis of psychiatric disorders.
1749451##1991-10-1##[Neurogenetics--the challenge for neurology. 1. Neurogenetic diseases].##Progress in molecular genetics has provided insight into a number of neurogenetic disorders. The chromosomal location of the genes for Huntington's disease, Wilson's disease, myotonic dystrophy and Friedreich's ataxia are now known. In families affected by these illnesses, linkage analysis can now be employed for presymptomatic or prenatal diagnosis. The genes for Duchenne and Becker muscular dystrophy and neurofibromatosis I have been cloned and sequenced, allowing the direct analysis of the genetic defect in many cases, and thereby providing further insight into the pathophysiology. In addition, the classification of several neurogenetic diseases, such as the hereditary motor and sensory neuropathies or the spinal muscular atrophies can now be based on the chromosomal location of the affected gene(s).
1923998##1991-10-1##Managing chronic hepatitis. Recent advances in diagnosis and treatment.##A variety of effective therapies are now available for chronic hepatitis of various causes. Most patients with autoimmune chronic active hepatitis respond to immunosuppressive therapy, and those with Wilson's disease respond to copper-chelating therapy. Patients with drug-induced chronic hepatitis improve with cessation of the medication. About 30% to 40% of patients with chronic hepatitis B infection respond to interferon alfa, as do about 50% of those with chronic hepatitis C infection.
1821465##1991-10-1##[Distal renal tubular acidosis in patients with Wilson's disease].##Renal affection is part of the clinical picture of developed Wilson's disease. The most frequent sign of affection of the distal nephron is distal tubular acidosis (DRTA), more frequently its latent form with a normal systemic pH, but inability to reduce the urinary pH below 5.5 after an acid load. More detailed assessment of the type of this disorder was not made so far. To elucidate in greater detail the pathogenesis of DRTA in Wilson's disease the authors examined renal acidification in 13 patients with bioptically verified Wilson's disease, using three acidification tests: 1) the test involving oral administration of calcium chloride (CaCl2), 2) the test involving infusion of sodium sulphate (Na2SO4) and 3) the test using an infusion of NaHCO3. In none of the examined patients with Wilson's disease manifest (complete) DRTA was found with systemic acidosis, however, in five patients latent (incomplete) DRTA was revealed, i.e. after administration of CaCl2 the pH of urine did not decline below 5.5. Patients with Wilson's disease and DRTA differed from patients with Wilson's disease and normal renal acidification by the age at the time of assessment of the diagnosis (30.4 +/- 3.6 vs. 20.75 +/- 2.14 years, p less than 0.02) and the duration of the disease (i.e. the time from assessment of the diagnosis to the acidification examination: 4.6 +/- 4.86 vs. 15.38 +/- 2.40 years, p less than 0.01). In three of four patients with Wilson's disease and DRTA who were given Na2SO4, after its administration the pH of urine did not decline below 5.2.(ABSTRACT TRUNCATED AT 250 WORDS)
1950459##1991-9-1##Does orthotopic liver transplantation heal Wilson's disease? Clinical follow-up of two liver-transplanted patients.##Two patients with Wilson's disease (WD) underwent orthotopic liver transplantation, one for subacute liver failure and the other for severe oesophageal haemorrhage. After transplantation both patients fully recovered within five months, and copper metabolism returned to normal. Follow-up examinations were continued for 4 and 6 years. Clinical as well as electrophysiological testing in these two patients yielded better results than in most of 12 WD-patients being conventionally treated for a similar period or even longer.
1804033##1991-9-1##[Advances in the treatment of the dystonias].##Except in Wilson's disease, few secondary dystonias are susceptible to benefit from an aetiological treatment. The somatic distribution of dystonia often determines the therapeutic strategy. Thus, stereotactic surgery may be the treatment of choice for hemidystonia while anticholinergic medication may alleviate generalized dystonia, particularly in childhood. Finally, local infiltrations of botulinum toxin are particularly useful for various forms of local and segmental dystonia. Certain subsyndromes as myoclonic dystonia, levodopa sensitive dystonia and paroxysmal choreoathetosis may benefit from relatively specific treatment strategies.
1959841##1991-9-1##[Abnormal hepatic copper accumulation and its significance in LEC rats developing spontaneous hepatitis and hepatoma].##The LEC rat is a mutant inbred strain isolated from Long-Evans rats, which spontaneously develops hepatitis and hepatoma with high frequency. In this study, copper profiles of LEC rats, including copper concentration in the liver and concentrations of copper and ceruloplasmin in the serum, were investigated. It was found that copper accumulated in the liver of LEC rats immediately prior to the onset of hepatitis with a concentration of more than 50 times that of normal LEA rats, and serum concentrations of copper and ceruloplasmin decreased markedly, which resembled biochemically characteristic features of human Wilson's disease. Administration of d-penicillamine (100 mg/Kg/day p. o), a chelating agent, reduced the hepatic copper level and completely inhibited the development of hepatitis in LEC rats. Copper also accumulated in both cancerous and non-cancerous liver tissues of three 29-month old male LEC rats which had spontaneously developed hepatocellular carcinomas. These findings suggest that the hepatitis in LEC rats is caused by copper toxicity, and that the abnormal copper metabolism may be involved in hepatic carcinogenesis in the LEC rats. Therefore, it is considered that the LEC rat will provide a promising animal model for not only elucidating the pathogenesis of Wilson's disease and developing treatment strategies of the disease, but also for studying the role of copper in hepatic carcinogenesis.
1940984##1991-9-1##Wilson's disease: normalisation of cortically evoked motor responses with treatment.##A newly diagnosed patient with Wilson's disease is reported in whom the only clearly pathological neurophysiological findings before treatment were abnormal electromyographic (EMG) responses evoked by transcranial magnetic brain stimulation. Serial examinations over 10 months following commencement of treatment with D-penicillamine revealed normalisation of EMG responses. Pathophysiologically, the initially abnormal EMG responses probably resulted from reversible impairment of impulse propagation along cortico-motor-neuronal pathways and/or a reduced excitability of cortical cells due to impaired function of the basal ganglia.
1803161##1991-9-1##[Clinical masking of Wilson's disease in practice].##
1870819##1991-9-1##Recurrent abortion and the diagnosis of Wilson disease.##We describe the first patient with Wilson disease and recurrent abortion who was effectively treated with oral zinc for both conditions. Between the ages of 21-26, this patient experienced seven successive unexplained abortions. At age 27, neurologic signs and liver function disturbances appeared. Wilson disease was diagnosed when Kayser-Fleischer rings were detected in the cornea. Decoppering therapy was instituted with zinc sulfate per os. By the age of 31, hepatic and neurologic signs had vanished. The patient conceived, and after an uncomplicated eighth pregnancy she delivered her first healthy child. Two years later, a ninth pregnancy was equally successful. The chance that Wilson disease may be the cause of recurrent abortion is small. However, because the disease is fatal if left untreated and because it is an underdiagnosed disease, we recommend screening for Wilson disease in cases of unexplained recurrent abortion when family history demonstrates consanguinity or neurologic, psychiatric, and/or liver disorders. A strategy to this end is proposed.
1872365##1991-8-1##Pregnancy and Wilson's disease.##
1884127##1991-8-1##Unusual magnetic resonance findings in Wilson's disease.##
1679032##1991-8-1##Esterase D and retinoblastoma gene loci are tightly linked to Wilson's disease in Chinese pedigrees from Taiwan.##Wilson's disease (WD) is a rare autosomal recessive disorder and has been mapped to the long arm of chromosome 13 (q14.1). We have analyzed the segregation of esterase D (ESD) and retinoblastoma (RB) gene loci in ten families of Chinese WD subjects living in Taiwan. The polymorphic information content (PIC) for ESD and RB was 0.18 and 0.31, respectively. We confirmed a tight linkage between these loci and WD with a lod score of 3.33 by multipoint linkage analysis. The data from this limited number of pedigrees also suggested the following order: centromere-WD-RB-ESD or centromere-ESD-RB-WD. ESD in conjunction with RB polymorphism would be useful in prenatal and presymptomatic diagnosis, as well as in carrier detection in informative pedigrees.
1919612##1991-8-1##Neurological and neuropsychiatric spectrum of Wilson's disease: a prospective study of 45 cases.##Forty-five patients with Wilson's disease (WD) were prospectively studied: 27 had neurological deficits, 12 hepatic signs, and 6 were asymptomatic. Kayser-Fleischer rings occurred in 23 of the neurological patients and in only 4 of the hepatic patients. Neurological features were extremely variable with respect to frequency and severity. Most frequent were dysdiadochokinesis (25 patients), dysarthria (23), bradykinesia (17), and posture tremor (14). Fifteen, mainly long-term treated patients, presented with rather discrete neurological abnormalities which predominantly consisted of dysarthria and various forms of tremor. Eight patients had a parkinsonian type of neurological WD associated with signs of an organic mood syndrome. Three patients were predominantly hyperkinetic, presenting with dystonic and choreatic movements. In 1 patient, ataxia was the predominant neurological feature. There was a clear-cut correlation between the severity of neurological impairment and the restriction in functional capacity. Nine patients were not able to engage in salaried employment or were retired. Psychiatric symptoms and behavioural disorders were common, varying from mild personality and psychological disturbances to severe psychiatric illness resembling psychotic disorders and major depressive syndromes. Significant mental deterioration was not found in the patients. Disturbances of mood were observed in 12 patients, all of whom had neurological abnormalities. There was a history of an attempted suicide in 7 patients, and a history of an organic delusional syndrome in 3.
1940953##1991-8-1##Penicillamine treatment of Wilson's disease and optic neuropathy.##
1940945##1991-8-1##Treating organic abulia with bromocriptine and lisuride: four case studies.##Abulia refers to an impairment of will, or the inability to initiate behaviour and action. There are reports of successful treatment of akinetic mutism, the most severe form of abulia, with bromocriptine. Four case studies are presented describing the successful treatment of abulia at a lesser severity than akinetic mutism with bromocriptine. Abulia was caused by brain damage due to alcohol in two cases, Wilson's disease and basal ganglia infarct in one each. Maximum bromocriptine dose varied from 25-70 mg. All improved considerably. Withdrawal or reduction of medication in three produced deterioration. The prescription of a neuroleptic drug had a similar effect in the fourth. One patient with a previous history developed a depressive relapse and so the drug was withdrawn and lisuride introduced. This produced a similar improvement. These cases highlight the value of identifying the syndrome of organic abulia and suggest that dopamine agonists may have a place in its treatment, though controlled studies are needed.
1838142##1991-8-1##SPECT imaging of dopamine D2 receptors with 123I-IBZM: initial experience in controls and patients with Parkinson's syndrome and Wilson's disease.##123I-(S-)-2-hydroxy-3-iodo-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl]-benzamide (123I-IBZM) is a highly selective CNS D2 dopamine receptor ligand suitable for SPECT. This study reports on IBZM-SPECT findings in 60 patients including eight controls and 52 patients presenting with disorders of the dopaminergic system, including idiopathic Parkinson's syndrome (IPS) (n = 18), Parkinson's syndromes of other aetiology (PS) (n = 24) and Wilson's disease (n = 10). SPECT was performed 2 h p.i. of 185 MBq 123I-IBZM. For semiquantitative evaluation basal ganglia to frontal cortex ratios (BG/FC ratios) were calculated. In controls BG/FC ratios of 1.55 +/- 0.05 S.D. were observed. Findings in IPS patients (BG/FC ratio: 1.51 +/- 0.05) were not different from controls. In PS patients striatal IBZM binding (BG/FC ratio: 1.35 +/- 0.11) was significantly (P less than 0.001) lower compared to the control and IPS groups. Asymptomatic patients with Wilson's disease presented normal IBZM binding. In those with neurologic symptoms IBZM fixation was markedly reduced. IBZM-SPECT has shown to be a suitable means for in vivo imaging of striatal dopamine D2 receptors in controls and various disorders of the dopaminergic system. Our preliminary data suggest that IBZM-SPECT is potentially useful for discriminating between IPS and PS (sensitivity: 100%; specificity: 83%). In patients with Wilson's disease IBZM accumulation seems to correlate with the presence of neurologic symptoms.
1715192##1991-7-1##Pancreatitis in acute hemolysis.##Forty cases of hemolysis (drop of hematocrit greater than 12%/12 h) were retrospectively analyzed for hyperamylasemia and pancreatic complications. In 15 subjects the serum amylase level was greater than 360 U/l, i.e., three times the normal range, in ten the amylase level exceeded 900 U/l. Excluding patients in circulatory shock and/or hepatic coma, acute pancreatitis as defined by an elevation of serum amylase and clinical signs (epigastric pain) was present in four, with additional ultrasound findings (pancreatic swelling) and/or laparatomy/postmortem findings in a further six subjects (total ten patients = 25%) with various causes of hemolysis: autoimmune hemolysis 2, microangiopathic hemolytic anemia 2, toxicemia, G-6-PDH deficiency, septic abortion, malaria, Wilson's disease, and hypophosphatemia, one case each. In all subjects acute renal failure and in seven an activation of intravascular coagulation was seen. Three patients died (33% vs 47% of all hyperamylasemic patients and 46% of the whole group), but none of the deaths was attributed to pancreatitis. Pancreatic postmortem findings were diffuse edema and patchy parenchymal necrosis in two cases and petechial bleeding in one case. We conclude that acute pancreatitis is a complication of massive hemolysis, occurring at a prevalence of above 20%. It may progress from diffuse edema and inflammation to focal necrosis, rarely if ever to gross hemorrhage, and does not contribute to the high mortality of massive hemolysis. Back pain in hemolysis might originate from the pancreas rather than from the kidneys.
1793699##1991-1-1##Wilson's disease, Kayser and Fleischer's sign and Walshe's treatment.##Wilson's disease is named after Kinnier Wilson (1878-1937), a famous British neurologist. It is an inherited condition, due to an excess of copper in the liver and brain. The mechanism is unknown, but the gene has been mapped to chromosome 13. The worldwide prevalence is about 30 per million. Patients present with liver disease and/or neuropsychiatric manifestations. Early diagnosis is crucial because there is an effective treatment. This treatment, usually with penicillamine, must be continued for life and without interruption. Liver transplantation may be lifesaving in patients with fulminant hepatitis, or with severe liver disease which is unresponsive to treatment.
1916955##1991-7-1##Kayser-Fleischer like ring in autoimmune chronic active hepatitis.##Kayser-Fleischer ring is considered an important diagnostic sign of Wilson's disease. We report a 9 year old boy with autoimmune chronic active hepatitis who exhibited Kayser-Fleischer like ring.
1800355##1991-7-1##Hydrops of the gall bladder in a child with Wilson's disease: a rare association.##
1800506##1991-7-1##Extensive CT scan abnormality in Wilson's disease.##A case of Wilson's disease with extensive white matter hypodensity, including in the basal ganglia, on CT scan is presented. Such extensive CT scan abnormality has not been described in Wilson's disease.
1681022##1991-7-1##Successful pregnancy after D-penicillamine therapy in a patient with Wilson's disease.##Infertility and amenorrhea are reported in most cases of Wilson's disease. In this report, we describe a case of Wilson's disease with pancytopenia and liver cirrhosis for over 4 years, without any specific treatment. After 2 years of D-penicillamine therapy, the patient became pregnant and delivered a liver mature female baby with a body weight of 2,800 g. Both before the pregnancy and after delivery, brainstem auditory evoked potential studies showed similar bilaterally abnormal prolongation in the III-V and I-V intervals. In visual evoked potentials, the P 100 latency was delayed bilaterally. Although serial evoked potential studies failed to show any improvement, a successful pregnancy was proven to be possible in a patient with Wilson's disease who had received regular D-penicillamine treatment.
1895127##1991-7-1##Mid-brain pathology of Wilson's disease: MRI analysis of three cases.##MRI scans were obtained from three patients with Wilson's disease, all of whom showed rigidity and dysarthria; two also showed tremor and dystonia. Two had been treated with D-penicillamine for seven and 14 years, respectively and their neurological abnormalities had improved, but the third patient had not been treated. T2-weighted MRI of the mid-brain in all three revealed the characteristic &quot;face of the giant panda&quot; sign, consisting of high signal intensity in the tegmentum except for red nucleus, preservation of signal intensity of the lateral portion of the pars reticulata of the substantia nigra and hypo-intensity of the superior colliculus. The clinical significance of these MRI abnormalities is discussed.
2067441##1991-7-1##Prostaglandin E1 for the treatment of primary non-function of the donor organ in liver transplantation.##
2067662##1991-7-1##Predictive testing for Wilson's disease using tightly linked and flanking DNA markers.##We studied DNA polymorphisms for five new chromosome 13 markers in 52 Wilson's disease (WD) families from Europe, North America, and the Middle East. There was significant evidence for linkage between the Wilson's disease locus (WND) and all the marker loci. Multilocus linkage analysis, using a genetic linkage map established from reference pedigrees, suggested that WND is most likely between D13S31 and D13S59, at distances of 0.4 and 1.2 centimorgans, respectively. Our results suggest that the chromosomal location of the Wilson's disease gene is the same in all families from the populations studied. This evidence and the availability of many close, flanking, and polymorphic DNA markers make possible accurate and informative testing of potential carriers and WD homozygotes in families with at least one previously affected child. An advantage of a genetic linkage test over other laboratory methods for prediction of genotype in WD is that a reliable diagnosis can be made at a much earlier stage in life, including prenatally. In addition, DNA testing can be used in place of an invasive liver biopsy procedure to confirm a diagnosis in patients with borderline serum ceruloplasmin levels. Presymptomatic identification will also allow therapeutic intervention to prevent symptoms before irreparable liver or neurologic damage occurs. We describe the implementation of prenatal and preclinical diagnosis for two families with WD.
1674812##1991-6-8##Wilson's disease with neurological impairment but no Kayser-Fleischer rings.##
1904528##1991-6-3##Acute and subacute fulminant hepatic failure: the role of liver transplantation.##
1887758##1991-6-1##Mode of action of triethylenetetramine dihydrochloride on copper metabolism in Wilson's disease.##The drug of choice for the initial treatment of &quot;decoppering&quot; in Wilson's disease, an inherited disorder of copper metabolism, is the chelating agent D-penicillamine. In the case of harmful side-effects an alternative drug is triethylenetetramine dihydrocholoride (trien or trientine). Using the 24-h-urine excretion of copper and the oral copper loading test with copper-64, a double function for trien was found: trien increases the urine copper excretion and decreases the intestinal copper absorption respectively.
1810242##1991-6-1##CT hypodensity on cerebral white matter in Wilson's disease.##Wilson's disease in an autosomal recessive disorder of copper metabolism where systemic manifestations are secondary to the accumulation of copper in hepatic, nervous and other tissues. In CNS, the structural lesions most commonly found by CT scan are ventricular dilatation, cortical atrophy, basal ganglia hyperdensities, and brainstem and cerebellar atrophy. Degenerative changes of cerebral white matter seen on early anatomo-pathologic studies, but were almost never found on CT scan from recently described patients. We report a case of Wilson's disease with an unusually rapid deterioration where asymmetric low-densities in the subcortical white matter were disclosed by CT scan.
1726403##1991-6-1##Inhibition of copper absorption by zinc. Effect of histidine.##Copper and zinc interact at the intestinal mucosal level, affecting copper absorption. Amino acids, such as histidine, may affect the absorption of these two elements by chelating these cations. The two mechanisms could have additive potential. This possibility was investigated using a duodenal-jejunal single-pass perfusion procedure in anesthetized rats. Copper absorption and tissue retention from solutions containing 0.1 mM copper were determined in the presence of either no zinc or equimolar zinc, or at a zinc/copper ratio of 10/1, either without histidine or with histidine at a 10/1 or 20/1 ratio to copper. Copper removal from the intestinal lumen was decreased by zinc, and further reduced by increasing concentrations of histidine. There was a greater accumulation of copper in the small intestine, reaching a maximum with a 10-fold excess of histidine. With zinc at a 10/1 ratio to copper, the addition of a 10- or 20-fold molar excess of histidine further decreased the net uptake of copper from the perfusate while greater copper accumulation in the tissue occurred. Histidine thus enhances the inhibitory effects of zinc on copper absorption, suggesting the application of convergent mechanisms for diminishing copper uptake. This could be relevant for the treatment of Wilson's disease.
2045766##1991-6-1##Zinc sulphate therapy for Wilson's disease after acute deterioration during treatment with low-dose D-penicillamine.##A 30-year-old woman with Wilson's disease was treated with low-dose D-penicillamine. After 12 days, treatment was changed to zinc sulphate because of severe neurological deterioration. The patient subsequently improved within a few days. During a follow-up period of 20 months, the effectiveness of therapy was evaluated by measuring copper and zinc levels in plasma and urine, and by 64Cu-loading tests. We conclude that sulphate therapy may be a satisfactory alternative, even when rapid deterioration occurs in the early stages of D-penicillamine treatment.
1859188##1991-5-1##Intellectual functioning in treated Wilson's disease.##
2040480##1991-5-1##Undetectable caeruloplasmin values in a patient with autoimmune chronic active hepatitis.##Caeruloplasmin is an alpha 2 protein produced in the liver that is responsible for transporting copper in the blood. Caeruloplasmin values are usually high in patients with chronic liver diseases, including chronic active hepatitis: low values, however, are characteristic of Wilson's disease. The case of a 17 year old woman with very low caeruloplasmin values and chronic active hepatitis of the lupoid type is described. Steroid treatment resulted in an increase in the caeruloplasmin concentration and clinical improvement.
1889988##1991-5-1##[Orthotopic liver transplantation at the Island Hospital. Initial experiences 1985-1990].##Between 1985 and 1990 22 orthotopic liver transplantations (OLT) were realized in 19 patients. Active infection and diffuse splanchnic venous thrombosis were the only contra-indications to the intervention. Sixteen patients were transplanted electively; three had to be retransplanted urgently. Three patients had an urgent primary transplant. The incidence of surgical complications related to liver implantation was fair. One patient (5%) developed a late portal vein thrombosis; another patient (5%) had to be retransplanted because of hepatic artery thrombosis. All patients presented one or more major postoperative complications. All, but one, patients had a rejection of the allograft; five of them needed treatment with mono- or polyclonal antilymphocytic sera to reverse the rejection. One patient was retransplanted because of a hyperacute rejection. The six-month survival in this series is 68.5% (13 of 18 patients); one patient died 7 months post-OLT due to a neurological complication of her Wilson disease. Quality of life (from 6 to 64 months post-OLT) is excellent in the 12 long-term survivors. This small experience of the Bernese transplantation program shows that liver transplantation is a safe surgical procedure allowing excellent quality of life in a majority of patients.
1917681##1991-5-1##Assessment of the hypothalamic-pituitary-testicular function in male patients with Wilson's disease.##Sixteen male patients with Wilson's disease were studied to detect potential endocrine dysfunctions. There was no clinical evidence of feminization in any of the patients, and the patient group spanned most pubertal stages. Gonadotropin, testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate, androstenedione, estradiol, prolactin, cortisol, thyrotropin, and free thyroxine levels were determined. Low or borderline luteinizing hormone (LH) levels were present in most of the patients. In six of the adult patients, a standard gonadotropin-releasing hormone (GnRH) test was performed. Five of the six patients had blunted LH and follicle-stimulating hormone (FSH) responses to GnRH. Increased androgen levels were found in eight of the patients. Sex hormone-binding globulin was normal in eight of nine tested patients. Three single-dose human chorionic gonadotropin (hCG) stimulation tests of six adult patients showed normal responses. Three other patients who had elevated baseline levels responded with modest increases. Since liver disease is usually associated with decreased androgen levels, it is difficult to account for the elevated androgen levels. Both increased androgen levels and copper accumulation in the hypophysis could be responsible for the blunted GnRH response.
2022751##1991-5-1##Spontaneous hepatic copper accumulation in Long-Evans Cinnamon rats with hereditary hepatitis. A model of Wilson's disease.##Long-Evans Cinnamon (LEC) rats, an inbred strain of a mutant rat isolated from Long-Evans rats, develop hereditary hepatitis. To elucidate the role of copper metabolism in the development of the hepatitis in LEC rats, we examined the copper concentration in the tissues and serum levels of copper and ceruloplasmin. Copper concentration in the liver of LEC rats was over 40 times that of normal Long-Evans Agouti (LEA) rats, while the serum ceruloplasmin and copper concentrations in LEC rats decreased significantly. The hepatocytes of LEC rats show steatosis in cytoplasm and pleomorphism of mitochondria, resembling the histologic features of the liver in Wilson's disease. These findings suggest that the hereditary hepatitis in LEC rats is closely associated with copper toxicity, and may be dealing with a rat form of Wilson's disease. Thus the LEC rats will provide a unique and useful animal model for clarifying the mechanism and for developing treatment strategies for Wilson's disease and other abnormal copper metabolism in humans.
2063117##1991-5-1##[Metabolic cirrhosis (hemochromatosis, Wilson's disease, erythropoietic protoporphyria)].##The possibility of a metabolic chronic liver disease must always be borne in mind since in certain cases treatment can prevent the lesions from getting worse. The clinical and biochemical context should suggest either (1) genetic haemochromatosis when faced with high serum iron and ferritin levels and elevated transferrin saturation or with a suggestive clinical context (melanoderma, diabetes, hypogonadism, arthropathy, myocardiopathy); or (2) Wilson's disease in young subjects, especially in the presence of neurological and ocular signs or of haemolytic anaemia; or (3) porphyria in case of cutaneous manifestations caused by exposure to sun light. Hence the importance of full clinical examination in patients with chronic liver disease.
1852038##1991-5-1##[Diffuse liver parenchymal diseases: the value of MRI compared to sonography and CT].##29 patients with diffuse liver disease were examined by ultrasound, CT and MRI. MRI imaging was performed using T1-and t2-weighted spin-echo-sequences and fast gradient-echo-sequences. The paramagnetic contrast agent Gd-DTPA was applied intravenously (0.1 mmol/kg). In all patients with hepatitis MRI enabled exact liver biopsy by delineation of inflammatory changes in cases of chronic or focal hepatitis. CT and ultrasound were superior to MRI in the detection of focal or diffuse fatty degeneration. However, MRI enabled an exact differentiation of fatty changes from neoplasm. In cases of fibrotic changes the most accurate findings could be shown by MRI. In patients suffering from hemochromatosis MRI supplied additional information compared to CT and ultrasound revealing significant reduction of signal intensity due to reinforced enhancement of iron. Concerning Wilson's disease MRI showed a characteristic pattern of parenchymal changes. The application of Gd-DTPA in cases of diffuse liver disease adds supplementary information about perfusion of liver parenchyma, but its value for diagnostic accuracy is only secondary.
1926144##1991-5-1##Triethylene-tetramine (trien) therapy for Wilson's disease.##Triethylene tetramine (trien), in increasing dose from 1.0-2.0 g/day to 2.5-3.0 g/day, was used for 4 Japanese patients with Wilson's disease who were intolerant of D-penicillamine (D-PC). Before the treatment, urinary copper excretion (UCE) was 70-96 micrograms/day. UCE increased to 1,512-2,352 micrograms/day on the day of initial administration, and remained at levels between 350-1,100 micrograms/day, thereafter. During 2 months of trien therapy, neurological deficits regressed in three patients, and only slightly in one patient. No adverse effects were observed. These results and the retrospective survey on 17 patients treated with D-PC confirmed that trien is less potent but a safer copper chelating agent than D-PC. The transient aggravation of neurological deficits seen in two patients during the early stage of the treatment suggested that trien, as D-PC, should be started in small doses and gradually increased.
2039955##1991-4-1##Wilson's disease: computed tomography and magnetic resonance imaging findings.##The condition of a patient with Wilson's disease was evaluated by magnetic resonance imaging (MRI) on initial presentation of the illness. The examination revealed mild atrophy of the superior vermis. Symmetric areas of increased signal intensity on T2-weighted images were detected in the anterior thalami, mesencephalic tectum and tegmentum. Marked symmetric hypointensities appeared in the head of caudate, pallida, substantia nigra and red nuclei. The histopathology of Wilson's disease suggests that these hypointensities may be secondary to the presence of protein-bound copper.
2001814##1991-4-1##Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure.##Establishing a diagnosis of fulminant Wilson's disease can be difficult because Kayser-Fleischer rings may not be present and parameters of copper metabolism, including serum and urinary copper, and serum ceruloplasmin levels are neither specific nor diagnostic. In this study, ratios of both the serum alkaline phosphatase to total bilirubin and aspartate transaminase to alanine transaminase were constructed to evaluate their usefulness in differentiating fulminant hepatic failure caused by Wilson's disease (n = 6) from other etiologies (n = 43). An analysis of the data showed that cutoff values of less than 2.0 for the alkaline phosphatase-total bilirubin ratio and greater than 4.0 for the aspartate transaminase ratio were associated with a diagnosis of fulminant hepatic failure caused by Wilson's disease only (P less than 0.001). The alkaline phosphatase-total bilirubin ratio of less than 2.0 provided 100% sensitivity and specificity in identifying fulminant hepatic failure caused by Wilson's disease from other types of fulminant hepatic failure.
2010159##1991-4-1##Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver.##The sex-specific and age-specific incidence rates of the major parenchymal liver diseases in a North European population were estimated using a computerized registry of all admissions to somatic hospitals in Denmark. The incidence was calculated by counting all incident cases of these diseases reported to the registry in the 5-yr period 1981 to 1985 and dividing the number of cases by the number of person-years at risk in this period. The incidence rates (per million person-years) were for men and women, respectively: infectious hepatitis, 109 and 71; toxic hepatitis, 19 and 22; chronic hepatitis, 27 and 29; alcoholic cirrhosis, 190 and 85; nonalcoholic nonbiliary cirrhosis, 110 and 82; primary biliary cirrhosis, 4 and 14. The pattern of the age-specific incidence rates was similar in men and women in infectious hepatitis, alcoholic cirrhosis, nonalcoholic nonbiliary cirrhosis and primary biliary cirrhosis. Toxic and chronic hepatitis had a higher incidence in women than in men only in older age groups. The incidence of idiopathic hemochromatosis, Wilson's disease, secondary biliary cirrhosis, portal vein thrombosis and Budd-Chiari's syndrome were less than four in both sexes.
1881500##1991-4-1##Fulminant hepatic failure: to transplant or not to transplant.##Despite progress in intensive care regimens and the introduction of various hepatic support procedures, the survival rate for fulminant hepatic failure remained around 20%. In the past few years, orthotopic liver transplantation has increased the survival rate to more than 50% and thus is generally considered the treatment of choice. However, since about 20% of the patients on standard therapy recover spontaneously, not all patients presenting with fulminant hepatic failure should undergo transplantation immediately. Therefore attempts should be made to identify the patients with &quot;potentially reversible&quot; liver disease in an early phase. In this article strategies for deciding which therapy fits the individual patient are proposed. The decision &quot;to transplant or not to transplant&quot; should be based on residual functioning liver-cell mass (e.g. factor V is less or greater than 15%), the presence or absence of systemic complications such as lactic acidosis and renal failure and the aetiology of the liver disease (e.g. reversible causes such as viral hepatitis B and irreversible causes such as Wilson's disease). A flow diagram has been constructed.
1828987##1991-4-1##[Laparoscopy in Wilson's disease].##
1883396##1991-3-1##Immunoenzyme determination of total serum ceruloplasmin. Application to Wilson disease.##Enzyme immunoassay for ceruloplasmin (CP)*, employing monospecific CP antibodies labeled with horse radish peroxidase was developed. This method permits to determine total content of CP, which is present in Wilson disease patients' blood in enzymatically active and enzymatically inactive forms. The evidence is presented that the method can be used for a direct determination of CP in blood serum. The minimal CP concentration which may be determined by enzyme immunoassay (IEA) is 5.10(-9) g/ml. The method was used for determination of CP concentrations in Wilson disease patients' blood with different disease severity. Analysis of blood samples taken from 6 Wilson disease patients with the use of IEA method revealed similar total CP concentrations. At the same time, the oxidase activities of CP in the blood of different patients varied more than sevenfold.
1993498##1991-3-1##Prognosis of Wilsonian chronic active hepatitis.##Twenty of 320 patients with Wilson's disease initially presented with chemical and laboratory features of chronic active hepatitis, confirmed histologically in 17. When first seen, cirrhosis was present in all 20 and was complicated by ascites and/or jaundice in 11. Within 1 week to 8 years of the onset of over liver disease the diagnosis of Wilson's disease was established, and treatment with D-penicillamine was promptly initiated in 19 patients. One man refused treatment and died 4 months later. Treated patients received D-penicillamine or trientine for a total of 264 patient-years (median, 14 patient-years). Abnormal water retention, for which salt restriction and diuretics were added to penicillamine or trientine, disappeared in all but 1 of the patients so affected. Symptomatic improvement and virtually normal levels of serum albumin, bilirubin, aspartate aminotransferase, and alanine aminotransferase followed within 1 year in the majority of subjects. One woman died after 9 months of treatment. Two patients, who became noncompliant with the therapeutic regimen after 9 and 17 years of successful pharmacological treatment, required liver transplants. These results indicate that the prognosis of specifically treated Wilsonian chronic active hepatitis is very good in spite of the presence of cirrhosis.
1864920##1991-3-1##Memory deficits in Wilson's disease: a response to Lang.##Lang (1989) suggested that patients with Wilson's disease do not have memory deficits, unless they suffer from severe neurologic impairment. Results from three recent studies conflict with this view. The interaction of neurologic and cognitive deficits in Wilson's disease is discussed.
2054207##1991-3-1##[Prevalence of several neurological diseases in the central provinces of the Iberian Peninsula in eighteen-year-old males].##The prevalence of several neurological diseases has been estimated in eighteen-year-old males living in the central provinces of the Iberian Peninsula (Avila, Badajoz, Caceres, Ciudad Real, Cuenca, Guadalajara, Madrid, Toledo and Segovia). To this end, the yearly recruitment census and the neurological evaluations in the recruits form each year between 1985 and 1989 were used. The yearly prevalence rates (per 10,0000) were evaluated for an overall population of 235,976 recruits. Particularly reliable and accurate, among the observed rates, were those related to epilepsy (513), multiple sclerosis (7.6), hereditary ataxias (10.6), neurological form of Wilson's disease (1.7), Tourette's disease (1.3), syringomyelia (0.9), focal neuropathies (74.6), diffuse neuropathies (17.8), myotonic dystrophy (5.5), congenital myotonia (4.7), myasthenia gravis (3.0), hypokalemic periodic paralysis (1.7), and myopathies as a whole (31.8). The possible usefulness to carry out studies with this outlook and the type of conditions more adequate for them are discussed.
1714215##1991-3-1##[Early detection of hereditary hemochromatosis and Wilson's disease].##
2043443##1991-2-1##Hyperlipidemias, lipid storage disorders, metal storage disorders, and ochronosis.##This review presents up-to-date information on many unusual causes of musculoskeletal disorders. These disorders are grouped together because in each there is abnormal accumulation of normal materials or accumulation of abnormal materials in cells or interstitial tissues. Most of these conditions or their associated musculoskeletal manifestations are rare. However, they may present to the adult or pediatric rheumatologist for diagnosis or therapy or both. Gout, because of its prevalence, has been excluded from this review, but it is included briefly in the discussion of the specific arthritides associated with hyperlipidemias. Disorders associated with abnormal lipid storage in which bone and joint pathology occur frequently include Gaucher's disease, histiocytosis-X, and multicentric reticulohistiocytosis. The rarer disorders of this type discussed are Fabry's disease, sea-blue histiocytosis, and Farber's disease. The abnormal accumulation of metal ions in hemochromatosis and in Wilson's disease are probably causative, either directly or indirectly, in the musculoskeletal features of these diseases, while in ochronosis, calcium crystal deposition accompanies the cartilage degradation characteristic of this disease.
2007459##1991-2-1##Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson's disease.##Wilson's disease associated with hepatic failure is not common and the underlying mechanism triggering the event is not known at present. We treated a 28-year-old Japanese woman with Wilson's disease who developed hepatic failure associated with hemolytic crisis just after delivery. She was diagnosed as having Wilson's disease at 12 years of age, at which time she started taking D-penicillamine. She had previously delivered two children without difficulty. When she found out she was pregnant this time, she stopped taking D-penicillamine in contrast to taking it faithfully during her first two pregnancies. On the day of delivery of her full-term baby, jaundice developed accompanied with severe hemolytic crisis. Plasma exchanges and blood transfusion were performed and D-penicillamine administration was started again. She gradually recovered and apparently was following a good clinical course. However, on day 30 the second hemolytic crisis occurred and subsequent liver failure led her to death on day 50. At autopsy her liver was cirrhotic and showed massive necrosis. Prophylactic oral administration of D-penicillamine and careful observation are therefore recommended to prevent hemolytic crisis during the perinatal period.
1850766##1991-2-1##Antidotal effects of dimercaptosuccinic acid.##Dimercaptosuccinic acid (DMS), HOOC-CH(SH)-CH(SH)-COOH, was first developed in China as an effective antidote for poisoning from many heavy metals, such as Pb, Hg, As, Cd, Sb, Tl, Au, Zn, Ni, Pt, Ag, Co and Sn. DMS increases the excretion of Ce, Pm, Sr and Po from the body. Hundreds of patients suffering from hepatolenticular degeneration (Wilson's disease) have been treated successfully with DMS. Recently, DMS was found to be effective also in treating certain non-metallic intoxications, like some of the new non-phosphate pesticides and mushroom poisonings.
2033396##1991-2-1##A comparison of the effects of penicillamine, trientine, and trithiomolybdate on [35S]-labeled metallothionein in vitro; implications for Wilson's disease therapy.##The synthesis of radiolabeled metallothionein was induced in rats in vivo by the injection of CuSO4 and [35S]-cysteine. Treatment of &quot;cold&quot; rat liver cytosol &quot;spiked&quot; with purified [35S] metallothionein with Penicillamine and Trientine showed that even at relatively high concentrations (up to 50 mg/g liver, wet weight), these compounds had no effect on the copper peak or the position of the [35S] label in the cytosol eluate after Sephadex G-75 gel filtration. By contrast, incubation of the &quot;spiked&quot; liver cytosol with Trithiomolybdate, even at relatively low concentrations (0.5 mg/g liver, wet weight), resulted in a transfer of metallothionein copper to high molecular weight protein fractions; the position of the [35S] apoprotein was unaffected. This copper &quot;stripping&quot; effect on metallothionein supports clinical and other evidence that thiomolybdates have a genuine decoppering effect in vivo whereas Penicillamine and Trientine have another mode of action and indicates that thiomolybdates might provide a more rational alternate therapy for Wilson's disease patients.
1992374##1991-2-1##Comparison of functional and structural brain disturbances in Wilson's disease.##We assessed the functional and structural brain disturbances in Wilson's disease (WD) by evoked potentials (EPs) and magnetic resonance imaging (MRI). All the 25 neurologically symptomatic and 44% of the 16 asymptomatic patients, assessed by both EPs (n = 48) and imaging (n = 41), had at least 1 abnormality of either prolonged EP conduction times, imaging-outlined presence of cerebral lesions, or brain atrophy. Our findings indicate that EPs and MRI are sensitive techniques for the evaluation of brain involvement in WD.
2060237##1991-2-1##[Clinico-radiological correlation of Wilson's disease by magnetic resonance imaging, computed and positron emission tomography].##Follow-up magnetic resonance imaging (MRI) and computed tomography (CT) examinations were performed on five patients with Wilson's disease at intervals from 6 to 29 months. We studied the clinical correlation with MRI and CT, and whether the examination of MRI and CT could be useful for evaluation of the therapeutic effect. Positron emission tomography (PET) was also carried out on 4 cases except for an asymptomatic case (patient 2, sister of patient 1). Close relationship has been observed by MRI between dystonia and the lesion of the lenticular nuclei, abnormality of smooth pursuit eye movements and the brain stem lesion, and severe dysarthria/dysphagia and the lesion of the caudate and lenticular nuclei, respectively. In patient 4, repeated MRI of an interval of 18 months demonstrated decrease of the abnormal high signal in the lateral part of the putamen on T2-weighted image in accordance with marked improvement of clinical manifestations. In patient 3, who had severe dystonia of the extremities and trunk, T2-weighted image showed high signals in the lenticular nuclei. Marked decrease of the high signal in the lenticular nuclei was observed by MRI in this patient after 29 months, when her neurological manifestations were markedly improved. Patient 5 with severe cerebellar signs disclosed abnormal signals in the middle cerebellar peduncles, brain stem and dentate nuclei in addition to low signals in the caudate and lenticular nuclei, and high signals in the lateral part of the putamen on T2-sequence.(ABSTRACT TRUNCATED AT 250 WORDS)
1994169##1991-1-23##[Early diagnosis is crucial for the prognosis of Wilson's disease].##
1849385##1991-1-11##Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS.##The therapeutic history of sodium diethyldithiocarbamate (dithiocarb) is briefly reviewed. Dithiocarb was discovered serendipitously in our laboratory 35 years ago for the specific treatment of nickel carbonyl poisoning. Since that time, the therapeutic efficacy of dithiocarb has been reported for many disorders, including: nickel, cadmium, thallium, copper, and mercury poisonings, experimental nickel carcinogenesis, protection against radiation damage to bone marrow, treatment of candidiasis in experimental animals, hepatolenticular degeneration (Wilson's disease), systemic lupus erythematosis, and human immunodeficiency virus infection (HIV). It has been used as an antagonist to cisplatin and cyclophosphamide toxicities, and as an antidote to hepatotoxicity induced by chloroform, carbon tetrachloride, and halothane. Most recently, it has been observed that the progression of HIV-1 infection is inhibited by dithiocarb administered intravenously or orally to patients with acquired immunodeficiency syndrome (AIDS). Attention is directed to the interactions of divalent cations to viral infections and to metal chelators (e.g., dithiocarb) as potential antiviral agents.
1810206##1991-1-1##[Advances in the treatment of the dystonias].##Except in Wilson's disease, few secondary dystonias are susceptible te benefit from an etiological treatment. The somatic distribution of dystonia often determines the therapeutic strategy. Thus, stereotactic surgery may be the treatment of choice for hemidystonia while anticholinergic medication may alleviate generalized dystonia, particularly in childhood. Finally, local infiltrations of botulinum toxin are particularly useful for various forms of local and segmental dystonia. Certain subsyndromes as myoclonic dystonia, levodopa sensitive dystonia and paroxysmal choreoathetosis may benefit from relatively specific treatment strategies.
1986725##1991-1-1##Initial therapy of patients with Wilson's disease with tetrathiomolybdate.##Patients with Wilson's disease who present with acute neurological symptoms often become clinically worse when initially treated with penicillamine. Other available anticopper drug therapies do not appear to offer a solution to this treatment problem. We are developing and evaluating a new drug, ammonium tetrathiomolybdate for this purpose. Theoretically, tetrathiomolybdate has optimal properties, including an immediate blockade of copper absorption and the property of forming complexes with copper in the blood, rendering the copper nontoxic. In this article, we present results from six patients treated with tetrathiomolybdate for up to 8 weeks as initial therapy. None of the five patients who had presented with acute neurological symptoms worsened. Also presented are methods of assay, preliminary stability studies, and methods of evaluating therapeutic end points with respect to copper metabolism.
1914527##1991-1-1##Isolation and regional localization of 25 anonymous DNA probes on a chromosome 13 hybrid panel.##Clones were isolated from two flow-sorted chromosome 13 libraries. Twenty-five clones were localized to various regions of chromosome 13, using a well-characterized panel of rodent x human hybrid cell lines. Eight DNA markers were localized to 13q14.2----q22, where the gene for Wilson disease, a recessive disorder of copper metabolism, was previously assigned. The new markers will be useful for the diagnosis of presymptomatic sibs of Wilson disease patients. We isolated six DNA clones proximal to the retinoblastoma gene, a region in which a translocation associated with rhabdomyosarcoma has been observed. Probes for both of these regions will be useful for the cloning of the genes involved in these diseases.
2036736##1991-1-1##Assessment of portal hypertension: understanding will improve treatment.##To many people it may be disappointing that many uncertainties remain with respect to the assessment of PHT. Only a few findings such as increased WHVPG and varices prove PHT. However, we have gained considerable knowledge. PHT is the consequence of a number of changes which involve the intrahepatic and extrahepatic circulation. Alcohol, viruses and drugs may disturb parenchymal architecture and cause cellular swelling, collagen and fibrin deposition and invasion with inflammatory cells. These processes finally may evolve into cirrhosis. Although in initial stages the parenchymal disturbance per se may account for PHT, increasingly impaired liver function results in metabolic changes which cause altered haemodynamics. Advanced PHT in parenchymal liver disease is the result of the complex interaction between local and systemic changes. The current techniques for the assessment of PHT are helpful for the qualitative aspects: increase in pressure can be assessed directly or indirectly; the portal venous system can be visualized even without arteriography. Gastroscopy remains a standard procedure for diagnosing PHT. Ultrasound-endoscopy is particularly helpful to confirm fundic varices and to assess changes after sclerotherapy. Increasingly, non-invasive methods to quantify PHT have become available such as the Duplex scanner. However, limitations and pitfalls need to be realized. The quantitative assessment remains (as yet?) a technique for research centres. It is obvious that the clinician in general practice can do without most of the more sophisticated techniques which have been discussed here. For the time being, PHT, and particularly variceal bleeding, is most often treated with endoscopic sclerotherapy. For that reason, only in a minority of the cases very detailed studies are required. However, the increasing knowledge opens new perspectives for the treatment and prevention of PHT on various levels. This may be a rather specific treatment of parenchymal liver disease (antivirals, d-penicillamine for Wilson's disease or venesections for haemochromatosis), drugs which may reduce local tissue damage via more general pathways (colchicine, steroids) and drugs which influence flow. Undoubtedly one of these years a more selective blocker of portal venous pressure will become available. Optimal assessment for that type of therapy makes it mandatory to master at least a few more advanced techniques. With respect to noncirrhotic PHT with causes which may vary from congenital or acquired clotting abnormalities to anatomical malformations (oesophageal web) and 'natural healthy herb tea', measures can be taken. It is clear that before treating any of the more rare causes, a proper diagnostic work-up is required.(ABSTRACT TRUNCATED AT 400 WORDS)
2044580##1991-1-1##Copper and liver disease.##There has been some limited progress in the understanding of the basic defect in Wilson disease and the gene concerned has been located to the chromosome region 13q14. Treatment with zinc has emerged as a definite alternative to penicillamine administration and some shortcomings and/or hazards of both forms of therapy have emerged as their modes of action have been studied more carefully. Tetrathimolybdate may have a place in treatment, especially when rapid complexing of copper is important. Hepatic copper accumulation occurs in a number of cholestatic diseases and they play an important part in pathogenesis and can occasionally lead to neurologic toxic effects. Copper overload in the newborn period when biliary excretion of copper is inefficient may establish a vicious cycle of copper accumulation and liver damage in Indian childhood cirrhosis and less frequently in babies in other countries.
1889768##1991-1-1##[Retinal changes in Wilson's disease].##Increasing loss of vision caused by peculiar macroscopic and functional retinal changes was the first ophthalmologic manifestation of Wilson's disease in a 22-year-old patient. Neither retinal changes nor great visual impairment has been described thus far in the literature concerning this disease. Likely correlations are discussed with Menkes syndrome, an X-linked inborn error of copper metabolism with onset in early childhood.
1894453##1991-1-1##The neuropsychiatry of Wilson's disease: a review.##Psychiatric symptoms are frequently encountered in Wilson's disease (WD). The recent resurgence of interest in neuropsychiatry has led to a more detailed consideration of the psychopathology associated with WD. As suggested by Wilson, disorders of affect, behavior and personality are the most common features. Contrary to Wilson's view, recent evidence suggests that such symptoms have an organic basis. Cognitive impairments tend to be mild and improve with treatment. There is a lack of recent evidence for an association between WD and organic delusional disorders.
2005054##1991-1-1##Overlooking Wilson's disease.##
1749217##1991-1-1##Clinical presentation of metabolic liver disease.##Some clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories: (i) Manifestations due to hepatocellular necrosis, acute or subacute, which can reveal galactosaemia, hereditary fructose intolerance, tyrosinaemia type I, Wilson disease and alpha 1-antitrypsin deficiency. Symptoms and signs suggestive of Reye syndrome should lead to a study of fatty acid oxidation and urea cycle enzymes. All these manifestations may necessitate a rapid diagnosis and treatment when liver dysfunction is severe. (ii) Cholestatic jaundice can reveal alpha 1-antitrypsin deficiency, Byler's disease, cystic fibrosis, Niemann-Pick disease and some disorders of peroxisome biogenesis. (iii) Hepatomegaly can reveal disorders with liver damage but also storage diseases such as glycogen storage diseases, cholesteryl ester storage disease and, when associated with splenomegaly, lysosomal storage diseases. Appropriate investigations for recognizing all these entities are proposed.
1901347##1991-1-1##The nigrostriatal dopaminergic pathway in Wilson's disease studied with positron emission tomography.##Movement disorders, including Parkinsonism, are prominent features of neurological Wilson's disease (WD). This suggests there may be dysfunction of the nigrostriatal dopaminergic pathway. To explore this possibility, five patients were studied using positron emission tomography (PET) with 18F-6-fluorodopa (6FD), and magnetic resonance imaging (MRI). We calculated striatal 6FD uptake rate constants by a graphical method and compared the results with those of 18 normal subjects. It was found that four patients with symptoms all had abnormally low 6FD uptake, and the one asymptomatic patient had normal uptake. PET evidence for nigrostriatal dopaminergic dysfunction was present even after many years of penicillamine treatment. It is concluded that the nigrostriatal dopaminergic pathway is involved in neurological WD.
1715423##1991-1-1##[A commercial immunoenzyme reagent for the determination of ceruloplasmin].##A diagnostic agent for enzyme immunoassay of ceruloplasmin has been developed. The method is highly sensitive and specific. The minimal detectable amount of ceruloplasmin is 25 ng/ml, variance coefficients with 1 lot being 2.6-7.3 percent and 4.2-10.8 percent within 3 lots. Blood serum ceruloplasmin concentration in health has made up 0.9 to 1.3 mg/ml. Ceruloplasmin levels were regularly shifted in Wilson's disease, cerebral lymphomas, sepsis, injuries, liver cirrhosis and other diseases.
1661845##1991-1-1##Abnormal conduction in corticospinal pathways in Wilson's disease: investigation of nine cases with magnetic brain stimulation.##Electromyographic (EMG) responses evoked by transcranial magnetic brain stimulation were studied in nine patients with Wilson's disease (WD). Six of the nine patients had prolonged central motor latencies (CMLs), reduced amplitude, or absent responses in at least one of the examined muscles. In one patient, abnormal EMG responses normalized following treatment with penicillamine. Pathophysiologically abnormal EMG responses might result from a potentially reversible impairment of corticomotoneuronal pathways and/or a reduced excitability of motoneurons due to basal ganglia dysfunction. The possible pathophysiological mechanisms are discussed.
8711340##1991-1-1##[Distal renal tubular acidosis in patients with Wilson's disease].##Renal affection is part of the clinical picture of developed Wilson's disease. The most frequent sign of affection of the distal nephron is distal tubular acidosis (DRTA), more frequently its latent form with a normal systemic pH, but inability to reduce the urinary pH below 5.5 after an acid load. More detailed assessment of the type of this disorder was not made so far. To elucidate in greater detail the pathogenesis of DRTA in Wilson's disease the authors examined renal acidification in 13 patients with bioptically verified Wilson's disease, using three acidification tests: 1) the test involving oral administration of calcium chloride (CaCl2), 2) the test involving infusion of sodium sulphate (Na2SO4) and 3) the test using an infusion of NaHCO3. In none of the examined patients with Wilson's disease manifest (complete) DRTA was found with systemic acidosis, however, in five patients latent (incomplete) DRTA was revealed, i.e. after administration of CaCl2 the pH of urine did not decline below 5.5. Patients with Wilson's disease and DRTA differed from patients with Wilson's disease and normal renal acidification by the age at the time of assessment of the diagnosis (30.4 +/- 3.6 vs. 20.75 +/- 2.14 years, p &lt; 0.02) and the duration of the disease (i.e. the time from assessment of the diagnosis to the acidification examination: 4.6 +/- 4.86 vs. 15.38 +/- 2.40 years, p &lt; 0.01). In three of four patients with Wilson's disease and DRTA who were given Na2SO4, after its administration the pH of urine did not decline below 5.2. After alkalination of the urine with sodium bicarbonate in all patients with Wilson's disease the pCO2 in urine was higher than 9.1 kPa and the gradient between pCO2 in urine and blood (U-B gradient of pCO2) was higher than 3.32 kPa. Latent (incomplete) DRTA is thus a frequent component of the clinical picture, in particular in Wilson's disease when diagnosed late. The disorder does not respond to administration of Na2SO4, the response of pCO2 to NaHCO3 administration is, however, normal. The results indicate that from the pathogenetic aspect probably the so-called gradient type is involved, characterized by the inability of the acidifying tubular cell in the distal nephron to secrete hydrogen ions against a high pH gradient.
2094200##1990-12-1##[Association of Wilson's disease with non wilsonian extrapyramidal syndrome in the same family].##Movement disorders, mostly dystonia, sometimes occur in heterozygotes for Wilson's disease (WD). A patient with metabolic abnormalities suggestive of heterozygote for WD and dystonia is reported. His niece showed the typical neurological and metabolic abnormalities of WD. This rare coincidence and the etiopathogenic mechanisms involved are discussed.
2292179##1990-12-1##Low-dose zinc therapy for maintenance treatment of Wilson's disease.##
2227300##1990-12-1##Heterotopic liver transplantation for fulminant Wilson's disease.##Wilson's disease may present with severe acute hepatocellular failure. The only effective treatment for fulminant Wilson's disease is liver transplantation, which may lead to reversal of the underlying disease. Some patients with cirrhosis who are too ill to undergo orthotopic liver transplantation have been treated with heterotopic liver transplantation. However, use of heterotopic liver transplantation for fulminant hepatocellular failure has not been successful. This case study involves a patient in whom a heterotopic liver transplant was successfully used for treatment of Wilson's disease presenting with fulminant hepatocellular failure.
2239872##1990-11-1##Clinical aspects of Wilson's disease.##
2240101##1990-11-1##Pregnancy in a patient with treated Wilson's disease: a case report.##Pregnancy should have a successful outcome in a patient with treated Wilson's disease if complications are excluded before conception. Chelating treatment must be maintained, although there is some concern about its teratogenicity. We describe the course of pregnancy in a patient followed up in our department.
1964048##1990-11-1##Interrelation between structure and protective action of normal and pathological ceruloplasmins during copper-induced lysis of red blood cells.##The origin of the difference between the protective action of ceruloplasmin (CP) from healthy donors blood and of ceruloplasmin-like protein (p-CP) from blood of patients with Wilson disease which they exert during copper-induced lysis of red blood cells (RBC) was elucidated. The difference is due to a significant change in the carbohydrate moiety of p-CP the major proportion of which (65%) does not contain mannose and acetylglucosamine residues. The data of chromatography on lentil lectin reveal that only 4% of p-CP molecules contain the fragment [table: see text] required for binding to RBC receptors. It was shown that the time-courses of copper accumulation in RBC of normal donors and in RBC of patients with Wilson disease (p-RBC) during copper-induced lysis differ markedly from each other. The p-CP is able to prevent copper accumulation in RBC and p-RBC to a significantly less degree than CP. It was also established that CP prevents the decrease of reduced glutathione (GSH) level in RBC to a greater extent than p-CP. In contrast to CP, the p-CP exerts no effect on the decrease in GSH concentration in p-RBC. These results may indicate that no interaction between Cu2+ and reduced glutathione takes place in p-RBC, in contrast to the situation occurring in normal RBC.
2227823##1990-11-1##Perspectives on Wilson's disease.##
2129845##1990-11-1##Wilson's disease in an Australian aborigine.##Wilson's disease is due to a genetically determined defect inherited as an autosomal recessive trait. Most reported cases have been caucasoid. This report describes a case of Wilson's disease in an Australian Aboriginal girl, only the second such case reported.
2129842##1990-11-1##Genetic heterogeneity in Wilson's disease.##
2086728##1990-11-1##Motor evoked potentials in Wilson's disease: early and late motor responses.##Motor evoked potentials following magnetic stimulation of the motor cortex and the spinal roots were studied in 13 patients with Wilson's disease (WD). The fast-conducting motor pathway function was normal in 9 patients. The cortically-evoked motor responses were absent in patients with cerebral white matter lesion and akinetic rigid syndrome. In addition to the primary or early motor response, late motor response was common in WD and occurred with a latency of 70-90 msec for the upper limb and 90-110 msec for the lower limb. The cause of the late motor response is unknown, but may be an enhanced late response infrequently observed in normal subjects.
2266710##1990-11-1##[D-penicillamine-induced IgA deficiency in the therapy of Wilson's disease].##Serum IgA deficiency was first noted in a 10 year old boy 8 months after the onset of D-penicillamine therapy. Special immunological examinations revealed a deficiency of the secretory component of IgA while cellular functions of T- and B-lymphocytes were normal. The patient showed discrete clinical signs compatible with IgA deficiency. Regular control of patients with Morbus Wilson and D-penicillamine treatment should include measurement of serum immunoglobulin levels.
2082176##1990-11-1##[Wilson's disease. Presentation of a case with special reference to the study of evoked visual potentials].##In the present work the Authors report one case of Wilson's disease showing peculiar characteristics diagnosed in pediatric-age patients. In this case, a deep electrophysiological visual analysis was carried out six years after diagnosis. The evoked visual potential alterations might be connected to a retina dysfunction. Further studies should be carried out in order to support such hypothesis.
2100134##1990-11-1##[Wilson's disease: computed tomography and magnetic resonance imaging].##Wilson's disease is an autosomal recessive hereditary disease in which the capacity of biliary copper excretion is reduced, resulting in a toxic accumulation of this metal in the liver, brain and other organs. The neuroimaging techniques, computed tomography (CT) and nuclear magnetic resonance (NMR), have been incorporated to the diagnostic workup in patients with suspected Wilson's disease (WD). We report two patients with WD in whom CT and NMR were carried out for the evaluation of the central nervous system (CNS). The lesions appeared as hypodense areas in CT or signal abnormalities in NMR over the involved structures: putamen, caudate nucleus, cerebellar dental nucleus, red nucleus and subcortical white matter. In one of the patients, hypointense signal areas were found over both putamen nuclei in T-2 times of NMR, which might correspond to cavitary necrosis or copper deposition. The lesion distribution suggests that vascular lesions might play a role in the mechanisms of tissue damage. These findings show that CT and NMR are very helpful to evaluate WD. NMR images are quite characteristic of this disorder.
2133599##1990-11-1##[Functional and histologic changes in the kidney in copper poisoning in rats].##The acute intoxication (by intraperitoneal way) and chronic intoxication (by inhalation, during one year) were carried out with pure copper. On the basis of experimental studies, it was established that the kidney was a critical organ in copper intoxication. On all rats acutely intoxicated damages of the function (similar to Fanconi's syndrome in Wilson's disease), diffuse pathologic lesions and presence of fine copper particles in protoplasm of proximal tubule epithelial cells, were found. By chronic intoxication it was proved that the organism could be loaded with copper through inhalation of copper particles. In chronic intoxication damages of renal functions were insignificant, but very heavy pathohistologic lesions were only focal and they influenced glomerules, proximal tubules, initial parts of Henle's loop and interstice. Copper was found in the form of strip-like deposits in glomerules and proximal tubule basal membrane, then in the form of fine and coarse granules in protoplasm of proximal tubule epithelial cells.
1977004##1990-10-20##Evoked potentials in assessment and follow-up of patients with Wilson's disease.##Treatment of 9 patients with Wilson's disease was prospectively studied with evoked potentials and magnetic resonance imaging (MRI). Oral penicillamine therapy led to a decrease in auditory brainstem (ABP) and somatosensory (SEP) conduction times in 6 and 4 neurologically symptomatic patients, respectively. ABP and SEP were normal in 3 other symptom-free patients. MRI showed cerebral lesions in 4 of 7 patients. Quantified indices of brain atrophy were unaffected by treatment. ABP and SEP may reveal a reversible component of the disease that cannot be detected by MRI, and may be a more sensitive measure of treatment efficacy.
2222268##1990-10-1##A yellow-green posterior limbal ring in a patient who does not have Wilson's disease.##
2279084##1990-10-1##[Comparison of the protective effects on the erythrocytes of ceruloplasmin from the blood of healthy donors and patients with hepatocerebral dystrophy].##The binding of the ceruloplasmin (CP) from the healthy donor's blood and of ceruloplasmin--like protein (p-CP) isolated from the Wilson disease patient's blood with erythrocytes (RBC) of healthy donors and with RBC of Wilson's patients (p-RBC) was investigated. It was shown, that the CP number of binding sites both on the RBC and p-RBC was significantly lower than that for p-CP, but Kd value for p-CP binding of the both types of erythrocytes was approximately 10 times higher than Kd value for CP. The protective action of CP on copper stimulated hemolysis is almost 3 times higher than that of p-CP. The protective action of CP on ferrous ion stimulated hemolysis doesn't correlate with its ferroxidase activity. On the contrary the protective effect of p-CP which has no ferroxidase activity is more powerful than that of CP.
2272595##1990-10-1##[Diagnostic differentiation of dementia diseases by modern imaging procedures].##We present a review on recent neuroimaging techniques, like x-ray computed tomography (XCT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission tomography (SPECT) in dementia and related diseases. Significant new findings have been obtained using techniques reflecting proton density, regional brain perfusion and brain metabolism. In dementia of the Alzheimer type, for example, temporoparietal and sometimes also frontal reductions in cerebral blood flow and metabolism are characteristic. The infarctions found in multi-infarct dementia are especially well visualized on T2-weighted MRI images. Pick's disease is characterized by brain atrophy and decrease of radiotracer activity in the frontal lobes. In huntington's chorea the metabolic rate on PET scan in the area of the caudate nuclei may be reduced even before signs and symptoms become apparent. Furthermore, neuroimaging provides us with fairly typical finding in Creutzfeld-Jakob's disease, alcoholic dementia, Wilson's disease, hydrocephalus, Parkinson's disease, progressive supranuclear ophthalmoplegia, Fahr's disease, and the olivopontocerebellar ataxias. Neuroimaging techniques, however, have always to be interpreted in conjunction with clinical findings, thus disclosing their full range of information.
2227943##1990-10-1##Close linkage of the Wilson's disease locus to D13S12 in the chromosomal region 13q21 and not to ESD in 13q14.##Wilson's disease (WD) is an autosomal recessive disorder resulting in copper accumulation notably in liver and brain tissue. Linkage of the WD locus (WND) to ESD at 13q14 was first shown by studies in families of Middle Eastern origin using the isozymic polymorphism of esterase D. Using RFLPs detected by the ESD cDNA we could not confirm this reported close linkage in an analysis of 17 WD families of northwest European origin. A tight linkage was detected, however, to the marker D13S12, located more distally at 13q21. No obligate cross-overs were detected in 63 gametes informative for this marker. Our data confirm an assignment of WND to 13q14-21. Its localization, however, seems to be more distal to ESD than previously reported. Although genetic heterogeneity cannot be excluded, the observed differences between the two populations are probably due to random variation.
2258535##1990-10-1##Use of zinc-copper metabolic interactions in the treatment of Wilson's disease.##Zinc acetate is becoming a well-established therapy for the treatment of Wilson's disease. It is excellent for maintenance therapy and for the treatment of the presymptomatic patient. Current evidence suggests that it will also be excellent for the treatment of the pregnant patient. Zinc acts by inducing intestinal cell metallothionein, which binds copper with high affinity, blocking its absorption, and causing its excretion in the stool. We have shown that zinc, even in doses as low as 25 mg daily, negatively affects copper balance. Zinc in doses of 50 mg three times daily, with all doses separated from food, controls the abnormal positive copper balance, blocks uptake of orally administered 64Cu, controls urine and plasma copper, prevents the reaccumulation of hepatic copper, and prevents the development or progression of symptoms of copper toxicosis in Wilson's disease patients. Zinc acetate will probably be licensed in the near future for the treatment of Wilson's disease. We recommend that physicians use urine and plasma copper, and urine zinc, as primary monitoring tools. In contrast to the comfortable situation with maintenance therapy, the initial treatment of acutely ill Wilson's disease patients is not well worked out. Patients with neurological disease often get worse initially on penicillamine, and zinc acts more slowly than is ideal. We have initiated studies of tetrathiomolybdate for this purpose. Studies of biliary secretions of normal subjects suggest that they excrete regulatory (excess) copper packaged in a protease-resistant ceruloplasmin fragment. This fragment is missing in Wilson's disease bile. The gene for Wilson's disease is on chromosome 13, close to the retinoblastoma locus.(ABSTRACT TRUNCATED AT 250 WORDS)
2077550##1990-10-1##[Wilson's disease in East Germany: in retrospect and perspectives -- an evaluation].##Wilson's disease is an autosomal recessive inherited metabolic disorder due to a disturbance of copper metabolism. Although the primary genetic defect is not known a longlife treatment is necessary for establishing a negative copper balance by removing the metal of the abnormal body stores. Experiences in handling with this disease in our country over a period of 20 years are reported. Especially epidemiologic findings, the diagnostic procedures and the strategies in therapeutic regimes are discussed. Future advances in genomic diagnostics are mentioned.
2074531##1990-10-1##[Intestinal absorption and urinary excretion of triethylenetetramine for Wilson's disease in rat].##Triethylenetetramine.2.HCl (trientine, TE) is an orphan drug for the treatment of Wilson's disease. There has been no reports regarding the absorption, distribution, metabolism, and excretion in the body. In the current study, the absorption and excretion of TE in rats were examined. The observed mean percentage amount of TE absorbed at the jejunum and ileum with the loop method for 1 h was 42.0% and 22.5%, respectively. Tight junction blocking agent inhibited the absorption of TE from the jejunum loop with 27%, but the absorption of TE from the ileum loop was not affected by this blocking agent. Therefore, the main absorption route for TE might be permeation across the plasma membrane of intestinal epithelial cells. TE and amikacin, a polycationic compound like TE, bound to the brush border membrane (BBM) of rat small intestine in the absence of inorganic ions such as Na+, K+, Ca2+, Mg2+ and Cu2+. But the binding of TE to BBM was inhibited markedly under the physiological concentration of these ions. The bioavailability of TE was below 10% and the plasma levels of TE in non-fasted rats were significantly lower than that observed in fasted rats. The urinary excretion of unchanged TE during 24 h was only 3.5% of the orally administered dose. However, the urinary excretion of total TE including metabolites, though they have not been identified, was 35.7%. These results suggest that low bioavailability of TE might be due to the rapid metabolism in the body after absorption from the gastrointestinal tract.
2401845##1990-9-1##Pancreaticobiliary secretion of zinc and copper in normal persons and patients with Wilson's disease.##The objectives of this study were (1) to examine basal and cholecystokinin-stimulated pancreaticobiliary secretion of zinc in normal subjects with zinc-adequate and zinc-deficient diets, and (2) to investigate whether basal and stimulated secretion of zinc was abnormal in patients with Wilson's disease before and after zinc therapy. Gastroduodenal intubation was performed in six healthy subjects and five patients with Wilson's disease. After intravenous infusion of octapeptide of cholecystokinin (40 ng/kg/hr) the pancreaticobiliary secretion of zinc increased from a basal rate of 283.1 +/- 75.8 nmol/L/min to a peak of 716.6 +/- 175.3 nmol/L/min in normal subjects. Normal subjects with a zinc-deficient diet had both lower basal (66.8 +/- 15.8 nmol/L/min) and stimulated (559.5 +/- 31 nmol/L/min) pancreaticobiliary secretion of zinc than with a zinc-sufficient diet. In contrast to the markedly reduced pancreaticobiliary secretion of copper, patients with Wilson's disease not treated with zinc had normal basal (226.6 +/- 126 nmol/L/min) and stimulated (728.7 +/- 195.5 nmol/L/min) zinc secretion. These studies indicate that a considerable amount of zinc is being secreted in pancreaticobiliary fluid in healthy subjects and there was no impairment of zinc secretion in patients with Wilson's disease. Our data also indicate that pancreaticobiliary secretion of zinc is dependent on the zinc status of the subjects, suggesting that endogenous secretion of zinc may play a significant role in the homeostasis of zinc.
2393743##1990-8-11##Wilson's disease in adults with cirrhosis but no neurological abnormalities.##
2378928##1990-8-1##Wilson's disease: a longitudinal study of psychiatric symptoms.##One hundred and twenty-nine cases of Wilson's disease (WD) were assessed at index admission and two follow-ups (F1 and F2) on a range of clinical and biochemical variables. The commonest psychiatric symptoms throughout were incongruous behavior, irritability, depression, and cognitive impairment. Among psychiatric cases, most improvements occurred in the interval index-F1, with subsequent leveling off. Significant improvement occurred only with incongruous behavior and cognitive impairment. Psychiatric cases whose psychiatric symptoms persisted to F2 differed from those who responded, in particular showing more dysarthria, incongruous behavior, and hepatic symptoms. Neuropsychiatric cases displayed more dysarthria and incongruous behavior than patients with neurological symptoms alone. Further evidence for associations between dysarthria and abnormal behavior emerged from this study.
2237391##1990-8-1##Wilson's disease presenting as acute fulminant hepatic failure.##A fatal case of fulminant hepatic failure in an adolescent is described. Post-mortem examination revealed the cause to be Wilson's Disease. This rare presentation is characterised by apparently atypical changes in copper metabolism. Wilson's Disease should be a differential diagnosis of any adolescent presenting in liver failure.
2275259##1990-8-1##[Copper in the feces--a marker for the effectiveness of zinc in the treatment of Wilson's disease].##In the present study we discuss the question of a useful, convenient control of the effectiveness of treatment Wilson's disease with zinc. It appears useful to determine the copper content in the dry matter of individual samples of the stools obtained before and in the course of the treatment. This treatment can be assumed effective if the stools copper content reaches the level found in healthy subjects (0.72 micromol/g dry weight) while keeping the patient on a low copper diet. Copper resorption in the gut of our patient was reduced only after 12 weeks of daily administering 136 mg of elementary zinc p.o.
2129820##1990-7-1##Genetic aspects of Wilson's disease.##Wilson's disease is an autosomal recessive, inborn error of copper metabolism. The basic defect is unknown but decreased biliary excretion of copper is associated with copper accumulation and damage to the liver, brain and other organs with variable clinical expression. The gene for the disease has been mapped to band 14.1-21.1 of the long arm of chromosome 13, and an increasing number of flanking DNA markers has become available in recent years. Family studies using these markers offer the first diagnostic tool which is independent of copper metabolism. This method has been applied successfully for carrier detection in siblings of patients and has the potential to be used for prenatal diagnosis. The results of linkage studies in families of different ethnic origins suggest that the disease is associated with a mutation at a single chromosomal region. The assignment of the gene to chromosome 13 and the availability of closely linked markers are the first steps towards cloning of the disease gene and eventually may lead to determination of the basic metabolic defect.
2129813##1990-7-1##Liver copper concentration in Wilson's disease: effect of treatment with 'anti-copper' agents.##Serial copper determinations have been made on the livers of 10 patients with Wilson's disease. Two were studied before and eight after the start of treatment in order to assess the effect, if any, on the concentration of the metal. In two patients who were receiving no therapy and in one in whom it had been discontinued, the level of copper rose. In the latter patient, resumption of treatment then resulted in a fall in the level of copper in the liver. A similar fall was seen in seven patients on continuous therapy. In one patient, a very poor complier, there was a tendency for the liver copper concentration to rise over a 5-year period. All three therapies investigated--penicillamine, trientine and tetrathiomolybdate--when taken regularly, appear to be effective in reducing liver copper levels. Sixty-nine single determinations of liver copper have been plotted against time on treatment. This shows that the copper concentration falls rapidly in the first year. Thereafter, there is no linear relationship between the duration of treatment and liver copper. Poor compliers have a higher liver copper concentration than do good compliers. Determinations made from different portions of the liver showed that in only one of 19 examples was there an overlap between the near normal and the abnormal range. The principal mechanism of action of 'anti-copper' agents in Wilson's disease appears to be the mobilization of copper from the tissues, but a secondary detoxifying action may come into play later.
2238766##1990-7-1##[Significance of the iron and copper content of the liver for the differential diagnosis of chronic liver diseases].##Liver iron and copper concentrations were estimated in 395 patients undergoing hepatological examination. Relations to clinical, morphological and laboratory data were evaluated. Liver iron concentrations were not significantly different in chronic hepatitis of viral, toxic or immunological origin. Liver iron levels exceeding 100 mg/100 g dry liver tissue (normal range up to 300 mg/100 g) were only found in idiopathic hemochromatosis (n = 8), in a patient with prophyria cutanea tarda and in a multiple transfused patient who suffered from aplastic anemia. Liver copper content was significantly increased in primary biliary cirrhosis compared to chronic hepatitis of other origin. Apart from untreated Wilson's disease (n = 3) copper levels higher than 25 mg/100 g dry liver tissue (normal range up to 6 mg/100 g) were measured in chronic active hepatitis B (n = 2), primary biliary cirrhosis (n = 9) and in chronic hepatitis of uncertain origin (n = 3). Therefore excess accumulation of copper in the liver was typical of Wilson's disease but less diagnostic than severely elevated liver iron stores of idiopathic hemochromatosis.
1716813##1990-7-1##Mercaptodextran--a new copper chelator and scavenger of oxygen radicals.##The therapy of copper poisoning with mercaptodextran inhibits the copper-induced haemolysis, whereas 2,3- dimercaptopropanesulfonic acid (DMPS) may accelerate such haemolysis. Some aspects of the mechanisms of these effects were investigated. The possible generation of activated oxygen species during the interaction of Cu++ and chelating thiols was studied using a chemoluminiscent method detecting oxygen radicals. It was found that incubation of DMPS with copper ions or erythrocyte membranes was accompanied by generation of oxygen radicals. Mercaptodextran added to similar suspensions did not lead to oxygen radical production. And unlike DMPS, mercaptodextran acted as a scavenger of radicals generated by the xanthine oxidase/acetaldehyde system. The different ability of the chelating thiols to cope with free radicals may explain their different potentials to protect against copper-induced haemolysis. Our results also indicate that mercaptodextran may be a useful therapeutic agent in cases of haemolytic crisis in Wilson's disease.
2264486##1990-7-1##[Wilson disease presenting as fulminant hepatic failure, acute hemolytic anemia and renal failure: report of one case].##Wilson disease presenting as fulminant hepatic failure, severe hemolysis and renal failure is rare in the literature. A ten-year-old boy--complaining of abdominal pain, jaundice, tea-colored urine, and anemia was admitted to this hospital; examination showed Kayser-Fleischer rings, anemia associated with hemolysis, mildly elevated serum transaminases, extremely elevated bilirubin levels, low serum ceruloplasmin level, slightly elevated serum copper, excessive 24-hour urine copper excretion, and severe renal function insufficiencies. Under the impression of Wilson disease with fulminant hepatic failure, the patient was treated by oral D-penicillamine 1 gm per day, intravenous zinc sulphate (about 8 mg per day elemental zinc), and given other supportive treatment. Unfortunately, the patient died of hepatic failure complicated with septic shock 21 days after the onset of symptoms. Autopsy found liver copper content was 586.92 ug/gm dry weight and kidney copper content: 300.19 ug/gm dry weight, abnormally high as compared with normal tissue. A review of the literature led to conclusion that the best treatment for Wilson fulminant hepatic failure is liver transplantation.
2353684##1990-6-1##Zinc therapy in Wilson's disease: observations in five patients.##We report our experience with zinc (Zn) therapy in five patients with Wilson's disease (WD). In addition to neurologic examination, evaluation of Kayser-Fleischer rings and liver function tests, copper (Cu) and Zn concentrations in liver tissue, plasma, and urine were periodically evaluated by spectrophotometry. Many of the patients had had side effects due to penicillamine (PCA). Oral Zn sulphate (220 mg tid) reduced the WD symptoms and resulted in normal urinary Cu excretion in all five patients. One patient who had a transient gastric complaint during Zn administration, and in whom a decrease in liver Cu content was not observed, did not show any improvement in liver histology. He resumed PCA therapy after 29 months of Zn therapy. We conclude that long-term Zn treatment in Wilson's disease can be a safe and effective alternative to Cu chelating agents. However, patients should be periodically monitored for their Cu/Zn status to assess patient compliance with therapy.
2368812##1990-6-1##X-linked recessive torsion dystonia in the Philippines.##The occurrence of an X-linked form of torsion dystonia in the Philippines was demonstrated by the genetic and biochemical analysis of affected males and their relatives. Thirty-six affected males were ascertained in 21 families by clinical neurologic evaluation. The mean age-of-onset of dystonia was 37.9 years with a range from 12 to 52 years. Neurologic symptoms began focally and progressed to either segmental or generalized involvement in all cases. Generalized dystonia developed in 78% of the patients after a mean duration of 6.8 years from the onset of symptoms. A family history of dystonia was elicited in 17 of the 21 kindreds, accounting for a total of 64 males and one possibly affected female, distributed among 224 individuals in 33 sibships. In 18 of the 33 sibships, 2 or more brothers reportedly had dystonia. There were 12 kindreds with a history of multigenerational dystonia. In those, only males of maternal ancestry were affected, and in 7 of these families, maternal grandfathers reportedly had dystonia. There were no instances of male-to-male transmission. Cytogenetic analysis did not show any X chromosome abnormalities in 4 affected propositi. Several secondary causes of torsion dystonia were excluded, including Wilson disease, aminoacidopathies, organic acidurias, oligosaccharidoses, and chronic hexosaminidase A and B deficiency. These findings substantiate the existence of an X-linked recessive form of primary torsion dystonia.
2222683##1990-6-1##Fulminant Wilson's disease: a report.##A 21 y/o female presented with fulminant hepatic failure and hemolysis. On the basis of the clinical presentation, levels of ceruloplasmin and serum copper a presumptive diagnosis of Wilson's disease was made. In spite of supportive measures and hemodialysis, the patient died one week after admission. Postmortem examination showed cirrhosis and increased copper stores in the liver, corroborating the clinical diagnosis of Wilson's disease. Study of the four siblings revealed that two are carriers, one is healthy and one may have the disease. Wilson's disease is a rare cause of fulminant hepatic failure that must be suspected specially when hemolysis is associated to the clinical picture. This mode of presentation is virtually fatal and early liver transplantation is the best form of therapy.
2196164##1990-6-1##Current therapy of chronic liver disease.##The study of chronic liver disease has been hampered by insufficient information relative to the pathogenesis of the many forms of hepatitis. Consequently, well-designed treatment strategies are frequently lacking. Wilson's disease is characterised by excessive copper accumulation in the liver and other organs. While d-penicillamine is clearly effective, many patients may not tolerate its many adverse effects. Trientine, oral zinc and unithiol have all shown promise as therapeutic alternatives. Autoimmune chronic active hepatitis responds well to prednisone and azathioprine. Cyclosporin has also produced clinical improvement in several case reports but no comparison has yet been made with the current standard therapy. Recombinant interferon-alpha (IFN alpha) has demonstrated the ability to inhibit hepatitis B viral replication, and the combination of oral corticosteroids followed by IFN alpha is more effective than either agent alone in eliminating viral replication in patients with chronic active hepatitis B. Currently, primary sclerosing cholangitis (PSC) has no standard medical management, but corticosteroids and methotrexate may each have a future role in its treatment. Drug treatment for primary biliary cirrhosis (PBC) has been disappointing, and early reports of success with d-penicillamine were not confirmed in large well-controlled trials. While some reports of improvement with several agents have been described, larger studies are still needed. Alcoholic liver disease continues to be associated with significant morbidity and mortality and numerous investigators have researched several different medical avenues of treatment. Success reported with androgens and the antithyroid agent propylthiouracil in alcoholic liver disease will need confirmation by other research before these agents can be recommended for routine use. Finally, colchicine may prove to be effective in slowing the rate of fibrosis in cirrhosis, but this has yet to be conclusively proven.
2379874##1990-6-1##Soluble interleukin 2 receptors in autoimmune chronic active hepatitis.##Children with uncontrolled autoimmune chronic active hepatitis have increased numbers of activated T lymphocytes expressing interleukin 2 receptors (IL2R). A soluble form of IL2R has recently been described whose proposed role is to downregulate T cell activation by competing for interleukin 2. We investigated whether a deficiency of soluble IL2R could account for the high concentrations of IL2R positive T lymphocytes in autoimmune chronic active hepatitis. Soluble IL2R was measured by enzyme-linked immunosorbent assay in the serum of 16 children with autoimmune chronic active hepatitis, eight with chronic liver disease due to hepatitis B virus infection, seven with Wilson's disease, nine with alpha 1 antitrypsin deficiency, and 15 healthy age matched controls. Soluble IL2R concentration was significantly higher in patients with autoimmune chronic active hepatitis than in healthy controls (mean (SEM) 475 (75) U/ml, 145 (8) U/ml respectively, p less than 0.01). Eleven patients who had active disease had significantly higher soluble IL2R concentrations (590 (89) U/ml) than the five cases with inactive disease (220 (36) U/ml, p less than 0.01). No difference was found between the controls and the patients with chronic liver disease due to hepatitis B infection, Wilson's disease, and alpha 1 antitrypsin deficiency. Percentages and absolute numbers of surface IL2R positive T cells as detected by immunofluorescence were significantly higher in the patients with autoimmune chronic active hepatitis (11.8% (1); 274/microliters (31)) than in controls (0.2% (0.1); 5/microliters (2), p less than 0.001), the highest values being found in those with uncontrolled disease. A significantly positive correlation was observed between concentrations of soluble IL2R and the percentage of T cells expressing IL2 receptors (r=0.67, p&lt;0.001). These results indicate that the high levels of IL2R positive T lymphocytes characteristic of autoimmune chronic active hepatitis are not due to a deficiency of soluble IL2 receptors.
2217665##1990-6-1##Wilson's disease: 35 years' experience.##Thirty-seven Chinese patients fulfilling the criteria for Wilson's disease seen during a 35-year period were reviewed. Males and females were equally affected. Twenty-two patients were symptomatic and 15 asymptomatic; most of them presented before the third decade. Thirty-one per cent of the relatives screened showed evidence of disease, and parents were rarely affected (13 per cent). Half of the adult symptomatic females presented with primary amenorrhoea. Liver laboratory tests were abnormal in only 50 per cent of patients, with gamma-glutamyltranspeptidase being the most sensitive index. Renal disease was infrequent. Serum caeruloplasmin level was the single biochemical parameter of prognostic significance (p = 0.0001). Seventy per cent of the symptomatic patients showed an improvement after treatment with penicillamine.
2191491##1990-6-1##A review of the biochemical roles, toxicity and interactions of zinc, copper and iron: II. Copper.##Copper is an essential nutrient for living matter. Through its cuproenzymes, copper displays a variety of metabolic functions. Atomic absorption spectrophotometry, radioisotope studies and establishment of cell and molecular biology have provided the necessary tools to study copper absorption, metabolism, physiology and biochemistry. The vital role of metallothionein in copper homeostasis is examined. Ceruloplasmin represents the molecular link between copper and iron metabolism. The genetic predisposition of copper toxicity has been attributed to the cause of Wilson's disease in humans. The interrelationships between copper and other dietary factors is addressed.
2382969##1990-5-1##Wilson's disease in Israel: a genetic and epidemiological study.##Clinical and family history data on persons affected with Wilson disease (WD) living in Israel between 1958 and 1984 were ascertained from the literature, hospital records and neurological and gastroenterological clinics. From this population of 51 families, representing a diversity of Middle Eastern. North African and European backgrounds, blood samples were collected from affected individuals in 21 families, their parents, sibs and other relatives for quantitative determinations of plasma copper and ceruloplasmin, liver tests and DNA analysis. Although the majority of patients have the hepatic form of the disease, hepatic and neurological cases were found among all ethnic groups. In fact, affected sibs in several inbred families who most likely inherited two copies of the same mutant allele had different symptoms. Gene frequencies were calculated for each of the populations taking into account inbreeding, probability of ascertainment, and estimated incidence. Although many of these communities have gene frequencies which are comparable to worldwide estimates, high prevalence of disease is maintained by consanguineous mating patterns. Probabilities of WND genotypes were calculated for 129 unaffected relatives who had an a priori risk of inheriting at least one WND allele using information from 10 DNA markers closely linked to the WND locus. There was no evidence that multiple loci are responsible for the observed clinical variability in this sample of families. Furthermore, studies of serum copper and ceruloplasmin levels in unaffected relatives suggest that phenotypic variability in WD may be due in part to an interaction of the WND locus with other genetic or non-genetic modifiers such as age.
2334309##1990-5-1##Wilson's disease. Development of neurological disease after beginning penicillamine therapy.##Patients with neurological symptoms and signs of Wilson's disease have been frequently noted to have a worsening of their condition after beginning chelation therapy with D-penicillamine. Presymptomatic patients, however, are not expected to develop neurological manifestations once appropriate therapy is begun. We describe a patient who was seen with hepatic disease and no neurological symptoms who became neurologically incapacitated soon after beginning penicillamine therapy. This case identifies an unexpected complication of penicillamine therapy that should be watched for in the presymptomatic patient who is beginning therapy.
2347848##1990-5-1##Pitfalls of diagnosis in the early stages of Wilson's disease.##Diagnosis of Wilson's Disease in the early stages may be elusive in patients presenting without neurological symptoms. A case history is presented which demonstrates the pitfalls in making the diagnosis. Presenting psychiatric symptoms were nonspecific. Ceruloplasmin level was initially elevated to normal range. Liver biopsy showed early nonspecific cirrhosis; staining for copper did not show the dramatic effects expected with Wilson's Disease. Neurological examination, including NMR, was within normal limits. Kayser-Fleischer rings are no longer considered pathognomic. Urinary copper excretion helped to establish the diagnosis.
2355785##1990-4-21##[Hemolytic anemia and Wilson's disease].##
2327394##1990-4-1##Acute hemolytic anemia and biliary colic as presenting manifestations of Wilson's disease.##
2353802##1990-4-1##Routine screen for Wilson's disease?##
2170275##1990-4-1##Wilson's disease presenting with refractory rickets.##
2141358##1990-4-1##Normal striatal glucose consumption in two patients with benign hereditary chorea as measured by positron emission tomography.##Positron emission tomography (PET) with [18F]-2-fluoro-2-deoxy-D-glucose (FDG) was used to investigate the regional cerebral metabolic rate of glucose consumption (rCMRGlc) in two patients with benign hereditary chorea (BHC) and 21 normal subjects. Relative and absolute values of cerebellar, striatal, thalamic, and cortical rCMRGlc were within normal limits for both patients with BHC, indicating that the choreic movement disorder encountered in these two patients was not caused by a decrease of energy metabolism in the striatum such as that found regularly in most patients with other forms of chorea (e.g. Huntington's and Wilson's disease).
2207352##1990-3-1##Molecular genetics of chronic liver diseases.##The molecular genetics of five common single gene and one polygenic chronic liver disease is discussed. In two of the single gene disorders, alpha 1-antitrypsin deficiency and cystic fibrosis, the gene responsible is now known and the repertoire of different mutations underlying the disease is being defined. In the other three single gene defects (haemochromatosis, polycystic liver disease and Wilson's disease) the chromosomal location of the disease allele is known. It is anticipated that recombinant DNA techniques will enable the genes responsible for these diseases to be cloned in the near future, thus allowing the biochemical abnormalities to be defined through reverse genetics. In many chronic liver diseases the relative contribution of genetic and environmental factors remains unclear. Evidence suggests there is a definite genetic component in predisposition to alcoholic cirrhosis; the role of putative candidate genes is discussed. It is hoped that the definition of a genetic locus linked to alcoholic cirrhosis will ultimately teach us more about the basic pathogenesis of this disease.
2311235##1990-3-1##Hyperparathyroidism in a patient with Wilson's disease.##We describe hyperparathyroidism in an 18-year-old man with Wilson's disease--the first report in the English literature of the simultaneous occurrence of these two conditions.
2344986##1990-3-1##[Therapeutic approaches to Wilson's disease].##
2332582##1990-3-1##Developmental changes in hepatic copper proteins in the guinea pig.##We have suggested that Wilson's disease is caused by failure to adapt from the fetal to adult mode of copper metabolism and that the study of liver copper ontogeny might provide clues to the pathogenesis of Wilson's disease. This study traces the developmental changes in hepatic copper binding proteins in the guinea pig. During the last trimester, as fetal hepatic copper increases, metallothionein is the major copper binding peak in both the soluble and particulate supernatant fractions. After birth this peak decreases in parallel with the fall in liver copper. Metallothionein is absent from adult soluble supernatant and copper is associated with superoxide dismutase and a high molecular weight protein. A novel low molecular weight copper binding component is present in the particulate supernatant of neonatal liver, but is absent from the adult. Unlike many other animals, but similar to man, the switch from the fetal to adult mode of copper metabolism occurs at birth. Comparison of the copper protein profiles of the fetus and neonate with Wilson's disease are required to test the hypothesis that Wilson's disease is caused by developmental arrest of copper ontogeny.
2352215##1990-3-1##[Wilson's disease. X-ray CT and MRI aspects of the brain in a case before treatment].##Wilson disease is an autosomal recessive disorder of copper metabolism. The case of a young girl is reported here, with CT and MRI data before any treatment. The unusual MR presentation on T2 weighted sequences is studied, and compared with those described in patients under treatment.
2172933##1990-3-1##[Liver cirrhosis in childhood. Considerations on 22 cases with different etiology].##Although rather uncommon and multifactorial in etiology, liver cirrhosis is a severe and often rapidly fatal disease in pediatrics. In our institution, during the last 15 years, 22 children with liver cirrhosis have been followed. The underlying predisposing condition was HBV infection (8 cases), CMV perinatal infection (2 cases), Wilson's disease (4 cases), chronic cholestasis (2 cases) and alcohol abuse (2 cases); in 4 cases no predisposing condition was evident. In all cases the histological examination of the liver was the diagnostic cornerstone. The mean age at diagnosis was 6 years and 8 months, with an early onset especially in the posthepatitis cirrhosis. In 10 out of 22 patients, cirrhosis was not preceded by an history of chronic liver disease. Poor subjective symptomatology was present in 13 of the cases, hepatomegaly in all, splenomegaly in 18 cases, signs of hepatic failure in 13 cases. In all patients various impairments of hepatocellular synthesis were detectable, especially during the period preceding the development of hepatic insufficiency. The mean time to cirrhosis was 5 years. The average duration of the follow up was 3 years and 4 months: during the follow up 6 patients improved, 5 patients showed no clinical or functional modifications of their hepatic disease, 3 patients worsened and 8 died. In order to perform suitable treatment of liver cirrhosis the need of early diagnosis and etiological definition should be emphasized.
2165877##1990-3-1##[Clinical analysis of 418 patients with Wilson's disease in traditional Chinese medicine and Western medicine therapy].##From 1974 to 1988, 418 cases of Wilson's disease were treated with TCM-WM in our hospital. 147 cases were of Wilson's type; 149 cases were of pseudosclerosis type; 40 cases were of abdominal and hepatocerebral type; 21 cases were of choreoathetosis type and 21 cases of other types. After a course of treatment for 3 to 6 months, 103 patients showed marked improvement and 286 made some improvement, but no effect was found in 22 patients and 7 deaths were observed. The results were as follows: (1) The mortality in the severe and moderate groups were significantly higher than the mild (P less than 0.05) and the marked effective rate was less than the latter (P less than 0.01). (2) The marked effective rate was lower in abdominal and hepatocerebral type, and no significant difference was found in recovery rate between Wilson's type and pseudosclerosis type.
2154449##1990-2-15##Detection of multiple forms of human ceruloplasmin. A novel Mr 200,000 form.##Three polypeptides with apparent Mr = 200,000, 135,000, and 115,000, reacting with antibody to human ceruloplasmin (Cp), were consistently found in sera of normal adult and newborn subjects, patients with Wilson's disease, as well as in the oxidase-active fraction of purified human Cp, resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The concentrations of the three Cp polypeptides were proportional to the total Cp oxidase activity measured in whole serum. Peptide mapping revealed that the three Cp polypeptides were closely related. Cross-linking of Cp135 resulted in dimers with electrophoretic mobility similar to that of Cp200. A common shift in electrophoretic mobility following N-glycanase treatment indicated that all three polypeptides were N-glycosylated, and that the apparent differences in molecular mass could not be related to the carbohydrate moiety. Immunoprecipitates of cell lysates of [35S]cysteine labeled HepG2 cells revealed the presence of two species of newly synthesized Cp polypeptides, Mr 200,000 and 135,000, which were secreted into the media. Secretion of Cp200 by the human liver appears to be physiologic and may be the result of posttranslational modification of Cp135.
2313310##1990-2-1##Trunkal myoclonus with spontaneous priapism and seminal ejaculation in Wilson's disease.##
2324767##1990-2-1##Brainstem auditory evoked potentials in Wilson's disease.##Twelve patients with Wilson's disease, aged 11-25 years, underwent brainstem auditory evoked potential (BAEP) study. The results were correlated to clinical, neuroradiological and laboratory data. Ten had prominent to severe neurological manifestations, suggestive of involvement of one or several CNS structures, and 2 were neurologically free. All had evidence of abnormal copper metabolism, and 8 had CT scan evidence of brain atrophy, or hypodense areas in basal ganglia, or both. The 2 patients without neurological manifestations as well as one with neurological signs had normal BAEP. One patient with neurological signs had increased N1 latency due to cochlear hearing loss, but normal interpeak intervals, while 8 of 10 patients with prominent neurological symptoms and signs had abnormal BAEPs (prolongation of NIII-NV interpeak interval). The value of NIII-NV interpeak interval correlated with the number of different neurological signs (neurological score) attributable to involvement of different CNS structures (r = 0.64 at P = 0.001). Abnormal BAEPs do not seem to be an early finding in Wilson's disease.
2303974##1990-2-1##Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting.##A 12-year-old boy with Wilson's disease developed exertional dyspnea, cyanosis, and finger clubbing 10 months after diagnosis. The hypoxemia was caused by arteriovenous shunting, demonstrated by radionuclide scanning and pulmonary arteriography. Orthotopic liver transplantation was performed after the development of severe hypoxemia. There was no apparent reversal of the intrapulmonary arteriovenous shunting and he died 10 days posttransplantation of multiple organ failure secondary to hypoxemia. Monitoring arterial oxygen saturation in children with cirrhosis is warranted since the presence of significant arteriovenous shunting may influence prognosis and decisions regarding liver transplantation.
2350924##1990-2-1##[High field magnetic resonance imaging in Wilson's disease].##Magnetic resonance imaging studies on 3 cases with Wilson's disease were performed, using high field magnetic resonance system of 1.5 tesla. All patients had neurological findings of tremor, rigidity, dystonia or dysarthria at onset. Two patients had been treated with D-penicillamine for 14 years and 7 years respectively, and one patient was not treated then. T2-weighted images revealed abnormalities of signal intensity in lenticular nucleus, thalamus, pulvinar, superior colliculus, lateral portion of substantia nigra, midbrain and pontine tegmentum, and cerebral and cerebellar white-matter. Especially noted were following three hitherto undescribed abnormalities; high signal intensity of globus pallidus which normally shows very low signal intensity, restoration of signal intensity of lateral portion of substantia nigra, and marked low signal intensity of pulvinar and superior colliculus.
2298126##1990-1-19##[Wilson's disease--critical deterioration under high-dose parenteral penicillamine therapy].##A 31-year-old man with Wilson's disease, not treated for the past 4 1/2 years, was admitted to hospital with brain concussion after a fall. While receiving penicillamine, 1 g i.v. four times daily, the neurological signs worsened and akinesia, mutism, tachy- and bradyarrhythmias, as well as transitory respiratory insufficiency developed. Serum copper concentration on the sixth day of treatment was markedly decreased to 28 micrograms/dl, rising to 60 micrograms/dl on the ninth day. 24-hour urinary copper excretion was at first 4500-5000 micrograms. Only after drastic reduction of the penicillamine dosage to 600 mg three times daily was there any improvement and after 11 weeks the patient was again able to walk and was discharged. Marked, mainly hepatic, copper depletion from the high penicillamine dosage was the likely cause of the patient's initial deterioration. To avoid cerebral complications penicillamine should be administered in gradually increasing doses.
2330819##1990-1-1##Neuropsychological findings in treated Wilson's disease.##Seventeen patients, treated for Wilson's disease (WD), underwent a set of neuropsychological tests and were compared with a closely matched control group. There were clear differences between the groups (chi 2-test, p less than 0.0001). Wilson patients with only hepatic involvement, however, did not at all differ from their controls. Wilson patients with neuropsychiatric signs differed from controls on a reasoning test (p = 0.0016), and the entire WD group differed on a perceptual speed task (p = 0.0025). Compared to normal test values, however, the patients' group means were all within plus or minus one standard deviation from the normal mean. Special testing procedures and construction of the test battery excluded a factor of motor deficits as a major cause for the differences. The neuropsychological findings are viewed in relation to other findings in patients with motor disorders and predominantly subcortical lesion sites. Wilson's disease may be a dementing condition, but not when treated adequately.
2371874##1990-1-1##Oral zinc sulphate treatment in Wilson's disease.##
2161227##1990-1-1##The protective effect of normal and pathological (Wilson disease) ceruloplasmins on human erythrocytes.##The binding of the ceruloplasmin (CP) from the healthy donor blood and of ceruloplasmin-like protein (p-CP) isolated from the Wilson patients' blood with erythrocytes (RBC) of healthy donors and with RBC of Wilson's patients (p-RBC) was investigated. It was shown, that the number of CP binding sites both on the RBC and p-RBC was significantly lower than that for p-CP, but Kd value for p-CP binding with both types of erythrocytes was approximately ten times higher than Kd value for CP. The protective action of CP on copper stimulated hemolysis is significantly higher than that of p-CP. The protective action of CP on ferrous ion stimulated hemolysis does not correlate with its ferroxidase activity. Contrariwise, the protective effect of p-CP which has no ferroxidase activity is more powerful than that of CP.
1966785##1990-1-1##Molecular forms of ceruloplasmin in hepatolenticular degeneration and their interaction with human erythrocyte ceruloplasmin receptor.##Immunochemical methods were used to show that the sera of homozygous and heterozygous carriers of the Wilsonian gene contain, together with normal ceruloplasmin (CP), a CP-like protein that differs from CP in its enzymatic, immunological, and physicochemical properties. The CP-like protein was isolated from the sera of patients with hepatolenticular degeneration (HLD) by means of affinity chromatography, and monospecific antibodies to this protein were obtained. The presence of an 80 kDa immunoreactive polypeptide specific to the CP-like protein was demonstrated by immunoblotting with antibodies to normal CP and monospecific antibodies to the CP-like protein. Analysis of the ratios of the molecular forms of CP in homozygous and heterozygous carriers of the Wilsonian gene indicated that this ratio reflects the dosage of the mutant gene. The kinetic parameters of the interaction of these proteins with the CP-specific receptor on the erythrocyte membranes from healthy individuals and from patients with Wilson's disease (HLD) were determined. The CP receptor on erythrocyte membranes in HLD patients is not altered and its interaction with normal CP has the same kinetic parameters as the binding of normal CP to the erythrocyte receptors from healthy individuals. The CP-like protein also retains the ability to bind to the CP-specific receptor but the ligand-receptor complex is less stable than in the case of normal CP. The possible mechanism of the molecular heterogeneity of CP in the Wilsonian mutation is discussed.
1966784##1990-1-1##Protective action of blood ceruloplasmin obtained from normal individuals on red blood cells compared with that from patients with Wilson's disease.##A ceruloplasmin-like protein (pathological CP, p-CP) was isolated from the serum of patients with Wilson's disease whose antigenic determinant was identical to that of ceruloplasmin (CP) obtained from the blood of normal individuals. Because the protective action of CP involves its interaction with receptors on red blood cells (RBC), the binding of CP and p-CP to the RBC from normal individuals and to those from patients with Wilson's disease (p-RBC) was investigated. The number of binding sites for CP on both types of RBC was significantly lower than that for p-CP. The dissociation constants for CP-RBC and CP-p-RBC complexes were very similar (1.15 and 1.37 nM, respectively), as were those for the complexes of p-CP with RBC and p-RBC (11.1 and 11.8 nM, respectively), but the binding constants for p-CP with RBC of both types were ten times higher than the CP binding constants. The ability of CP to prevent Cu(2+)-induced lysis of RBC was significantly higher than that of p-CP. The protective action of CP and p-CP during RBC lysis in two Fe(2+)-containing systems did not correlate with their oxidative and ferroxidase activities. On the contrary, the protective effect of p-CP, which had significantly lower oxidase activity and no ferroxidase activity, was greater than that of CP.
2379260##1990-1-1##The effect of D-penicillamine on metallothionein mRNA levels and copper distribution in mouse hepatocytes.##Penicillamine increases the levels of metallothionein (MT) mRNA in a time and concentration dependent manner without altering either the rate of copper uptake or the amount of copper within the cell. The effect is dependent on the presence of intracellular copper, however, since depletion of copper by chelators blocks the effect, and does not alter the ability of dexamethasone to stimulate mRNA production. Penicillamine did not alter the distribution of 64Cu in the hepatocytes, as measured by fast protein liquid chromatography (FPLC), although the pattern may be affected by the amount of MT present. The data indicates that penicillamine removes copper from some intermediary ligand, thereby making it available to induce metallothionein. It is possible that this is part of the therapeutic action of the chelator in the treatment of Wilson's disease.
2073472##1990-1-1##[The pediatric liver transplant. The surgical aspects].##The Liver Transplant Program was begun at &quot;La Paz&quot; Children's Hospital on January 1986 after a long period of experimental activities. This was the first experience in the Madrid Community. From January 1986 to June 1989 we made 32 orthotopic liver transplants in 25 patients, seven received a second graft and one them received a liver segment because the donor had a large liver. 114 patients were evaluated but only 84 were considered candidates for liver transplantation. The different diseases of the transplants were: biliary atresia (9), Alagille syndrome (4), deficit alpha 1-antitrypsin (3), autoimmune hepatitis (2), neonatal hepatitis (1), Byler disease (1), Wolman disease (1). absent bile ducts (1), Wilson disease (1). Surgical technique was the same that has been described by Starzl using Eurocollins and lactate Ringer. In the 100% we made multiorgan procurement, liver and kidneys, 7% with heart and two heart-lung with hypothermia. In one occasion the donor operation was done out of the country (RFA--Düsseldorf). We never used by-pass during anhepatic phase. Arterial reconstruction was done by end-to-end anastomosis and in five patients we used aortic graft. Our arterial thrombosis rate was 18%. In one patient the portal vein was atrophic and we used a femoral graft between superior mesenteric vein and donor portal vein. For biliary reconstruction we used Roux-en-Y with intraluminal stent in 18 cases and choledocho-choledochus anastomosis in seven cases. Four patients had biliary complications: two biliary fistulas secondary to arterial thrombosis, biliary stenosis and bowel perforation by the intraluminal stent.(ABSTRACT TRUNCATED AT 250 WORDS)
2171843##1990-1-1##Tremor of tongue and dysarthria as the sole manifestation of Wilson's disease.##Neurological form of Wilson's disease in children usually manifests with dystonia as the initial sign. Tremor of extremities, dysarthria and ataxia may follow. Copper deposits in gray and white matter along with the basal ganglia. A pediatric case presenting with tremor of the tongue and dysarthria as the only findings of Wilson's disease is reported. Tongue tremor should also be taken into notice within the basal ganglia symptomatology.
2152263##1990-1-1##[Fulminant Wilson's disease in Costa Rica. Clinico-pathological study of 7 cases].##In the last eighteen years, from 1972 to 1989, around 150 cases of Wilson's disease have been diagnosed in Costa Rica (6/100.000 inhabitants). In the San Juan de Dios Hospital, 120 cases have been studied during this period, seven of whom died with a picture of acute hepatic insufficiency, hemolytic anemia, encephalopathy, intestinal bleeding and renal insufficiency. In four of the cases, postmortem histopathologic studies were done with high resolution microscopy, which revealed extensive submassive necrosis of the liver, with severe cholestatic, lytic and acidophilic necrosis with nodular, irregular regeneration and specially microvacuolar steatosis, different from that observed in other forms of fulminant hepatitis. With the clinical, laboratory and histopathologic findings, we concluded that fulminant Wilson's disease is a well-defined pathological clinical entity of fatal evolution with no response to therapy, including early treatment with penicillamine and steroids.
2182083##1990-1-1##Assessment of liver transplantation.##Liver transplantation, one of the most technically difficult of all solid organ transplant, is effective in extending the lives of carefully selected adult patients who have end-stage organ failure due to irreversibly damaged livers. Factors that influence the outcome of liver transplantation include the specific liver disease, patient's health status, and the presence or absence of extrahepatic disease or disorder. The outcome of liver transplantation has been improved significantly by the introduction of cyclosporine and continues to be improved by the use of newer immunosuppressants such as OKT3 monoclonal antibody and antithymocyte globulin for the prevention of graft rejection. The quality of life for those who survive one or more years was generally good. Survival rates were good for patients with primary biliary cirrhosis, primary sclerosing cholangitis, hepatitis B (antigen negative), alcoholic cirrhosis, alpha-1-antitrypsin deficiency disease, Wilson's disease, and primary hemochromatosis. Patients with liver malignancies, with the possible exception of those with epithelioid hemangioendoepithelioma, had poor outcomes, while patients presenting with other end-stage liver diseases had variable outcomes.
2292473##1990-1-1##The cytopathology of metal overload.##Researchers have been able to demonstrate the cytotoxicity of copper overload in animal models. This has allowed them to not only localize the intracellular distribution of copper but also to study directly the subsequent organelle injury at the ultrastructural level. The lesions seen in copper overload appear to vary from species to species. In humans, marked mitochondrial abnormalities are seen in Wilson's disease while diet overloaded rats show nuclear destruction and various membranous abnormalities. Sequestration of copper within lysosomes appears to protect hepatocytes from its toxicity. However, the mechanism by which the metal is incorporated into lysosomes is not known.
2324883##1990-1-1##Treatment of Wilson's disease with triethylene tetramine hydrochloride (Trientine).##Penicillamine is the drug of choice for the treatment of Wilson's disease, whatever the stage of the illness. Toxic manifestations may preclude the use of this life-saving drug in some patients and discontinuation of penicillamine therapy usually leads to death. We report our experience with Trientine in seven patients, aged 13 to 33 years, with Wilson's disease who developed toxic manifestations with penicillamine that required discontinuation of therapy. These include two with nephrosis, one with neutropenia, two with thrombocytopenia, and one each with a SLE-like and a Henoch-Schonlein-like syndrome. The patients were treated for periods from 6 weeks to 16 years with a dose of 0.5 to 2 g/day. Trientine proved to be an effective alternative copper chelating agent in the treatment of Wilson's disease in patients with penicillamine-induced neutropenia, thrombocytopenia, SLE, and nephrosis. No serious untoward side effects were noted.
2299611##1990-1-1##Macromastia in a woman treated with penicillamine and oral contraceptives. A case report.##A patient with Wilson's disease treated with penicillamine developed severe hirsutism. After treatment with oral contraceptives, her breasts enlarged rapidly, and she experienced cyclic mastodynia. Around the time of her breast enlargement she also developed gingival hyperplasia.
2266811##1990-1-1##Cerebral abnormalities in Wilson's disease as evaluated by ultra-low-field magnetic resonance imaging and computerized image processing.##The cerebral involvement of a 13-yr-old boy with Wilson's disease was serially evaluated during the first 18 mo of D-penicillamine treatment. An ultra-low-field magnetic resonance imaging (ULF MRI) system, operating at 0.02 T, with computerized image processing was used. The half-yr period prior to the clinical diagnosis was set, the patient had showed poor school performance, emotional lability, deteriorating handwriting, progressively slow, gross, and fine motor functions, and a fixed rigid smile. No overt signs of liver disease were found. With D-penicillamine treatment (1-1.5 g/d) a continuous improvement was seen. The pretreatment MRI investigation showed pronounced pathological transformation in the basal ganglia. However, changes were seen also in most other parts of the brain indicating diffuse involvement. During treatment the computerized MR images became gradually more normal. The current magnetic resonance imaging system with computerized image processing is a sensitive and simple method for evaluation of subtle parenchymal changes of the brain.
2259359##1990-1-1##Involvement of corticospinal tract in Wilson's disease. A study of three cases with transcranial stimulation.##Muscle responses evoked by transcranial stimulation were studied in three patients with Wilson's disease. Abnormalities indicating involvement of corticospinal tract were demonstrated in one patient. In keeping with recent evoked potential studies, this finding suggests that lesions in Wilson's disease may affect structures other than the extrapyramidal system.
2267049##1990-1-1##[Hepatolenticular degeneration].##Hepatolenticular degeneration (Wilson's disease) is a hereditary disease in which metabolic disorder of copper leads to its accumulation in the liver, brain, cornea and kidneys with consequent pathologic changes in those organs. Hereditary mechanism of the disease is autosomal recessive with prevalence of 30-100 per 1,000,000 inhabitants. Etiology of this disease is not yet explained. There are two hypotheses. The first one is that it is the disorder of ceruloplasmine metabolism caused by insufficient synthesis of normal ceruloplasmine, or synthesis of functionally abnormal ceruloplasmine. The second one is: the block of copper biliar excretion which is the consequence of the liver lysosomes functional defect. Pathogenetic mechanism of disease is firstly long-term accumulation of copper in the liver, and later, when the liver depo is full, its releasing in circulation and accumulation in the brain, cornea, kidneys and bones, which causes adequate pathologic changes. Toxic activity of copper is the consequence of its activity on enzymes, particularly on those with -SH group. There are two basic clinical forms of the disease: liver disease or neurologic disease. Before puberty the liver damage is more frequent, while in adolescents and young adults neurologic form of the disease is usual. The liver disease is nonspecific and characterized by symptoms of cirrhosis and chronic aggressive hepatitis. The only specificity is hemolytic anemia which, in combination with previous symptoms, is important for diagnosis of the disease. Neurologic symptoms are the most frequent consequence of pathologic changes in the basal ganglia. In our patients the most frequent symptoms were tremor (63%); dysarthria, choreoathetosis and rigor (38%); ataxia and mental disorders (31%); dysphagia and dystonia (12%), diplopia, hypersalivation, nystagmus and Babinski's sign (6%). Among pathologic changes in other tissues and organs the most important is the finding of Kayser-Fleischer ring in the cornea as a result of copper accumulation. Its importance for precise diagnosis is great. The diagnosis of the disease is based on anamnesis, clinical examination, specific and nonspecific laboratory tests. The therapy of choice is penicillamine. If we use it early, the result will be good remission in the majority of patients. Late diagnosis or delay in treatment cause death which is the result of bleeding from esophageal varices or basal ganglia disease. Immunologic damages caused by penicillamine demand interruption of therapy and substitution by three-ethyl-tetra-amine (TETA). We also use zinc salts and tetratiomolibdate in therapy of this disease. Pathogenesis, clinical picture and therapy of the disease are based on our own results.
2215906##1990-1-1##Cranial MRI in Wilson's disease.##Thirty-eight patients with biochemically proven Wilson's disease underwent magnetic resonance-imaging (MRI) of the brain as well as neurological examinations. The patients were scanned using spin-echo (SE) sequences; the neurologist was looking for typical symptoms: dysarthria, tremor, ataxia, rigidity/bradykinesia and chorea/dystonia. Pathological MR findings believed secondary to this uncommon inherited disorder of copper metabolism were found in twenty-two subjects. Focal abnormalities were seen in the lenticular, thalamic and caudate nuclei as well as in brain stem and white matter; these lesions were best demonstrated on T2-weighted sequences as hyperintense areas. In eight patients we found diffuse brain atrophy with consecutive widening of the ventricular system. Five subjects showed mild, nineteen severe neurologic deficits. Generally there was no correlation between MR findings and clinical neurological symptoms; the impairment of cell-metabolism causing functional alterations of the brain precedes morphological changes. During treatment with the copper chelator D-penicillamine there seemed to be a phased course of disease. Shortening of T1-relaxation due to paramagnetic influence of copper was not seen; a possible explanation could be intracellular deposition--a proton-electron-dipolar-dipolar-interaction would therefore be impossible.
2095555##1990-1-1##[Prenatal diagnosis: a chance? risk? dilemma?].##In research on congenital metabolic disorders, a biochemist can choose between the theoretical and the practical approach. The diagnosis of metabolic diseases relies on 1) the determination of the presence of metabolites under normal conditions that are direct substrates of the defective enzyme (e.g., the Gm2 ganglioside in the brain tissue of a patient with Tay-Sachs disease); 2) the determination of the lack or insufficiency of the direct product of the defective enzyme (e.g., aryl sulfatase A in the cells of patients with metachromatic leukodystrophy), hormone (hypothyroidism), or receptor (congenital hypercholesterolemia); 3) determination of substance whose reduction was established by experimentation, but the cause of the decrease is not known (ceruloplasmin in Wilson's disease); and 4) DNA analysis. Metabolic impairment of genetic origin is not treatable. The disease can be prevented by 1) removing the inappropriate metabolite (e.g., copper accumulation can be avoided by giving penicillamine or zinc salts); 2) limiting those substances in the critical phase of childhood that are components of the defective enzyme (e.g. gluten reduction in colic and protein in phenylketonuria); 3) supplementing the insufficient metabolite (e.g., phosphate in hypophosphatemia by sound for 12 hours a day); 4) protecting the patients (e.g. from light in porphyria); and 5) treatment by substances (giving coagulation factor VIII in hemophilia and thyroid hormones in hypothyroidism). There is a dilemma in subjecting patients to a diagnosis of progression to Huntington's chorea 20 years in advance or informing them about the high risk of hereditary disease for the next child (25% for the recessive and 50% for the dominant mode). Ethical committees have usually opted for a recommendation of selective abortion in clear-cut cases. Increasingly refined diagnostic methods have magnified the responsibility of the biochemist.
1981625##1990-1-1##[The use of positron-emission tomography in psychiatry].##Positron-emission tomography (PET), a noninvasive analytical method, made possible the detection of regional alterations in the central nervous system, thus demonstrating &quot;in vivo&quot; the presence of biochemical alterations and the organization of cerebral function in the pathological states. The study of glucose cerebral metabolism velocity, performed recently with the aid of PET, reveals that in the patients with thymic disorders the values recorded for the bipolar syndromes differ from those recorded the for unipolar ones. At the same time, the direct measurement of the activity of the neuroanatomic structures involved in schizophrenia and their response to neuroleptics was possible. This technique and the F-fluoro-desixiglucose method were also applied to the patients with Alzheimer's disease, multi-infarct dementia, Huntington's disease. Wilson's disease and Parkinson's disease. Suggestive alterations of glucose metabolism velocity were noticed and the neuroanatomic structures involved in the pathological manifestations could be specified.
2359903##1990-1-1##[Wilson's disease in a Saudi Arabian female patient. Rapid changes in cerebral x-ray computed tomography].##Reports on Wilson's disease from Arab countries in the Middle East are rare, while the high frequency of consanguineous marriages should increase the prevalence of autosomal recessive diseases. The case of a 20-year old woman, born from first degree cousins in a relatively isolated area of Saudi Arabia, is reported. The presentation initially led to the diagnosis of catatonic schizophrenia but neurological deterioration occurred rapidly. Brain CT was normal 2 months after the clinical onset of the disease but showed necrosis of both putamens 15 months later. Diagnostic difficulties and the rapid brain CT changes are commented.
2331824##1990-1-1##[Neuroradiological studies of Wilson's disease by computed tomography and magnetic resonance imaging].##Three cases of Wilson's disease were imaged by computed tomography and magnetic resonance. They were characterized by common findings. CT scan showed atrophy of cerebral cortex, caudate head, midbrain and cerebellum, and areas of low absorption in the caudate head, putamen, globus pallidus, posterior limb of internal capsule, thalamus and midbrain. The T2-weighted MRI imaging demonstrated marked hyperintensity in the putamen, retrolenticular part of internal capsule, thalamus and midbrain. In 2 patients, these high intensity areas were decreased by chelating therapy. Improvement of the increased intensity on T2-weighted images led to the suggestion that the area of marked hyperintensity area might be edema or demyelination rather than neuronal loss or cavitation.
2618580##1989-12-1##Wilson's disease: clinical groups in 400 cases.##Existence of clinical subgroups among cases of Wilson's disease has long been postulated and various classifications suggested but none statistically tested. This study analyses, by means of pattern recognition techniques, 400 cases from 4 series including our own (n = 195). Factor analysis (to summarise variables) and cluster analysis (to derive groups of patients) were performed. From each series 4 clusters were derived, each containing a &quot;hepatic&quot; and at least one &quot;neurological&quot; cluster, other clusters being &quot;mixed hepatic &amp; neurological&quot; (3 series) and &quot;asymptomatic&quot; (3 series). Two series contained 2 &quot;neurological&quot; clusters; one dividing in terms of age and the other in terms of presence or absence of psychopathology. At least 2 factors, &quot;hepatic&quot; and &quot;neurological&quot;, emerged from each series. Reasons for differences are discussed. In conclusion, Wilson's disease is not homogenous: clinical groupings are supported by statistical classification.
2589927##1989-12-1##Wilson's disease. Psychiatric symptoms in 195 cases.##A series of 195 cases of Wilson's disease were assessed retrospectively on a range of variables, including psychiatric, neurologic, and hepatic symptoms, and biochemical data as recorded at first admission to a specialist clinic. Ninety-nine patients (51%) were rated as displaying some evidence of psychopathologic features, and 39 (20%) had seen a psychiatrist before the diagnosis of Wilson's disease. The most common psychiatric features were abnormal behavior and personality change, although depression and cognitive impairment were also rated frequently. Schizophrenialike psychoses were rare, apparently occurring at no more than chance frequency. Psychiatric symptoms were related to neurologic rather than hepatic symptoms, and certain symptoms (incongruous behavior, irritability, and personality change) had a particularly significant relationship with bulbar and dystonic disorders but not with tremor. Psychiatric manifestations are important in Wilson's disease, and many of the psychopathologic features seem to have an organic basis.
2592854##1989-12-1##Treatment of Wilson's disease with zinc. VII. Protection of the liver from copper toxicity by zinc-induced metallothionein in a rat model.##Patients with Wilson's disease often have a further increase in hepatic copper when given zinc as an initial treatment, although there is no associated clinical deterioration. To better understand this situation an animal model was developed in which copper-loaded rats are treated with zinc administered subcutaneously. In the presence of equal amounts of copper loading in liver, control rats show hepatic damage but zinc-treated rats do not. Zinc-treated rats have much higher levels of hepatic metallothionein. Gel filtration studies reveal that much of the hepatic copper in zinc-treated rats is in this metallothionein fraction, whereas the copper in control animals is primarily associated with fractions of high or low molecular weight. Subcutaneous zinc therapy also induces intestinal, but not brain, metallothionein. We interpret these findings to indicate that zinc therapy protects against copper toxicity in liver by induction of hepatic metallothionein, which sequesters copper in a nontoxic form.
2592853##1989-12-1##Treatment of Wilson's disease with zinc. VI. Initial treatment studies.##Eleven patients with newly diagnosed Wilson's disease were treated with zinc acetate as their sole anticopper therapy. Treatment duration was 8 to 37 months. Three of the patients had symptoms; in eight who were presymptomatic, diagnosis was made because of affected siblings who had symptoms. All patients did well clinically. Copper absorption was suppressed, as reflected by blockade of absorption of orally administered copper 64. Values for 24-hour urine copper and nonceruloplasmin plasma copper (freely available copper) were reduced. Values for liver-derived serum enzymes were also generally reduced in patients who had pretreatment elevations. Percutaneous liver biopsies were done initially and repeated in seven of the patients after 12 to 35 months of zinc therapy. In five of these patients a second biopsy specimen showed higher levels of copper than the first. In three of these five a third biopsy 6 to 23 months after the second revealed liver copper values that either had returned to the baseline value or were lower. One patient's initial biopsy specimen showed active inflammation, which subsided with therapy. All of the biopsies revealed histologic scarring typical of cirrhosis, and this did not appear to change over the course of therapy. We conclude that hepatic copper may increase temporarily during early zinc therapy but that the accumulated copper is sequestered in a nontoxic form. On the basis of animal studies we postulate that this sequestered copper is primarily bound to the high levels of hepatic metallothionein induced by zinc. Zinc appears to be a reasonable option for the initial treatment of patients with Wilson's disease, particularly those with presymptomatic disease.
2592852##1989-12-1##Zinc treatment of Wilson's disease.##
2591410##1989-11-1##Hypercalciuria and nephrolithiasis in Wilson disease.##
2807170##1989-11-1##Presymptomatic Wilson's disease: further questions and comments.##
2808820##1989-11-1##A blistering eruption associated with Wilson's disease.##
2478644##1989-11-1##Treatment of Wilson's disease with zinc. V. Changes in serum levels of lipase, amylase, and alkaline phosphatase in patients with Wilson's disease.##We noted a frequent increase in the serum enzymes amylase, lipase, and alkaline phosphatase in patients with Wilson's disease who are receiving zinc acetate therapy (25 or 50 mg elemental zinc three times daily). Typically, values are normal before the initiation of zinc therapy, increase to slightly above normal after a few weeks of therapy, and stabilize at the high normal range after approximately a year of treatment. Very large dosages of zinc (800 mg/day) produce even further elevation of serum lipase and amylase without the symptoms of pancreatitis. Pancreatic pathologic studies of a zinc-treated rat model receiving dosages equivalent to up to 25 times the effective dosage in a human being, which is based on milligrams of zinc per kilogram of body weight, reveal that no lesions are induced by zinc treatment in the pancreas. We interpret these findings to indicate that extended maintenance therapy with zinc does not pose a risk of pancreatic damage in patients with Wilson's disease.
2633173##1989-11-1##Two and half years of oral zinc sulphate therapy in an adult patient with Wilson's disease.##
2678257##1989-11-1##Hyperechoic medulla of the kidneys.##Eighteen patients were identified in whom ultrasound (US) of the kidney demonstrated a hyperechoic medulla. Diagnoses in the patients included gout in seven; Sjögren syndrome in two; medullary sponge kidney in two; primary aldosteronism in two; and Lesch-Nyhan syndrome, hyperparathyroidism, glycogen storage disease type XI, Wilson disease, and pseudo-Bartter syndrome in one each. The pathogenesis of the echogenicity was evaluated by comparing the findings from computed tomography and conventional radiography. It appears that a hyperechoic medulla is caused by hyperuricemia, medullary nephrocalcinosis, or hypokalemia. US is considered to be useful in evaluating renal involvement in patients with these diseases.
2623249##1989-11-1##[Wilson's disease: difficulties in diagnosis and therapeutic management in our country].##The clinical analytical and therapeutic results of a retrospective study of 11 cases of Wilson's disease carried out in &quot;La Fe&quot; Hospital in Valencia are presented. The disease had a neurological onset in 5 cases, an hepatic onset in 4 cases (3 acute hepatitis and 1 chronic hypertransaminemia), 2 cases started as an acute hemolytic anemia; one of the outbreaks occurred during a period of treatment interruption. Diagnosis showed some difficulty in one case since the disease was associated with positive hepatitis B markers, positive anti HIV antibodies and initially normal ceruloplasminemia values. The diagnostic difficulties derived from the interpretation of ceruloplasminemia, and blood and urine copper levels are pointed out as well as the difficulties encountered in our environment to determine intrahepatic copper levels and to perform a kinetic study with radioactive copper both of which are of vital importance to confirm doubtful cases. Two patients became pregnant in the course of the disease having normal pregnancies and deliveries, without any apparent abnormalities in the newborns. Treatment with D-Penicillamine was started in 9 cases, observing a low to moderate intolerance in 7 cases; there was one case of severe intolerance for which treatment had to be interrupted. The new therapeutical approaches based on the use of trientine (not available in our country) are discussed, together with the expectations of liver transplant in this disease.
2807195##1989-10-1##Hepatic morphology and histochemistry of Wilson's disease presenting as fulminant hepatic failure: a study of 11 cases.##Eleven cases of Wilson's disease presenting as fulminant hepatic failure were analysed retrospectively to determine the specificity or otherwise of the histological findings. All cases were cirrhotic, eight with a micronodular pattern. There was marked parenchymal collapse with ductular proliferation and mild inflammation. Other features included cholestasis, hepatocyte necrosis, microvesicular fat and nuclear vacuolation. Orcein staining demonstrated copper-associated protein in the periphery of cirrhotic nodules in all cases and also variably within nodules in eight cases. Copper was demonstrable by the rhodanine method in similar locations but the staining reaction was qualitatively weaker in all cases. Characteristically, there was staining of both parenchymal and mononuclear phagocytic cells. This triad of cirrhosis, strong copper-associated protein deposition and copper positivity was not present in a control group of 20 cases of fulminant hepatic failure of other aetiology and with a similar clinical presentation. It is concluded that in the clinical context of fulminant hepatitis the presence of cirrhosis should raise the suspicion of Wilson's disease and that, with routinely processed and stained tissue, including autopsy tissue, the diagnosis can be made histologically.
2638315##1989-10-1##Atypical Wilson disease--a case report with CT scan.##A case of atypical Wilson disease is being reported. Possible mechanism of the process, diagnostic features and CT appearance of brain is described. Early detection and therapy with copper chelating agents result in neurologic and performance improvement of patients.
2601108##1989-10-1##[MR imaging of the brain in Wilson's disease].##Two cases of Wilson's disease, who had been treated for eight years, were examined by MRI at 1.5 tesla. MRI of both cases demonstrated lesions with prolonged T1, prolonged T2 and partially shortened T2 in bilateral lentiform nuclei. Lesions with prolonged T1 &amp; T2 may reflect small cavitary lesions. On the other hand, shortened T2 area may be caused by copper deposits.
2571037##1989-9-30##Use of apomorphine to test for dopamine responsiveness in Wilson's disease.##
2805592##1989-9-1##Expression of the caeruloplasmin gene in the adult and neonatal rat liver.##1. It has been suggested that low levels of serum caeruloplasmin in Wilson's disease result from the failure to switch from a fetal to an adult mode of caeruloplasmin gene expression. To investigate postnatal expression of the caeruloplasmin gene, steady-state levels of caeruloplasmin messenger RNA in adult and neonatal rat liver were measured. 2. Copper parameters observed in neonatal rats were similar to those seen in Wilson's disease: hepatic copper concentration was significantly elevated (neonatal 164 +/- 35 micrograms/g, adults 50 +/- 8 micrograms/g, P less than .001) and serum copper and caeruloplasmin levels were low (neonatal 0.5 +/- 0.1 microgram/ml, adults 1.3 +/- 0.2 microgram/ml, P less than .001; neonatal 0.20 +/- 0.04 arbitrary units, adults 0.69 +/- 0.16 arbitrary units, P less than .001), respectively. 3. Caeruloplasmin messenger RNA levels were analysed by Northern and dot blotting using a 32P-labelled caeruloplasmin complementary DNA probe. A caeruloplasmin messenger RNA of approximately 4.4 kilobases was detected in both adult and neonatal rat liver, with no significant difference observed in steady-state levels. 4. A step subsequent to caeruloplasmin gene transcription must therefore be impaired in neonatal rats.
2805722##1989-9-1##Verbal recall and recognition abilities in patients with Wilson's disease.##Tests of memory and verbal fluency were administered to 19 neurologically impaired Wilson's patients, 12 non-neurologically impaired Wilson's patients and 15 normal control subjects. Wilson's patients with neurologic disease recalled significantly fewer words on the delayed recall version of the Rey Auditory Verbal Learning Test than control subjects (p less than .05) but they showed no impairment on the recognition version of this test. On a verbal fluency test (FAS) requiring the subject to retrieve items from different categories, Wilson's patients with neurologic disease generated significantly fewer words than control subjects (p less than .01). Results suggest that retrieval memory is mildly impaired in the neurologic WD group but rate of learning and rate of forgetting is normal.
2795240##1989-9-1##Trace metal interactions in vivo: inorganic cobalt enhances urinary copper excretion without producing an associated zincuresis in rats.##The effects of cobalt chloride on copper and zinc metabolism in male Sprague-Dawley rats were examined. These effects were compared with those of penicillamine, a chelating agent utilized in the therapy of the genetic abnormality of copper metabolism in humans, Wilson's disease. Cobalt elicited an increased (approximately 4-fold) urinary excretion of copper lasting through 72 h following a single cobalt dose. In contrast to the marked increase in urinary zinc excretion produced by penicillamine, cobalt greatly reduced (approximately 75%) zinc output in urine. Tissue copper and zinc concentrations were measured after treatment with cobalt at doses ranging from 12 to 60 mg/kg body weight. Substantially reduced (approximately 25%) renal copper concentration was observed at 1 and 3 d after cobalt administration. In addition, cobalt produced a concurrent dose-dependent elevation (up to 1.6-fold) in hepatic zinc concentration. Cytosolic zinc was eluted from a Sephadex G-75 column in the molecular weight region associated with metallothionein. Time-dependent induction of metallothionein concentration (10-fold) in liver by cobalt was confirmed by the cadmium/hemoglobin affinity assay. The ability of inorganic cobalt to elevate zinc concentration in liver and produce increased urinary copper excretion without the zincuresis that normally accompanies penicillamine administration represents a newly defined biological property of this essential trace metal.
2569616##1989-8-19##Copper deficiency in Wilson's disease.##
2597916##1989-8-1##Wilson's disease: a prospective study of psychopathology in 31 cases.##A prospective neuropsychiatric study of 31 consecutive subjects with Wilson's disease is reported. Exploratory factor analysis yielded four factors: neurological, cognitive, hepatic/depressive and psychiatric. Significant associations were found between a 'psychopathic' personality factor and neurological and dysarthria scores. The d' and beta coefficients of a signal-detection memory task dissociated: the former correlated only with Mini-Mental State and Benton visuospatial task; and the latter with depressive symptoms. Using discriminant function analysis, there was efficient classification of 'psychopathic' personality by dysarthria, and of individual depressive symptoms by disturbance of gait. Biochemical markers of hepatic dysfunction were significantly associated with certain depressive symptoms. No evidence emerged to support the putative association with schizophrenia-like psychosis.
2760187##1989-8-1##Is Wilson's disease a dementing condition?##A case presentation in this journal by Rosselli, Lorenzana, Lasselli and Vergara (1981) has raised the issue of intellectual deterioration in Wilson's Disease. Relevant findings in the recent literature are discussed.
2770433##1989-8-1##Copper overload in the developing guinea pig liver: a histological, histochemical and biochemical study.##The copper profile in Wilson's disease resembles that of human and guinea pig neonates. Microvesicular steatosis is characteristic of early histological damage in Wilson's disease. The aim of this study was to relate the histological, histochemical and ultrastructural changes seen in developing guinea pig liver to the developmental pattern of liver copper in these animals. Copper-stressed and control guinea pigs were studied. Liver biopsies were stained with haematoxylin and eosin, rhodanine (for copper), orcein (for copper-associated protein) and oil Red 0 (for fat). Selected specimens were examined by electron microscopy. Liver and serum copper levels and copper oxidase activity were also determined. Fetal liver copper increased during the last trimester of pregnancy, reaching five times the adult level in the perinatal period and falling rapidly in the 4 days after birth. Marked steatosis developed in both control and copper-stressed guinea pig liver. The fat score correlated strongly with liver copper concentration (r: 0.60; p less than 0.001). Orcein and rhodanine staining correlated with liver copper concentration (r: 0.52 and r: 0.40 respectively, p less than 0.01). Marked prenatal hepatic steatosis and its postnatal clearance correlates with changes in liver copper concentration. This experimental model provides an opportunity to study the pathogenesis of hepatic steatosis and the relationship between copper retention and steatosis.
2671636##1989-8-1##Neurologic manifestations of hepatic disease.##Neurologic complications of hepatic disease are not uncommon and involve the CNS more often than the peripheral nervous system or muscles. Progress in the therapy of neurologic disorders associated with hepatic failure has occurred in recent years. Notably, exciting developments in the treatment of hepatic encephalopathy with benzodiazepine antagonists will lead to a better understanding of the pathophysiology of this encephalopathy. The future use of these agents may eventually help reduce the morbidity and mortality of hepatic encephalopathy. The role of this class of drug in other metabolic encephalopathies remains to be established. Furthermore, new therapeutic and surgical alternatives to the treatment of Wilson disease also enhance our therapeutic options. The fate of patients with Wilson disease with fulminant hepatic disease and those patients unable to tolerate or unresponsive to penicillamine therapy has been greatly improved.
2683105##1989-8-1##Fulminant hepatic failure and orthotopic liver transplantation.##1. Twenty-four patients were transplanted for fulminant hepatic failure at the University of Nebraska Medical Center from 1986 (July) to 1988. Long-term survival is about 58%. 2. FHF is an increasingly common indication for liver transplantation. 3. Cerebral edema, organ availability, and late referral are obstacles to improved survival. 4. Randomized trials have not been performed to demonstrate that transplantation is superior toother therapies. For some etiologies, such as acute Wilson's disease, in which mortality is 100%, transplantation is clearly indicated. For other etiologies, such as acetaminophen-induced FHF, in which clear gains in survival have been shown using more conservative therapies, the decision to transplant patients becomes more difficult. As all forms of therapy improve, all patients will benefit.
2568563##1989-7-22##Wilson's disease patients can be decoppered.##
2662723##1989-7-1##Wilson's disease.##Wilson's disease, an autosomal recessive disorder of copper metabolism, most often becomes apparent in adolescence and may present with a multitude of signs and symptoms. Early diagnosis and treatment can prevent irreversible damage to the liver and the central nervous system. The diagnosis is confirmed by hepatic biopsy and quantitation of copper in the tissues. Treatment is chelation of excess copper. If untreated, Wilson's disease is fatal.
2697201##1989-7-1##[Wilson's disease. Hepatic manifestations].##
2627165##1989-7-1##[Wilson's disease: a report of 4 cases. Follow-up study of a patient for 33 years].##Wilson's disease is a rare disorder with relatively few studies about long term evolutional aspects. The aim was to relate 4 cases emphasizing their polymorphic clinical and laboratorial aspects and the evolutional study of one of them for 33 years and whose treatment enabled the disappearance of the symptoms and the signals of the disease.
2567812##1989-7-1##Potential confusion of neuroleptic malignant syndrome and Wilson's disease.##
2641294##1989-7-1##1H NMR studies on protein binding of histidine, tyrosine and phenylalanine in blood plasma.##The binding of histidine (His), phenylalanine (Phe) and tyrosine (Tyr) to macromolecules in blood plasma and serum has been investigated by high resolution 1H NMR spectroscopy. In single pulse and spin-echo spectra of quality control bovine serum and normal human plasma, there are no resonances in the chemical shift range to high frequency of delta = 5.3 ppm when measured in the pH* (meter reading, uncorrected for the presence of 2H2O) range 3 to 8.5. On acidification of the plasma to pH* less than 2.5, resonances from His and Phe are observable. In plasma from patients with Wilson's disease, weak signals from His and Tyr are seen in spin-echo spectra at pH* 7.6, but increase in strength on acidification and signals from Phe appear at pH* 1.8. Addition of standard solutions containing Tyr, His and especially Phe and Trp to plasma at neutral pH* results in poor recovery of their expected signal intensity in spin-echo spectra. Addition of 2 M urea to bovine plasma at pH* 4.5 results in the appearance of Phe signals. These data are consistent with Phe and Tyr (and to a lesser extent His) being bound in or to a macromolecular structure at neutral pH from which there is relatively slow exchange with the free solution environment. Experiments with model solutions suggest that serum albumin has a high capacity for binding aromatic amino acids (stabilized by hydrophobic interactions) at neutral pH and this is responsible for the NMR-invisibility of Tyr and Phe in blood plasma.
2800377##1989-7-1##[Wilson's disease--a factor in the differential diagnosis in hepatopathies].##The authors give an account on the incidence of Wilson's disease in two sisters (17 and 8 years). In the older one the diagnosis was established after 8, years in the younger one three years after the first laboratory sings of hepatopathy. As to the range of available laboratory methods in the diagnosis of Wilson's disease, in particular serum ceruloplasmin, serum copper and copper in urine are assessed as well as increased accumulation of copper in hepatic tissue. With regard to the serious character of Wilson's disease and the possibility of effective treatment it is important to rule it out in all cases of obscure hepatopathies, in particular in children and adolescents. It is important to take into account also atypical clinical and laboratory manifestations of Wilson's disease.
2567467##1989-6-24##Can Wilson's disease patients be decoppered?##
2656182##1989-6-2##[Indications for liver transplantation in Wilson's disease with a fulminant course].##In two 19-year-old girls with Wilson's disease the condition took a fulminant course, including a poor general state, marked haemolysis and ascites. In the first patient the diagnosis was histologically confirmed only after three weeks, and onset of treatment with penicillamine was therefore delayed. With this medication the concentrations of alkaline phosphatase, cholinesterase and total bilirubin returned to normal, but again became abnormal after about seven weeks. Despite substitution of clotting factors thromboplastin time remained reduced. She died 82 days after the onset of symptoms. In the second patient, treatment with penicillamine was started at once, without waiting for histological confirmation. All laboratory values became normal and remained so. It is concluded from these observations that liver transplantation is indicated if the abnormal values for cholinesterase, thromboplastin time and bilirubin do not remain normal after six weeks and if the initial suppression of alkaline phosphatase continues or occurs again.
2744040##1989-6-1##Oral zinc sulphate as primary therapeutic intervention in a child with Wilson disease.##An 8-year-old boy with an hepatic form of Wilson disease was treated with oral zinc sulphate as the primary and sole therapy. After 4 months, liver function had dramatically improved, and the parameters characterizing copper metabolism had also normalized.
2754543##1989-6-1##Metallothionein and copper in liver disease with copper retention--a histopathological study.##We have examined the relationship between (a) histochemically demonstrable copper using rubeanic acid, (b) copper-associated protein (CAP) using orcein, and (c) immunoreactive metallothionein (MT) using DNP hapten sandwich staining and have correlated these with histological lesions in 95 liver biopsies from patients with conditions associated with hepatic copper retention, 4 fetal livers, and 25 histologically normal adult controls. No copper or CAP was present in normal adult liver but periportal CAP was present in fetal liver. MT was present in hepatocytes of normal livers with a predominantly perivenular (centrilobular) cytoplasmic distribution varying in staining intensity; all fetal hepatocytes stained strongly for MT. Fifty-two of 95 (55 per cent) abnormal livers contained CAP and 42 (44 per cent) contained both CAP and copper. In CAP-positive livers, the commonest histological lesions were piecemeal necrosis and cholestasis. CAP was present in (a) 15/15 cases of primary biliary cirrhosis including early cases with minimal pathology; and (b) 5/5 cases of Wilson's disease, 6/6 cases of biliary atresia, and 3/9 cases of sclerosing cholangitis. In other conditions, it was present in 25-50 per cent of cases. MT distribution was abnormal in most CAP-positive livers. Necrotic hepatocytes were intensely MT-positive and in Wilson's disease had a characteristic appearance.
2712173##1989-5-1##Psychopathology in patients with Wilson's disease.##The authors used the MMPI to assess psychopathology in neurologically impaired and neurologically asymptomatic patients with Wilson's disease. Neurologically impaired patients showed more psychopathology on the schizophrenia and depression scales and had a significantly higher rate of severe depression.
2523911##1989-5-1##D-penicillamine-induced elastosis perforans serpiginosa in a child with juvenile rheumatoid arthritis. Report of a case and review of the literature.##Elastosis perforans serpiginosa is a rare complication of D-penicillamine therapy. It has been reported to occur in Wilson's disease and cystinuria, usually after many years of high-dose therapy. We report a case of D-penicillamine-induced elastosis perforans serpiginosa with unique clinical features occurring in a 10-year-old child with juvenile rheumatoid arthritis who received only 71 gm of the drug over 9 months. The case is also unusual because of the short course and low cumulative dose of drug received and because of the calcification of elastic fibers. The calcification of elastic fibers suggests that this case may represent an unusual variant of elastosis perforans serpiginosa or an overlap with pseudoxanthoma elasticum. All reported cases of D-penicillamine-induced elastosis perforans serpiginosa are reviewed, and histopathologic and electron microscopic findings are presented. The theoretic mechanisms of action of D-penicillamine on elastic tissue synthesis and morphology are discussed.
2736129##1989-5-1##[A case of Wilson's disease recovering from severe brain damage--special reference to trientine and D-penicillamine therapy].##
2564907##1989-4-15##Homing in on Wilson's disease.##
2712535##1989-4-1##Gaze distractibility in Wilson's disease.##We describe the case of a patient with Wilson's disease who was first seen with distractibility of gaze fixation. Clinical and magnetic resonance imaging studies suggest that the disorder was probably due to frontal lobe involvement.
2705894##1989-4-1##Deterioration of Wilson's disease following the start of penicillamine therapy.##
2744017##1989-4-1##Hypercalciuria and nephrolithiasis as a presenting sign in Wilson disease.##A 9-year-old boy presented with recurrent episodes of renal colic. One year later Wilson disease was diagnosed. Evaluation of liver function and assessment of serum copper, caeruloplasmin concentration and urinary copper excretion in any child presenting with nephrolithiasis is suggested.
2472436##1989-4-1##Hepatocellular carcinoma in Wilson's disease. Case report and review of the literature.##A 33-year-old man with Wilson's disease developed hemoptysis and radiographic evidence of nodular pulmonary infiltrates. A premortem diagnosis of hepatocellular carcinoma was made on the basis of alpha-naphthylannidase stains of pulmonary tissue obtained by open lung biopsy. We review all previous cases of Wilson's disease with this unusual complication and discuss the role of copper in hepatic oncogenesis as well as the alpha-naphthylannidase stain for the diagnosis of hepatocellular carcinoma.
2524739##1989-3-25##[Wilson's disease and mucopolysaccharidosis. Association of 2 genetic diseases in the same patient].##
2618803##1989-3-1##[A case of Wilson's disease studied using magnetic resonance: a new approach?].##Wilson's disease is a genetically determined disorder of copper metabolism with increased deposition in brain and liver. With current imaging techniques--CT scan and conventional Nuclear Magnetic Resonance (NMR)--it has been possible to demonstrate oedema, neuronal loss and reactive gliosis, but not copper deposition. In the present study we report the observations, done in one patient, using a new high magnetic field (1.5 Tesla) NMR device. In these circumstances, we are able to expand the CT scan analysis by showing not only the oedema and the brain cell death but also the probable existence of copper deposits. Will this be true, it is first instance in which it has been possible to demonstrate, by a non invasive method, increased copper deposition in Wilson's disease. This possibility may be important to monitor the therapeutic efficacy of chelating agents and also to distinguish asymptomatic homozygous patients from heterozygous healthy carriers.
2919605##1989-3-1##Two case studies from a family with primary Fanconi syndrome.##We report two cases from a family with primary Fanconi syndrome. A 39-year-old white woman with a history of frequent bone fractures developed hypophosphatemia, hypouricemia, hypokalemia, metabolic acidosis, and renal glycosuria. Her 15-year-old son had renal glycosuria without metabolic acidosis. Both had mildly to moderately impaired renal function. Determination of amino acids in 24-hour urine specimens confirmed the generalized nature of aminoaciduria. Acid-loading, bicarbonate-loading, and phosphate-loading tests revealed that the mother had proximal (type II) renal tubular acidosis and excessive renal loss of phosphate for her level of renal function. These tests for the son were normal or within normal limits of his renal function. Known causes of Fanconi syndrome, such as cystinosis and Wilson's disease, were excluded by slit-lamp eye examination and leukocyte cystine level determination. One unexpected finding in the son was the preseNce of nephrocalcinosis on x-rays; a percutaneous needle biopsy of the kidney showed tubular atrophy, interstitial fibrosis, and calcium oxalate crystal deposits. The two cases presented here represent a familial variety of the primary Fanconi syndrome, a rare entity with a limited number of cases reported in the literature.
2491190##1989-3-1##[Determination of copper in hepatic tissue for the diagnosis of Wilson's disease].##Three young patients had clinical data compatible with Wilson's disease (WD); all of them had high serum levels of ceruloplasmin without Kayser-Fleischer rings (K-F), the urinary copper level being very low, not supporting the Wilson's disease diagnosis. This reason was why we decided to detect the amount of copper in the liver tissue, which was very high in all patients, confirming the disease. We would comment that WD of abdominal type does not usually have the K-F rings, which made the diagnosis difficult. An algorithm is proposed to be applied in each case were WD is suspected.
2602537##1989-3-1##Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.##An analysis has been made of presenting symptoms and course in 87 patients with predominantly hepatic Wilson's disease. In 30 patients, in whom the diagnosis was made relatively quickly, response to treatment was excellent and all recovered although two had severe haemolytic crises. Mean age of onset was 11 years (range five to 22). Nine patients suffered toxic reactions to penicillamine and were then treated with trientine. In 22 patients the diagnosis was made after neurological symptoms had supervened; in 20 the signs of hepatic damage had disappeared despite the lack of treatment but in two hepatic signs persisted until the central nervous system was affected. In the 20 patients in whom signs of liver disease resolved spontaneously there was a time interval of from one to eight years before neurological signs developed. All 22 patients in a third group died of hepatic disease without central nervous system involvement. In 19 cases duration of the illness was brief and the diagnosis was made very late or at post-mortem examination. One patient survived with chronic progressive liver damage for 20 years; diagnosis was also made at post-mortem examination. Mean age at death was 15 years. The diagnosis was made retrospectively in 13 patients who died. In two of these the diagnosis was confirmed by determination of the liver copper concentration on tissue saved at postmortem examination; in the other 11 the diagnosis is probable since other siblings developed a similar illness, proven to be Wilson's disease. Age range for these patients was eight to 13 years. Duration of the illness from onset to death was nine days to four years (mean 10 weeks). There was no example of primary carcinoma of the liver in this series.
2711817##1989-2-1##Visual and brain stem auditory evoked responses in Wilson's disease.##Sensory evoked potentials were studied in 15 patients with Wilson's disease. Thirteen patients were investigated with pattern reversal visual stimulation. A prolonged P 100 latency of the VEP was present in 7 patients. Brain stem auditory responses were evoked in 12 patients. Prolongation of III-V and I-V interpeak latency was found in 8 patients. The evoked potential studies demonstrated subclinical disturbances in optic and caudal brainstem auditory pathways. Further studies are in progress to evaluate the role of these techniques in monitoring the therapy of newly diagnosed cases.
2923791##1989-2-1##The effect of carbon tetrachloride on the copper-laden rat liver.##Copper is believed to be hepatotoxic in Indian Childhood Cirrhosis and Wilson's disease. However, copper-loading causes only minimal hepatic damage in animal models. The hypothesis was therefore proposed that a second hepatic insult may precipitate or perpetuate liver injury in a copper-laden liver. In non-copper-dosed rats CCl4 (10 mmol/kg, i.p.) produced elevated serum AST (809 +/- 298 IU/l, normal 20 +/- 5) and ALT (295 +/- 157 IU/l, normal 6 +/- 1) and extensive liver cell necrosis, portal tract inflammation, fat deposition, and perilobular hepatocyte ballooning. In rats whose liver copper was elevated from 75 +/- 13 to 461 +/- 13 micrograms/g by oral copper supplementation, CCl4 produced much smaller increases in AST (492 +/- 80 IU/l) and ALT (172 +/- 57 IU/l) and mild focal liver cell necrosis. Fat deposition and perilobular vacuolation were not reduced. Prior copper-loading of rats unequivocally protected against the CCl4-induced liver injury. Triglyceride accumulation, however, was apparently unaffected. The possible interactions of copper with prostaglandin-mediated inflammation and with free-radical-induced liver damage are discussed.
2536348##1989-2-1##Detection of anti-liver cell membrane antibody using a human hepatocellular carcinoma cell line.##A radioimmunometric technique for the detection of autoantibodies to liver membrane antigens has been developed using Alexander cells, a human hepatocellular carcinoma cell line. After incubation of Alexander cells with serum, antimembrane antibodies were detected by addition of 125I-labeled Protein A. Binding ratios in 15 children with uncontrolled autoimmune chronic active hepatitis and in seven children with primary sclerosing cholangitis were significantly higher than in 18 age-matched normal controls. Nine patients with inactive autoimmune chronic active hepatitis, 13 with alpha 1-antitrypsin deficiency and five with fulminant hepatic failure had ratios similar to controls. In nine patients with Wilson's disease, there was a modest but significant increase in binding ratio. In four children with autoimmune chronic active hepatitis, binding ratios fell during effective immunosuppressive therapy. Sera from patients with systemic lupus erythematosus or rheumatoid arthritis gave normal results, excluding that binding derives from Fc-mediated immune complex capture. A positive correlation was found between Alexander cell binding values and anti-liver-specific protein antibody titers, suggesting that the two assays detect antibodies against shared antigenic determinants. The Alexander cell assay is a simple, rapid and sensitive technique to detect antibody to liver cell membrane antigens.
2563776##1989-2-1##Carrier detection and early diagnosis of Wilson's disease by restriction fragment length polymorphism analysis.##Wilson's disease, a rare autosomal recessive disorder, has been recently mapped to the long arm of chromosome 13 (q14.1). In this study, we carried out linkage analysis between three chromosome 13 DNA markers, D13S1, D13S10, D13S2, the locus for the red cell enzyme esterase D (ESD), and the Wilson's disease locus (WND) in 17 Wilson's disease families of Italian descent, mostly from Sardinia. We confirmed a tight linkage [theta = 0.00, Z (theta) = 4.07] between the WND and ESD loci, and provided suggestive evidence for linkage [theta = 0.00, Z(theta) = 1.85] of the WND locus with D13S10. Multipoint linkage analysis indicated the following order: centromere-D13S1-D13S10-WND-ESD-D13S2. RFLP analysis at these two loci in our families allowed us either to define the carrier status (50%) or to exclude the homozygous state (25%) in the great majority of unaffected sibs.
2724779##1989-2-1##[Variations in the composition of breast milk in Wilson's disease].##Wilson's disease is a rare genetic disorder of copper metabolism with autosomal recessive inheritance. It occurs between the 6th and 45th year of life. An early and reliable diagnosis, if possible in the preclinical stage, is the prerequisite for starting therapy in time. By the treatment the quality of life and the expectation of life are raised considerably. If consistent treatment is given, there will be no objections to pregnancy in Wilson's disease. It should be interrupted only in case of marked portal hypertension and in the presence of oesophageal varices. The examination of the breast milk of a patient suffering from Wilson's disease showed a reduction in the trace elements copper and zinc. It may be necessary to think of copper and zinc substitution in children fed with breast milk only.
2642686##1989-1-1##Penicillamine dermatopathy with lymphangiectases. A clinical, immunohistologic, and ultrastructural study.##The term penicillamine dermatopathy refers to the characteristic hemorrhagic skin lesions found in persons receiving long-term penicillamine therapy for either Wilson's disease or cystinuria. These lesions are thought to develop as a result of faulty collagen and elastin synthesis. We describe a patient with Wilson's disease who developed extensive penicillamine dermatopathy. In addition, histologic, immunochemical, and ultrastructural studies revealed multiple lymphangiectases with blood vessel to lymphatic anastomosis within these lesions, a finding not previously reported. The possible relationship to defective collagen and elastin formation are considered.
2720821##1989-1-1##[Atypical symptomatology and course of Wilson's disease. Case report].##
2784729##1989-1-1##Anti-lymphocytic antibodies in autoimmune chronic active hepatitis starting in childhood.##Anti-lymphocytic antibodies (ALA) have been described in a variety of autoimmune disorders. We have investigated the presence of ALA in autoimmune chronic active hepatitis (aCAH) starting in childhood. Using a modified Terasaki technique ALA were found in 17 of 18 patients with aCAH but in only one of 15 patients with alpha-1-anti-trypsin deficiency or Wilson's disease and three of 27 age-matched healthy controls (P less than 0.0005 for both). Sera from 12 patients with uncontrolled aCAH had significantly higher cytotoxicity values than sera from six children with inactive diseases (P less than 0.01). ALA were directed to T but not B lymphocytes and were not reactive with specific HLA antigens. No preferential killing was observed against CD4 or CD8 positive T lymphocytes. Characterization of ALA revealed them to be cold-reactive IgM. The possible role of ALA in aCAH is discussed.
2538281##1989-1-1##Clinical, CT and evoked potential manifestations in Wilson's disease with cerebral white matter involvement.##Four patients with Wilson's disease had CT manifestations of cerebral white matter lesions involving frontal lobes in two patients but extending to other cerebral areas in the remaining two. Two patients with extensive white matter involvement were bed-ridden with generalized flexion rigidity and spasticity, but the other 2 patients led an independent life with minimal extrapyramidal symptoms. Three patients developed tonic focal seizures with or without secondary generalization. Scalp-recorded somatosensory evoked potentials (SEPs) over the affected hemispheres were absent but the spinal SEPs and brain stem auditory evoked potentials were preserved. The evoked potential data support the CT findings that the white matter involvement in Wilson's disease was primarily confined to the cerebral hemispheres.
2663256##1989-1-1##Wilson's disease: an update, with emphasis on new approaches to treatment.##
2606134##1989-1-1##Long-term care and management of Wilson's disease in the GDR.##Diagnosis, long-term management and family investigations of Wilson's disease are provided by selected clinical institutions in the GDR. From 187 patients detected since 1949, 111 are alive. In spite of the principal effectiveness of penicillamine treatment, confirmed by the disappearance of most of the central nervous system symptoms and successful professional rehabilitation of many patients, insufficient therapeutic discipline, psychosocial disturbances and penicillamine side-effects forcing its substitution by zinc or triethylenetetramine dihydrochloride in 14 cases need our further attention.
2695345##1989-1-1##The circulation of fluid at the limbus (flow and diffusion at the limbus).##Diffusion of molecules, e.g. ions, proteins, etc. and flow of water takes place across the physiological limbus. This 'structure' is estimated to be a zone approximately 1 mm in width and to bridge the anatomical limbus. The source of most molecules that diffuse into the corneal stroma across the limbus under normal circumstances is the perilimbal vascular system with its rich capillary bed. Small ions are lost within 2-3 mm of movement into the stroma, whereas larger molecules may diffuse to the centre of the cornea. Diffusion or flow may be bidirectional; however, it is anticipated that the majority of the flow, albeit small, is inward toward the cornea. The sclera, compared to the corneal stroma, has been found to be less resistant to fluid flow, but more resistant to diffusion of ions and larger molecules. Under normal circumstances, there have been few substances identified of importance that diffuse or flow across the limbus in either direction. There are a number of substances that traverse the limbus that are of importance in disease states, e.g. Wilson's disease, with the corneal Kaiser-Fleischer ring and angiogenic factors stimulating corneal neovascularisation. Under normal circumstances, the limbus would, therefore, seem to be more important as a zone that restricts flow and diffusion rather than an area of active molecular movement.
2806955##1989-1-1##Non-caeruloplasmin copper and ferroxidase activity in mammalian serum. Ferroxidase activity and phenanthroline-detectable copper in human serum in Wilson's disease.##It is thought that 5-10% of human serum copper consists of copper ions complexed with histidine, amino acids or albumin. The phenanthroline assay developed by Gutteridge (Biochem. J. 218, 983-985; 1984) is shown to measure all these forms of copper down to a sensitivity of 0.1 mumol/dm3, yet it does not detect any copper ions in freshly-prepared serum or plasma from rats, mice, rabbits or guinea-pigs, or freshly-prepared serum from humans. It is concluded that the &quot;non-caeruloplasmin copper pool&quot; is much smaller than has previously been supposed. No phenanthroline-detectable copper could be measured in serum freshly prepared from four patients with uncomplicated Wilson's disease, but it could be measured in serum from a patient with fulminant hepatic failure. After liver transplantation, concentrations of phenanthroline-detectable copper in this patient fell to zero within two days. Studies on the ferroxidase activity of freshly-prepared serum or plasma samples shows that little ferroxidase II activity is present in samples from healthy adults or from the patient with Wilson's disease and fulminant hepatic failure. In all the patients, ferroxidase I activities are sub-normal. Freshly-prepared plasma or serum samples from several animal species generally show lower ferroxidase I and greater ferroxidase II activities than do human samples, but only in rabbits does ferroxidase II account for a high proportion of total plasma ferroxidase activity. Storage of biological fluids can cause release of copper from caeruloplasmin and a rise in ferroxidase II activity; these events may have confused some earlier studies.
2512451##1989-1-1##Nuclear magnetic resonance brain study in a case of Wilson disease.##
2501585##1989-1-1##Cultured skin fibroblasts: useful for diagnosis of Wilson's disease?##The copper content of and radiocopper uptake in fibroblast cultures were studied to evaluate their usefulness for the diagnosis of Wilson's disease. We used methods closely related to those described in the literature, and applied these to cell lines of six patients with Wilson's disease and 12 controls. The results were: (1) The copper content of the cytosol of skin fibroblasts derived from patients with Wilson's disease was lower than that of controls when the cells were grown in a medium with a low copper concentration (0.7 mumolL-1); increased copper concentration (157 mumol L-1 in the medium failed to demonstrate any difference between normal fibroblasts and those derived from patients with Wilson's disease. (2) Radiocopper uptake studies did not differentiate between normal fibroblasts and fibroblasts from patients with Wilson's disease. We conclude that the cytosolic copper content of fibroblasts grown in a low copper medium is a potential diagnostic tool in Wilson's disease. At present not all controls can be distinguished from the Wilson cells; ways must be sought, therefore, of improving the technique.
2656969##1989-1-1##Liver transplantation in infants and children.##Orthotopic liver transplantation has become an accepted form of therapy for advanced liver disease. Over a 44-month period, we performed 27 liver transplants in 25 pediatric recipients, including 14 infants (mean age, 7.2 months; mean weight, 5.9 kg) and 11 children (mean age, 9.0 years; mean weight, 34.8 kg). Indications for transplantation were biliary atresia (16), tyrosinemia (3), chronic hepatitis with cirrhosis (2), fulminant hepatic failure (2), and one patient each with Wilson's disease and primary hepatoma. Eighteen patients (72%) had undergone a previous laparotomy, including 19 Kasai procedures in 13 patients with biliary atresia. The average time on the waiting list was 26.8 days (range, 1 to 60), and no patients died while awaiting transplantation. Mean preservation time was 6.9 hours (range, 2 to 13.5), employing cold storage with Collin's solution (16), or more recently, UW solution (11). Urgent liver transplantation was performed in seven cases (25.9%), although at present, we perform liver transplantation as a scheduled semielective procedure with extended preservation times in stable patients. The recipient hepatectomy and orthotopic liver transplantation were performed by standard techniques, with venous bypass used in three cases. Biliary reconstruction was performed with a Roux limb in 16 and via choledochocholedochostomy in ten cases, while arterial reconstruction was end-to-end hepatic artery in 21, and aorto-aortic anastomosis in the remaining six. Two hepatic artery thromboses (7.4%) and two biliary complications (7.4%) occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
2702608##1989-1-1##Dermal alterations in patients with Wilson's disease treated with D-penicillamine.##Wilson's disease is characterized by accumulation of copper and D-penicillamine favors its elimination. However, penicillamine binds to precursors of intermolecular crosslinks both in collagen and elastin, and could lead to alterations of these two fibrous proteins. In the present report skin biopsies from patients with Wilson's disease, treated with 900 mg/day of D-penicillamine, for 5, 9, 58 and 60 months, were studied by electron microscopy and compared with findings obtained from skin biopsies of age-matched normal subjects. Clinically, the elasticity and consistency of the skin of Wilson's patients was not modified by D-penicillamine treatment. The ultrastructural organization of collagen fibrils appeared normal in the adults treated with D-penicillamine for 5-9 months. In a 15-year-old girl, treated for 48 months, a high number of collagen fibrils were swollen and unreeved. Elastin fibers were altered in all patients. The alterations were mostly pronounced in the reticular dermis, were proportional to the time of treatment, and consisted of polymorphous aggregates of elastin connected to apparently normal elastin fibers. A stereological analysis, on EM pictures from the patient treated for 60 months, and from an age-matched control, showed a significant decrease in the percentage of collagen and of the mean area occupied by each collagen bundle in the reticular dermis of the patient compared to control; on the contrary, the number of elastin fibers per unit area increased significantly, and the mean area of each elastin fiber decreased. The volume density of elastin was similar to control. The results indicate that prolonged administration of penicillamine to humans induces alterations in the deposition of dermal collagen and elastin.
2657145##1989-1-1##Fulminant hepatic failure without evidence of cirrhosis in a case of Wilson's disease.##We treated a sixteen-year old Japanese girl with fulminant hepatic failure in Wilson's disease. The diagnosis of Wilson's disease was made immediately after the admission because of low serum copper and ceruloplasmin levels with high urinary copper excretion. Her hepatic failure was accompanied by bouts of hemolytic crisis. In spite of the administration of D-penicillamine and repeated plasmapheresis, she died of hepatic failure four months later. At autopsy, the surface of the liver was smooth. The histology of the liver showed massive necrosis. There were only a few remaining scattered hepatocytes, in which copper was revealed by Rhodanine staining. There was no evidence of cirrhosis. The livers of the previously reported cases of Wilson's disease accompanied by fulminant hepatic failure were all cirrhotic. Our case indicated that Wilson's disease could occur as true fulminant hepatic failure without preceeding neurological and hepatological signs and the evidence of cirrhosis.
2761476##1989-1-1##[Case reports of patients with hepatolenticular degeneration-Wilson's disease with emphasis on work capacity].##We presented four patients with hepatolenticular degeneration--Wilson or hepatocerebral dystrophy-Wilson-Konovalov by soviet authors. Our cases were nervous variable of this disease or pseudosclerose (Westphal-Strumphell). The first three patients showed rigid--trembling and one trembling form of disease. All, patients were male. We think that it is very important early identification of this disease, to reduce time from acute manifestation to make a diagnosis and to apply appropriate therapy. This time period in our cases lasted from 0 to 4 years. Except use d- penicillamine (to 900 mg/daily) we think that is also very important use the acidum ascorbicum (to 4.5 gr/daily). This acidum shows less consumption of d- penicillamine and has low complication. Recurrent working ability begins with disappearance of neurological phenomenology and with rehabilitation of psychic status. All our patients we examined by ergometric and psychological tests and we obtained in results working ability population. In our experience and from therapeutic results to make this diagnosis does not mean a priori definite working ability.
2732577##1989-1-1##[A case of Wilson's disease who developed status epilepticus during D-penicillamine therapy].##
2530611##1989-1-1##Oculomotor abnormalities in diseases of the basal ganglia.##Disorders of eye movements have been described in diseases of the basal ganglia for over a century. Recent neurophysiological and clinical work has greatly clarified the oculomotor role of these structures: their major involvement appears to be in the generation of &quot;voluntary&quot; saccades, and in the suppression of &quot;reflex&quot; saccades. The observed abnormalities of saccadic eye movements in Huntington's (HD) and Parkinson's (PD) diseases conform very well to predictions based on a combination of known disease pathology and recent neurophysiological work. This is not quite the case for other types of eye movement, such as smooth pursuit, largely because the exact role of the basal ganglia in their generation has not been defined neurophysiologically. Several diseases other than HD and PD both involve the basal ganglia and have effects on eye movements; such diseases include progressive supranuclear palsy and Wilson's disease. Unfortunately, the pathological processes in these conditions are too widespread to allow comment on how well oculomotor abnormalities fit in with predictions.
2718108##1989-1-1##[A case of hepatocerebral dystrophy (Konovalov-Wilson's disease) in twins].##
2785725##1989-1-1##Wilson's disease in young children from northern India.##Though Wilson's disease is not uncommon, there is paucity of reported cases from northern India. Out of 500 new cases registered during 1979-1986 in Chandigarh, nine were diagnosed to have Wilson's disease. Six children presented with a primary liver disease, two with neurological manifestations while one was an asymptomatic sib. All children with hepatic presentation were aged 8 yr or less (mean 6.5 yr). Kayser-Fleischer rings were demonstrable in 8 patients. The disease affects Indian children at a younger age and the diagnosis should be considered in those presenting with an typical hepatic/neurological disorder, Early diagnosis and treatment is mandatory for appropriate management.
2800818##1989-1-1##[Analysis of trace elements of the brain and liver tissues in Wilson's disease].##In a patients with extrapyramidal-cortical form of the Wilson-Konovalov disease, brain and liver tissues were tested for Ca, Cu, Fe, Ka, Mg, Mn, Mo, P, Pb, Se, Sn, Sz, Zn, S, using plasma emission spectrometry. The tissues autopsied from 2 cerebral hemorrhage victims served as controls. Hepatic Cu concentration was increased 24-fold (6.89 mumole/g of tissue dry weight); Cu accumulation in the brain cortex and basal ganglia were 10 times as high as control levels; hepatic (8.78 mumole/g) and brain cortical (2.23 mumole/g) Zn contents were higher than controls, respectively by factors of 2 and 1.7; hepatic S content (289.4 mumole/g) was 1.2 times the control level; Mn brain content was above the control value. Mg was below the appreciable amount in the brain that was not the case in control. On the contrary, Sr was detected only in basal ganglia and liver in the patient and not detected in control tissues. Pb content in the patient's liver was above the control level.
2633562##1989-1-1##[Experience in heterozygote detection in Wilson-Konovalov mutation based on the study of molecular forms of ceruloplasmin].##A specific novel molecular form of ceruloplasmin (CP) was detected in the sera of Wilson's disease patients and their closest relatives using two-dimensional cross-immunoelectrophoresis. This protein shares some antigenic properties with normal CP but is not completely identical to the latter. Besides, anomalous CP has no oxidase activity of normal CP and differs from it in electrophoretic mobility in agarose and polyacrylamide gels. Anomalous CP was purified to homogeneity and monospecific antibodies to this protein were obtained. The quantitative analysis showed that the ratios of normal CP to anomalous CP in homo- and heterozygous carriers of the &quot;Wilsonian&quot; gene are reproducibly different and can be used as a diagnostic test allowing the differentiation between these groups.
3197624##1988-12-16##[&quot;Diabetic&quot; proliferative retinopathy and nodular glomerulosclerosis without diabetes mellitus].##A 65-year-old woman of normal weight, hospitalized because of pleuritis, was found to have chronic renal failure (creatinine clearance 20 ml/min). Renal biopsy (light and electron-microscopy) revealed nodular glomerulosclerosis (Kimmerstiel-Wilson disease), described as a diabetes-specific renal change. Fundoscopy discovered bilateral proliferative retinopathy as seen in diabetes. But oral and intravenous glucose tolerance tests were normal, excluding a manifest diabetic metabolic disorder. No other cause of the glomerulosclerosis (such as amyloidosis or multiple myeloma) was found. The patient had been overweight for a time when younger, reversed by dieting. It is suggested that the &quot;diabetic&quot; changes in the kidneys and eyes without diabetes could be the result of a transitory disorder of glucose tolerance during the period of obesity.
3147183##1988-12-1##Copper distribution among serum proteins in paediatric liver disorders and malignancies.##Fractionation of normal serum on Sephadex G-150, followed by determination of copper, caeruloplasmin and albumin concentrations, indicated that only approximately 71% of total serum copper was associated with caeruloplasmin; less than previously reported values. Seven per cent was associated with a high molecular weight protein, designated 'transcuprein', 19% with albumin and 2% with amino acids. Compared with adult serum the concentrations of caeruloplasmin and of copper associated with caeruloplasmin were low both in serum from neonates and in serum from patients with symptomatic Wilson's disease. However, in contrast to the neonate, Wilson's disease patients exhibited a raised total serum copper and raised non-caeruloplasmin-copper. In Indian Childhood Cirrhosis serum caeruloplasmin and caeruloplasmin-copper levels were normal, whilst the non-caeruloplasmin-copper was raised. Elevated non-caeruloplasmin-copper in Wilson's disease and Indian Childhood Cirrhosis may therefore represent an overspill into the serum from a copper-laden liver. Children with malignancy showed increased serum concentrations of copper and caeruloplasmin. Both caeruloplasmin-bound and non-caeruloplasmin-bound copper concentrations were elevated. It remains to be determined whether increased 'transcuprein'- and albumin-bound copper result from a sequestering of copper released from peripherally utilized caeruloplasmin, or are associated with increased rates of caeruloplasmin synthesis.
2464523##1988-12-1##Survey of copper granules in liver biopsy specimens from various liver abnormalities other than Wilson's disease and biliary diseases.##Copper granules in hepatocytes were examined by the p-dimethylaminobenzylidene rhodanine method in 965 liver biopsy specimens obtained from patients with various liver abnormalities other than Wilson's disease and biliary diseases. The granules were found in chronic active hepatitis (incidence of positive cases: 17.2%) and alcoholic fibrosis (22%) with lobular disarray and fibrosis, nonbiliary liver cirrhosis (28%), and drug-induced cholestasis (15%). Copper granules were present in the periportal or periseptal hepatocytes where the granules were mainly found in the perinuclear cytoplasm. These intracellular and intralobular distribution patterns of copper granules resembled those of primary biliary cirrhosis. These data suggest that hepatic fibrosis and lobular disarray with fibrosis in these chronic liver disease may lead to distortion or interruption of small biliary branches followed by disturbance of bile flow and deposition of copper granules. Copper stain seems to provide a valuable information for assessment of progression of these chronic liver diseases. Impaired biliary excretion seems important in deposition of copper granules in drug-induced cholestasis.
2853189##1988-12-1##Cell proliferation and the aetiology of hepatocellular carcinoma.##The liver is, under normal conditions, mitotically inactive and relatively resistant to chemical carcinogenesis. When rat or mouse hepatocytes are stimulated to divide, however, the liver becomes exquisitely sensitive to carcinogenesis. The heightened sensitivity of dividing liver cells to carcinogens is one of the most dramatic phenomena in the field of experimental chemical carcinogenesis and is reproducible with a wide variety of chemical agents and experimental conditions. This same phenomenon seems to apply to humans, as circumstances that produce a sustained hepatocellular proliferation in man are associated with an increased risk of hepatocellular carcinoma (HCC). These include inborn errors of metabolism (e.g., haemochromatosis, Wilson's disease, hereditary tyrosinaemia) as well as alcoholism. A recent editorial in this Journal suggested that any condition resulting in cirrhosis is also associated with an increased risk of HCC, and this may in turn be due to regenerative hyperplasia always present in cirrhotic liver (Johnson PJ, Williams R. J Hepatol 1987; 4: 140-147). In the case of HCC associated with hepatitis B virus (HBV) infection, the possibility must be entertained that chronic HBV infection serves to produce a sustained hepatonecrosis with concurrent (regenerative) hyperplasia. This proliferative state would in theory serve to increase the liver's susceptibility to environmental dietary carcinogens and may tend to increase the risk of HCC by this indirect mechanism. Until a molecular mechanisms is demonstrated whereby HBV produces a defined cellular lesion that endows hepatocytes with a malignant phenotype, it should not be assumed that HBV is a direct cause of HCC.
3070751##1988-12-1##[Sonography of the liver in Wilson's disease. Sonographic studies of the liver in Wilson's disease--significance for assessing prognosis?].##Five patients with Wilson's disease with prognostically different hepatic manifestation were studied via ultrasound. Three of them presented histologically with fatty changes, fibrosis and interspersed areas of normal parenchyma. In these three patients, a peculiar ultrasound picture of the liver was observed which was quite different from the findings in the two others and which has not yet been recognized in the context of Wilson's disease. The parenchymal echo pattern was of increased echogenicity with numerous roundish foci of decreased echogenicity resembling metastatic liver disease. In contrast, the echo texture of the two patients with chronic active hepatitis leading to hepatic failure, was coarse, diffusely enhanced and without focal lesions. These findings indicate that ultrasound may help to define Wilson patients with good prognosis for the predominance of fatty changes and fibrosis in the liver.
3189332##1988-11-1##Eight closely linked loci place the Wilson disease locus within 13q14-q21.##Wilson disease (WD) is an autosomal recessive disorder resulting in an accumulation of copper in the liver, brain, and other organs. The WD locus (WND) has previously been linked to esterase D (ESD) and localized to 13q14-22. With the large Centre d'Etude Polymorphisme Humain cohort, a refined map of DNA markers from this region was constructed, with the following locus order: D13S1-D13S21-D13S22-D13S10-ESD-RB-WND-D 13S26-D13S12-D13S2. A significant excess of male recombination was observed between D13S21 and D13S22. Intervals distal to D13S22 showed an excess of female recombination. When these markers were tested on 19 WD families from a variety of ethnic backgrounds, the two closest loci were shown to be RB and D13S26. The retinoblastoma gene locus (RB) was shown to be proximal to WND at a distance of 4.4 centimorgans (cM), and D13S26 was placed distal to WND at a distance of 4.0 cM. ESD was assigned proximally at a distance of 9.4 cM. In all families studied WND was linked to one or more of the loci ESD, RB, or D13S26.
3069174##1988-11-1##Psychiatric complications of some basal-ganglia disorders.##Many basal-ganglia disorders are complicated by psychological disturbances and most are aggravated by emotional tension. These relationships are considered in the context of parkinsonism, Sydenham's chorea, Huntington's disease, Wilson's disease and a number of generalized and localized varieties of dystonia.
3150729##1988-11-1##GFAP immunohistochemical analysis of Alzheimer type II cells in Wilson's disease.##
3183119##1988-11-1##Acquired hepatocerebral degeneration: MR similarity with Wilson disease.##Acquired hepatocerebral degeneration (AHD) is a neurologic syndrome occurring in the presence of chronic hepatic disease, which results in permanent neurologic aberrations. The syndrome shares many of the clinical manifestations of Wilson disease, however, distinction can be made with slit lamp examination and biochemical studies. Cranial magnetic resonance (MR) imaging of a patient with AHD revealed increased signal intensity in the dentate nuclei bilaterally on T2-weighted images indistinguishable from Wilson disease. The MR findings of Wilson disease as described in the literature are not specific and further investigation with slit lamp examination and biochemical studies is warranted to distinguish between the two entities.
3199280##1988-11-1##Wilson's disease associated with pancreatitis.##A 12-year-old boy presented with a 2-month history of abdominal pain and distention. A diagnosis of Wilson's disease was established, and D-penicillamine therapy was initiated. An associated pancreatitis was diagnosed on presentation, based on elevated serum amylase and an enlarged pancreas ultrasonically. Subsequently, an 18-month follow-up disclosed no abdominal pain, with repeatedly normal serum amylase level and a normal pancreas on ultrasonography. Since abdominal pain is a common symptom in Wilson's disease on presentation, this possibility should be considered in untreated patients. It is concluded that pancreatitis may be associated with Wilson's disease, possibly because of copper deposition in the pancreas, and is probably responsive to copper chelation therapy.
3058917##1988-11-1##Liver transplantation therapy for children: Part 2.##End-stage liver disease affects nearly 300 children annually in the United States. Based upon the annual birth rate in the United States of 3.1 million, the incidence of the most prominent causes of liver disease in children (biliary atresia, alpha 1-antitrypsin deficiency, Wilson's disease, and neonatal hepatitis), and the frequency of end-stage liver disease in each disorder. Liver transplantation now offers these children at least a 65%, and in some series as high as 85%, chance of surviving at least 2 years postoperatively. Much of this improvement is attributable to advances in immunosuppression. However, one must not underestimate the importance of the tremendous knowledge that has been gained in the care of a large number of these patients over the last decade. The major barriers standing in the way of wider application of liver transplantation include the reluctance of primary care physicians to refer patients for early consideration, the growing crisis in the availability of donor organs, and the lack of adequate numbers of centers involved in performing adequate numbers of procedures. The major hurdles to overcome in order to affect further improvements in results include more specific immunosuppression, more accurate means of diagnosing rejection, better techniques of organ preservation, and further optimization of the care of both candidates preoperatively and recipients after transplantation.
3077448##1988-11-1##[Radiological and ultrasonographic examinations in Wilson's disease].##
3066102##1988-10-1##Glial fibrillary acidic protein immunohistochemical study of Alzheimer I &amp; II astrogliosis in Wilson's disease.##This study compared the relationships of the development of both Alzheimer I &amp; II cells to reactive astrogliosis and also their distributional patterns in the demyelinated and non-demyelinated lesions in 6 cases of Wilson's disease by the use of PAP immunohistochemical technique for glial fibrillary acidic protein (GFAP). The development of GFAP positive Alzheimer I (A-I) cells was found to be directly proportional to the capability of reactive astrogliosis, and inversely proportional to the severity of Alzheimer II (A-II) change. The GFAP negative A-II cells could be identified morphologically into 2 subtypes: one with well-developed nuclei, the other with &quot;shrunken&quot; nuclei. They were believed to stand for the &quot;compensatory&quot; and &quot;decompensatory&quot; stages of this dynamic astrogliotic process respectively. The distribution patterns of these 2 types of astrogliosis were different: A-I cells were found only in the regions of demyelination with intensive reactive astrogliosis, while A-II cells were found diffusely in both the grey and white matter, affecting both the protoplasmic and fibrous astrocytes without special predilection.
3262293##1988-10-1##Unusual MR findings in CNS Wilson disease.##
3214251##1988-10-1##[Wilson's disease with liver copper in normal concentration].##The cases of 2 children with Wilson's disease revealed by persistent hypertransaminasemia are reported. Blood ceruloplasmin concentration was low but the liver content of copper was lower than usually seen in presymptomatic forms of the disease. The apparently low liver copper concentration could be explained by an unusually important steatosis.
2973362##1988-10-1##Technetium-99m HMPAO imaging in patients with basal ganglia disease.##Technetium 99m hexamethylpropylene-amine oxime (HMPAO) is trapped by cerebral grey matter and the basal ganglia on its first pass through the brain. To assess its potential for studying patients with diseases of the basal ganglia, a study of 15 normal volunteers and 32 patients with known or suspected basal ganglia disease have been investigated. Sixteen patients with idiopathic Parkinson's disease showed no abnormality of the basal ganglia and varying degrees of cerebral underperfusion consistent with their intellectual status. Eight patients with Huntington's chorea showed a characteristic pattern of reduced or absent caudate nucleus uptake. Patients with diseases affecting the basal ganglia, such as Fahr's disease, Wilson's disease and hemibalismus had varying degrees of basal ganglia underperfusion as demonstrated by an HMPAO scan. We believe that this new radiopharmaceutical for the demonstration of cerebral blood flow shows significant potential for the diagnosis and management of patients with basal ganglia disease.
3052696##1988-10-1##Wilson's disease and epilepsy.##The relationship between Wilson's disease and epilepsy is explored, both in the literature and in a series of 200 cases of Wilson's disease. Details of 44 literature and 14 personal cases of both disorders are presented. The prevalence on December 1, 1986 of epilepsy in the Cambridge series was 6.2%, ten times higher than that of epilepsy in the general population. Seizures in Wilson's disease occur at any stage of the disease, but often begin shortly after the start of treatment. Prognosis of seizures was comparable with the best quoted figures for idiopathic epilepsy: at 7 years 60% of cases had been seizure-free for at least 5 years, and 75% for at least 2 years. Possible mechanisms of seizures are discussed. Penicillamine-induced pyridoxine deficiency is probably not involved in more than a minority of cases. It is more likely that a direct effect of copper deposition is responsible for most of the seizures.
3220225##1988-10-1##[Massive microvesicular steatosis and Wilson's disease].##
2976785##1988-10-1##Wilson's disease: how it changed a young woman's life.##Wilson's disease is an inherited disorder which affects the body's ability to metabolize copper. The resulting copper toxicosis can involve all body organs but especially the liver, brain, cornea and kidneys. This article presents a review of the disease and a case study demonstrating how the disease changed a young woman's life, presenting many challenges to her, her family, her nurses and other care providers.
3200124##1988-10-1##Hypoceruloplasminemia and ultrastructural changes resembling Wilson's disease in nonalcoholic liver steatosis. A clinical and pathological study of five cases.##We report five cases of asymptomatic patients with persistently abnormal liver function tests in whom copper metabolism abnormalities resulted in a misleading suspicion of Wilson's disease. Ceruloplasmin levels assessed by nephelometric immunoassay, single radial immunodiffusion and the enzymatic method averaged 53.8, 61 and 52.8% of the mean value obtained in age- and sex-matched controls (p less than 0.001). Twenty-four-hour urinary copper excretion was higher than the normal range in three instances. Four patients exhibited hypertriglyceridemia. Liver histology showed fatty change with or without sinusoidal fibrosis. Electron microscopic examination unexpectedly disclosed mitochondrial and lysosomal changes identical to those described in Wilson's disease. The present observations indicate that biochemical and ultrastructural changes suggestive for Wilson's disease may be observed in the absence of increased liver copper content. Whether such cases represent isolated cases of heterozygosity for the Wilson's disease gene remains to be elucidated.
3265815##1988-10-1##Wilson's disease in the Arabian Peninsula.##
3068911##1988-10-1##Liver transplantation and Wilson's disease.##
3266299##1988-9-1##An unusual concurrence of myotonia congenita and Wilson's disease.##
3274209##1988-9-1##Abnormal copper metabolism: another &quot;non-Wilson's&quot; case.##We describe a patient with extrapyramidal neurologic disease and an abnormal copper profile with hepatic copper accumulation, but no cirrhosis histologically, thus excluding a diagnosis of Wilson's disease (WD). We compared and highlighted the differences between similar previously reported cases of abnormal copper metabolism and true WD and suggest a spectrum of disease due to abnormal copper metabolism resulting in varied histochemical expression.
3050707##1988-9-1##Management of an oroantral fistula in a patient with Wilson's disease: case report and review of the literature.##After removal of an impacted maxillary third molar, an oroantral fistula developed in a patient with Wilson's disease. Management consisted of antibiotics, decongestants, irrigation, and surgical closure. Complications of treatment did not directly involve the disease but, rather, were related to the therapeutic agent penicillamine. Penicillamine causes interference between the cross links of tropocollagen molecules and cleaves newly formed molecules. Reduction in dosage is recommended when surgery is planned to increase collagen formation and, thus, healing. Such a measure was undertaken in this case. The patient healed uneventfully. A review of Wilson's disease and a case report are presented.
2900362##1988-8-20##Diagnosis and treatment of presymptomatic Wilson's disease.##In ninety families with at least one proven case of Wilson's disease, seen over 32 years, all close relatives were examined and &quot;presymptomatic&quot; disease was diagnosed in 30. 11 had one or more abnormal physical signs when examined and 7 of these had Kayser Fleischer rings. In a further 10 patients the abnormalities of copper metabolism were so pronounced as to leave no doubt as to the diagnosis. 6 patients were not seen until they had been on treatment for 2 years or more; in some, much of the evidence on which the diagnosis was based is not available. In 3 patients there were only minor histological abnormalities in the liver and no increase in urinary copper but other indices of copper metabolism pointed to a diagnosis of Wilson's disease. 2 patients had transient neurological signs after starting treatment; otherwise, all but one (who died in an accident) have remained well for up to 26 years.
3417439##1988-8-1##A paramagnetic agent causing ochronotic arthropathy.##Magnetic resonance imaging (MRI) identified a paramagnetic substance in the hyaline cartilage of the hips and knees in a patient with ochronosis. Chemical studies characterized the paramagnetic agent as melanin. The free radicals contained in melanin were shown to initiate cytotoxicity. The loss of cartilage in ochronotic arthropathy now can be explained at the electron level using the superoxide theory of oxygen toxicity. Inappropriate metabolism of oxygen also may explain early cartilage degeneration in hemochromatosis, hemosiderosis, and Wilson's disease.
3264035##1988-8-1##Single photon emission computed tomography (SPECT) in a patient with Wilson's disease.##Single photon emission computed tomography (SPECT) with 133Xe inhalation was studied in a patient with Wilson's disease, who had the low-density lesions in the bilateral ganglia and a small calcified lesion in the left basal ganglia on computed tomography (CT). SPECT showed the regional cerebral blood flow (rCBF) of the basal ganglia area. The values of the rCBF in these areas are 77 to 91 ml/100g/min in the right, and 56 to 77 ml/100g/min in the left. Further study is needed to prove the pathological role of rCBF for the basal ganglia lesion in the patient with Wilson's disease.
3292186##1988-7-8##[Orthotopic liver transplantation in Wilson's disease and acute liver failure].##Liver histology demonstrated progressive cirrhosis in a 19-year-old girl with a subacute form of Wilson's disease. Despite D-penicillamine administration her liver functions rapidly deteriorated further. Orthotopic liver transplantation was performed. Postoperatively there were two mild rejection episodes, an organic psychiatric syndrome and generalized tremor. Copper metabolism and clinical symptoms became normal postoperatively. Five months after the transplantation she was in a good general condition, able to continue her education.
2484540##1988-7-1##Distribution of 14 elements in various rat tissues following hypophysectomy, thyroparathyroidectomy, adrenalectomy, and castration.##The tissue distribution of 14 elements was simultaneously determined in rats 28 d after hypophysectomy (HPY), thyroparathyroidectomy (TPTY), adrenalectomy (ADY), and castration (CTN). The elements Na, K, Ca, Mg, Fe, S, P, Rb, Sr, Mn, Cu, and Zn were investigated in whole blood, plasma, brain, liver, kidney, heart, skeletal muscle, and bone. Additionally Mo was determined in kidney and liver. The following results were obtained: 1) With regard to hormone deficiency: HPY induced the most noticeable variations on all the elements tested owing probably to the direct and indirect effects of adenohypophyseal hormones. ADY led to the expected modification of Na and K but also to a Sr accumulation and a Rb depletion. TPTY induced a sharp decrease in plasma and tissues Ca, an increase in plasma P, but did not disturb the two elements in bone. An increase of Rb in many tissues and of Fe in heart, kidney, and liver were also observed. CTN had little consequences except in bone whose Cu and Fe contents were increased; 2) With regard to element variations: K, Mg, and S underwent little change. Discriminations were revealed between elements such as K and Rb, Ca and Sr, Ca and Mg, and Cu and Zn. The changes of Rb and Sr were consistent with regulatory mechanisms. The accumulation of Fe and Cu in tissues such as liver after HPY, TPTY, and ADY, suggest that the hormonal deficiencies could worsen the hemochromatosis and Wilson's disease; 3) With regard to plasma and tissues: No correlation appeared in element levels between plasma and other tissues. Brain was the least affected and liver, kidney and bone the most.
2455626##1988-7-1##Neurophysiological evaluation of the central nervous impulse propagation in patients with sensorimotor disturbances.##Motor evoked potentials (MEPs) to transcranial stimulation (TCS) and somatosensory evoked potentials to median nerve stimulation (MN-SEPs) were examined in 74 patients affected by multiple sclerosis (MS = 49 cases), amyotrophic lateral sclerosis (ALS = 9 cases), cervical cord lesions (7 cases), Parkinson's disease (PD = 5 cases), Huntington's chorea (HC = 2 cases), Wilson's disease (WD = 1 case), subacute combined degeneration (SCD = 1 case). MN-SEPs were altered in 38% of arms in MS with a higher incidence in clinically affected than in clinically 'silent' arms (= 77.8% vs. 27.5%). MEP alterations were found in 54% of examined arms, mostly because of a prolongation of the motor CCT. This index was invariably altered in the affected arms, whilst it was involved in 40% of the 'silent' ones. Twelve out of 18 arms displayed abnormal MEPs in ALS. These were mainly due to an absent response, even if moderate motor CCT prolongation and 'giant' MEPs were also encountered. MN-SEPs were altered in 3/18 arms. By recording MEPs from proximal and distal upper limb muscles, cues on the level of abnormal propagation were obtained in patients suffering from 'focal' lesions of the spinal cord. Combining SEP records enhanced the diagnostic yield in this field. Both MEPs and SEPs were normal in patients with PD and HC, whilst abnormally prolonged CCTs were found in the case with WD. MEP and SEP recording revealed central propagation abnormalities coupled to a severe clinical picture of the peripheral nerve involvement (as in the case of SCD).
3292368##1988-7-1##Wilson's disease: transplantation when all else has failed.##
3204085##1988-7-1##Wilson's disease in south India and experience with zinc therapy.##
3264567##1988-7-1##Effect of D-penicillamine treatment on brain metabolism in Wilson's disease: a case study.##Sequential measurements of brain glucose metabolism were carried out in a patient with Wilson's disease, before and after successful treatment with D-penicillamine. They demonstrate an evolution of regional metabolism consistent with clinical improvement. The first study showed marked hypometabolism in the putamen on both sides. The second analysis showed bilateral improvement, with predominant residual deficits in the right putamen, while clinical symptoms of striatal dysfunction persisted on the left side. This observation suggests that positron emission tomography is able to follow the neurological evolution in cases of Wilson's disease.
2904976##1988-7-1##Neuroleptic malignant syndrome in a patient with Wilson's disease.##
3235901##1988-7-1##[A case of Wilson's disease presenting with hemolytic anemia].##
3163469##1988-6-1##Linkage of the Wilson disease gene to chromosome 13 in North-American pedigrees.##Wilson disease (WD) is an autosomal recessive disorder resulting in copper accumulation to toxic levels. Patients may present with neurologic, hepatic, or hematologic disease at any age between the first and fifth decade of life. Because of clinical heterogeneity, genetic heterogeneity in the etiology of the disease has been proposed. Recently, linkage of the WD locus to loci on 13q has been demonstrated in five Middle-Eastern kindreds. We have used esterase D and several polymorphic markers on 13q to investigate linkage in WD pedigrees from the United States and Canada. Ten kindreds, three with hepatic and seven with neurologic presentations, were informative, yielding a lod score of 2.189 at a recombination fraction of .06 with probe 7F12 at D13S1. Patients were generally of mixed European background, but one particularly informative pedigree was Hispanic. Our data confirm the provisional assignment of the gene for WD to 13q. More specifically, our findings indicate that, irrespective of ethnic background or clinical presentation, the linkage to 13q will be present in most pedigrees. The relative lack of linkage heterogeneity indicates that closely linked polymorphic loci on 13q can be useful in prenatal and presymptomatic diagnosis and in heterozygote detection.
3048201##1988-6-1##[Liver pathology in Wilson's disease].##
3214340##1988-6-1##Pregnancy in a woman with Wilson's disease treated with zinc.##
3135996##1988-6-1##[The topography of P300 in neuropsychiatric pharmacotherapy. III. Cognitive P300 fields in an organic psychosyndrome (Wilson's disease) before and during treatment with D-penicillamine].##Beside senile dementia of Alzheimer's type (SDAT) there are also dementive syndromes due to a disturbance in metabolism. In a case with a disturbance of copper metabolism (Wilson's disease) a similar P300-pattern was found as described in SDAT with signs of a frontal amplitude elevation. Under therapy with d-penicillamine the frontal P300-positivity moved from frontal to parietal structures. Combined with this migration was an amelioration in cognitive function. This single-case study underlines the significance of P300-topography in the evaluation of therapy effects in dementive disorders.
3164702##1988-6-1##Human esterase D gene: complete cDNA sequence, genomic structure, and application in the genetic diagnosis of human retinoblastoma.##The gene encoding human esterase D (EsD), a member of the nonspecific esterase family, is a useful genetic marker for retinoblastoma (RB) and Wilson's disease. Previously we identified a cDNA clone from this gene and determined its chromosomal location. In this report, we present the complete cDNA sequence of the human EsD gene. A long open reading frame encoded a predicted protein of 282 amino acids with molecular weight of 30 kD. A computer-assisted search of a protein sequence data base revealed homology with two other esterases, acetylcholinesterase of Torpedo and esterase-6 of Drosophila. Homologous region were centered around presumptive active sites, suggesting that the catalytic domains of the esterases are conserved during evolution. Three genomic clones of this gene were also isolated and characterized by restriction mapping. At least ten exons were distributed over a 35-kb (kilobase pair) region; each exon contained an average of 100 basepairs (bp). A polymorphic site for Apa I, located within an intron of the esterase D gene, can be used to identify chromosome 13 carrying defective RB alleles within retinoblastoma families.
3164701##1988-6-1##Predicting genotypes at loci for autosomal recessive disorders using linked genetic markers: application to Wilson's disease.##Recently, the Wilson's disease locus (WND) has been mapped to the long arm of chromosome 13. We have analyzed segregation of several chromosome 13 markers flanking the WND locus and used multipoint linkage analysis to determine the most likely WND genotype of each of 57 unaffected individuals in 5 Wilson's disease families. Approximately 46% of these could be classified as carrier (heterozygote), homozygous normal, or homozygous affected (not yet symptomatic) with a probability of at least 90%, while 77% could be classified with a probability of at least 80%. Our results demonstrate that even though there is a significant decrease on average in serum copper concentration in Wilson's disease heterozygotes compared to normal homozygotes, other sources of variation in serum copper concentration are much greater and preclude use of serum copper to detect heterozygotes for Wilson's disease. Subsequent analyses showed that a familial component, independent of WND genotype, is the major factor accounting for variation in ceruloplasmin levels among unaffected individuals; age is another factor accounting for more variation in copper levels among unaffected individuals than WND genotype.
3403885##1988-6-1##Drug therapy in Wilson's disease.##
3367473##1988-5-27##Wilson's disease in The Merck Manual: corrections.##
3376299##1988-5-16##[Wilson's disease presenting with severe hemolytic anemia].##
3282470##1988-5-1##Ultrasonography in Wilson disease.##
3358700##1988-5-1##Neuropsychological impairment in Wilson's disease.##To examine the neuropsychological deficits of patients with Wilson's disease (WD), 19 neurologically impaired patients with WD were administered the Wechsler Adult Intelligence Scale (revised), Wechsler Memory Scale, Dementia Rating Scale, Wisconsin Card Sorting Test, Boston Naming Test, Trail Making Test, and Animal Naming Test. Their test scores were compared with those of 12 neurologically asymptomatic patients with WD and 15 normal controls. The neurologically impaired patients scored lower than did the control group on the Performance IQ, Full-Scale IQ, Dementia Rating Scale, and Trail Making Test, and they scored lower on the Wechsler Memory Scale than did both the asymptomatic and control groups. The major areas of deficit for the neurologically impaired WD group were in motor and memory functioning. Computed tomographic and neurologic examinations of the neurologically impaired patients with WD generally reflected abnormalities of the basal ganglia.
3396953##1988-5-1##Chronic hepatitis in childhood: the spectrum of the disease.##During a multicentre study of chronic hepatitis in childhood diagnosed by biopsy, the spectrum of the disease has been evaluated in 196 consecutive patients, including 157 from Northern Italy and 39 from Southern Italy. Only 31% of patients in the former group and 27% in the latter were symptomatic when first seen: the majority of cases being seen after familial screenings for hepatitis B virus (HBV) markers or during intercurrent infections, thus suggesting that the frequency of chronic hepatitis in childhood might be largely underestimated in our area. In Southern and Northern Italy 83% of symptomatic and 95% of asymptomatic patients were hepatitis B surface antigen (HBsAg) positive in serum; only 15 (8.3%) of these children were born to mothers known to be HBsAg positive at delivery, but a high circulation of HBV was found in their families: in fact more than 65% of household contacts in Northern Italy and more than 90% in Southern Italy had serological evidence of past or ongoing HBV infection. These data indicate that, although familial screenings for HBV could have enhanced the percentage of HBsAg positive asymptomatic cases, chronic hepatitis in Italian children is mainly caused by HBV infection acquired in the familial setting through horizontal transmission. Such findings also emphasise the importance of mass vaccination of infants as the most effective means to prevent chronic type B hepatitis in childhood in our area. Among HBsAg positive children 55% had histological features of chronic active hepatitis and 85% were hepatitis Be antigen (HBeAg) positive in serum. Anti-HBe positive hepatitis was significantly more frequent in Southern than in Northern Italy in parallel with the significantly higher prevalence (17%) of hepatitis delta virus infection in that area. Of the 16 HBsAg negative cases included in the study three had autoimmune hepatitis, three Wilson's disease, one alpha1 antitrypsin deficiency, and nine had cryptogenic hepatitis, often associated to mild liver lesions resembling those seen in our adult patients with chronic non-A, non-B hepatitis unrelated to percutaneous exposure.
3221958##1988-5-1##[Treatment of Wilson's disease with Zincteral].##In 27 patients with reliably diagnosed Wilson's disease treated previously with penicillamine (Cuprenil, Polfa) for from 10 months to 12 years penicillamine was withdrawn due to various adverse effects and replaced with zinc sulphate (Polish preparation Zincteral) in doses of 200 mg 4 times daily for 12 months. The neurological status was improved in 6 cases. No adverse effects of zinc sulphate were observed.
3412983##1988-4-4##[Effectiveness of zinc sulfate in the treatment of Wilson's disease].##
3355392##1988-4-1##Zinc therapy as the initial treatment for Wilson's disease.##
3358817##1988-4-1##Wilson's disease presenting as isolated arthritis of the hip.##
3391232##1988-4-1##Wilson disease in Turkish children.##
3407008##1988-4-1##Successful long term oral zinc in florid Wilson's disease: a case report.##We describe the clinical course of a patient with florid, predominantly neurological, Wilson's disease who developed serious toxic effects of d-penicillamine therapy but responded well to long term oral zinc sulphate. A congenital portosystemic shunt has decompressed the portal bed adequately to prevent the development of varices. We also documented the return to normal of a grossly abnormal pancreolauryl test after withdrawal of zinc.
3407002##1988-4-1##Protean manifestations of Wilson's disease: a review of seven Saudi patients.##The clinical picture and laboratory data of five symptomatic and two asymptomatic cases of Wilson's disease in four unrelated Saudi families are reported. More than one member was affected in two families. The oldest and youngest patients were twenty and eight years respectively. The two oldest patients were siblings and presented with neurological disturbance only while the youngest two were unrelated and had predominantly hepatic involvement. A mixture of hepatic cirrhosis and extrapyramidal syndrome was encountered in one patient only and Kayser-Fleischer rings in three. The initial presentation of one patient who subsequently developed cirrhosis closely simulated subacute glomerular nephritis. Although only three patients showed clinical or biochemical evidence of liver disease either initially or in later stages, liver biopsy demonstrated a spectrum of morphological changes in all the seven cases. These findings indicate that a positive family history, Kayser-Fleischer rings and simultaneous hepatic and brain involvement need not be present and that subclinical hepatic involvement may be commoner than is generally realised in Wilson's disease. That seven cases were seen at one centre, which takes a largely unselected patient population, in a four-year period only, suggests that this preventable and treatable disease may be frequent in Saudi Arabia.
3293546##1988-3-1##[Indications for liver transplantation in Wilson's disease].##We report the case of a 12 year-old boy with Wilson's disease, presenting with decompensated liver cirrhosis. Medical treatment failed to prevent fulminant liver failure in less than one month. Emergency liver transplantation was successfully performed. This report led us to review the prognosis of Wilson's disease with liver failure according to the present results of liver transplantation.
3341945##1988-3-1##Wilson's disease.##
21253151##2011-1-22##Liver disease in general practice.##A wide spectrum of liver disease is seen in general practice. For the most part, asymptomatic increases in transaminase may be followed for several months, but the treatable conditions described should be ruled out early on. It is essential do diagnose as promptly as possible Wilson's disease, hemochromatosis, autoimmune heaptitis, and hepatitis B. Drugs are a frequent cause of wild transaminitis. Heavy alcohol consumption as a cause of liver disease must always be suspected, but may be difficult to prove.
3390974##1988-3-1##Neuropathological findings in penicillamine-treated patients with Wilson's disease.##We report the terminal neurological impairment, amount of penicillamine taken, neuropathology and cerebral copper content of eleven patients with Wilson's disease treated for as long as 17 years. Therapy was accompanied by complete resolution of neurologic symptomatology in five patients and significant improvement in the neuro-psychiatric manifestations in six. Abnormal glial cells were seen in all the brains; gross or micro-cavitary changes were present in the putamina of eight. Of the four sets of observations, there was virtually no correlation between the degree of neurologic dysfunction - if any - in the months before death and either the amount of penicillamine taken or the cerebral copper content. There was, however, a fair degree of correlation between the severity of the neuropathologic findings and cerebral copper content.
2972748##1988-3-1##Lid-opening apraxia in Wilson's disease.##A student was diagnosed as having Wilson's disease only after the severe, intermittent inability to open his eyes led him to seek neurologic evaluation. Although lid-opening apraxia is usually a symptom of diffuse extrapyramidal disease, it has not previously been reported in Wilson's disease.
3343539##1988-3-1##Copper toxicity in Wilson's disease: an absorbing problem.##
3125292##1988-3-1##Studies of cholecystokinin-stimulated biliary secretions reveal a high molecular weight copper-binding substance in normal subjects that is absent in patients with Wilson's disease.##Copper is unique among cations in that its balance is regulated by the liver. The liver regulates copper balance by excretion of copper (we call it regulatory copper) in the bile destined for loss in the stool. However, most copper secreted into the gastrointestinal tract, for example, that in saliva and gastric juice, is reabsorbed. The biochemical mechanism by which the normal liver &quot;packages&quot; regulatory copper to prevent its reabsorption is not understood. Whatever the mechanism, it appears to have failed in Wilson's disease, because patients with Wilson's disease do not excrete adequate amounts of regulatory copper in their bile to prevent copper accumulation. In the present work, we have studied cholecystokinin-stimulated biliary secretions obtained by intestinal intubation of five normal subjects and five patients with Wilson's disease. Studies of these secretions reveal: (1) that normal but not Wilson's disease biliary samples had a copper-containing peak in the void volume from Sephadex G-75 columns; (2) that the amount of copper in this peak extrapolated to 24 hours of secretion was appropriate to maintain normal copper balance; (3) that the amount of copper in this peak increased with dietary copper supplementation of normal subjects; (4) that normal but not Wilson's disease biliary samples cross-reacted with each of two ceruloplasmin antibodies; and (5) that the high molecular weight Sephadex G-75 fraction from normal but not from Wilson's disease biliary samples cross-reacted with ceruloplasmin antibody. We postulate that the high molecular weight copper-containing substance observed with Sephadex chromatography in normal biliary samples but absent in Wilson's disease samples is the copper-packaging mechanism for copper balance regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
3336426##1988-2-4##The efficacy of oral zinc therapy as an alternative to penicillamine for Wilson's disease.##
3348368##1988-2-1##Metabolism of 25-hydroxyvitamin D in copper-laden rat: a model of Wilson's disease.##Wilson's disease results in excess tissue accumulation of copper and is often complicated by skeletal and mineral abnormalities. We investigated vitamin D metabolism in rats fed a copper-laden diet rendering hepatic copper content comparable with that found in Wilson's disease. Injection of 25-hydroxyvitamin D3 [25(OH)D3] resulted in reduced 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in copper-intoxicated rats. In vitro 25(OH)D-1 alpha-hydroxylase activity was impaired in renal mitochondria from copper-intoxicated animals. Activity was also inhibited in mitochondria from controls when copper was added to incubation media. Impaired conversion of 25(OH)D to 1,25(OH)2D occurs in copper intoxication and suggests that altered vitamin D metabolism is a potential factor in the development of bone and mineral abnormalities in Wilson's disease.
3361051##1988-2-1##Wilson's disease.##The following case involves a young man initially diagnosed as having a mental disorder. Confirmation of Kayser-Fleischer rings on the cornea greatly assisted in the final diagnosis of Wilson's disease (hepatolenticular degeneration).
3361541##1988-2-1##The arthropathy of Wilson's disease: clinical and pathologic features.##Twenty-two patients with Wilson's disease were evaluated for arthropathy with history, examination, and radiographs. Knee arthroscopy with cartilage and synovial biopsies was performed in 4 patients. Radiologic findings were minimal, including osteophytes, subchondral cysts, and joint space narrowing. Chondrocalcinosis was observed in 3 patients. Cartilage and synovial biopsies studied by energy dispersive elemental analysis showed copper and sulfur diffusely throughout cartilage in 2 of 4 patients. No crystals were found. The finding of copper in cartilage biopsies suggests that copper deposition may be a factor in the etiology of arthropathy, although definitive studies remain to be performed.
3276972##1988-2-1##Postdilution hemofiltration in the management of acute hepatic failure: a pilot study.##We conducted a pilot study to assess the feasibility and efficacy of postdilution hemofiltration (PDHF) in the management of acute hepatic failure. From January 1984 through May 1986, we encountered seven patients with acute hepatic failure and entered these consecutive patients in the study; three had non-A, non-B hepatitis and one each had type B hepatitis, fulminant Wilson's disease (hepatolenticular degeneration), acute allograft (liver) failure, and acute fatty liver of pregnancy. Two of these seven patients were unable to undergo PDHF because of a precarious hemodynamic status. Of the five patients treated with PDHF, four had amelioration of hepatic encephalopathy; in two of these patients, a close temporal relationship was noted between the improvement and the procedure. Four patients had appreciable thrombocytopenia related to PDHF and bleeding complications. Our preliminary results support a possible role for PDHF as a temporary artificial liver support system for patients with acute hepatic failure.
2447721##1988-1-1##Diagnosis of a case of Wilson's disease by cytochemical staining of fine needle aspirates of the liver.##
3203124##1988-1-1##Neonatal and adult copper-64 metabolism in the pig and the possible relationship between the ontogeny of copper metabolism and Wilson's disease.##The copper profiles of neonatal mammals differ from those of the adult; in man they are similar to those found in people with Wilson's disease (WD). WD patients handle an intravenous bolus of radioactive copper in a characteristic manner which aids diagnosis. In view of the similarity between neonatal mammals and WD patients, we have studied the fate of an intravenous bolus of 64Cu injected into neonatal and adult pigs. In adult pigs, plasma 64Cu activity fell for 10 h and then slowly increased over the next 14 h as newly synthesised caeruloplasmin was secreted. In the neonate a secondary rise in 64Cu activity was not observed. Gel filtration of the soluble supernatant revealed significant differences in the association of 64Cu with hepatic copper proteins. In adults 64Cu associated predominantly with superoxide dismutase whilst in the neonate the 64Cu associated with metallothionein and a protein of high molecular weight. This study indicates that 64Cu export from the neonatal pig liver is in many ways similar to that found in WD. Additionally, there are similarities in the profile of hepatic 64Cu-binding proteins.
3337919##1988-1-1##Haemolytic anaemia as initial manifestation of Wilson's disease.##Common manifestations of Wilson's disease are disorders of the liver and brain. A rare complication of this inherited disease is acute intravascular haemolytic anaemia. We report the case of a 33-year old female patient who was admitted to the hospital with acute haemolysis as the initial symptom of Wilson's disease. The haemolysis preceded the definitive diagnosis by 20 months. It is concluded that in any case of unclear haemolytic anaemia, especially in adolescents or in young adults, Wilson's disease should be considered.
3251700##1988-1-1##Pharyngeal dysmotility in a patient with Wilson's disease.##
3209054##1988-1-1##An expected decrease in the incidence of autosomal recessive disease due to decreasing consanguineous marriages.##A recent decline in consanguineous marriages in Japan should have resulted in a decrease in the incidence of autosomal recessive disorders. Theoretical estimates were made of the chronological decrease in the incidence using a formula for Hardy-Weinberg expectation in a partially inbred population and applying appropriate consanguinity rates, taken from the literature, during the period from 1942 to 1983. Theoretically estimated also, using Nei's extended Dahlberg's formula, is a chronological decrease in the proportion of first-cousin marriages among the parents of affected individuals. The estimated decrease in both indices during the period was substantial, and greater in disorders of low gene frequencies. The incidence of major autosomal recessive disorders was estimated to have decreased by 40 to 80% during the period. The proportion of first-cousin marriages among the parents of affected individuals dropped from 40-70% in 1945 to 5-15% in 1983. Theoretical estimates of the magnitude of the decrease in the incidence and in the proportion of first-cousin marriages among the parents agreed fairly well with those of observed figures in phenylketonuria and Wilson's disease.
2905314##1988-1-1##Partial linkage map of chromosome 13q in the region of the Wilson disease and retinoblastoma genes.##Genetic linkage maps are useful tools for defining the location of disease genes. Previously published maps of human chromosome 13 have been incomplete and have had ambiguities of order in the vicinity of the Wilson disease (WND) and retinoblastoma (RB1) genes. We have defined a six-locus map of this region using a large reference pedigree from Venezuela. Our map provides landmarks which will aid in the localization of WND, in determining the extent of deletions in retinoblastoma, and in the mapping of other marker loci.
3280434##1988-1-1##[Fulminant hepatitis in Wilson's disease--diagnostic and therapeutic problems].##
3275696##1988-1-1##Improvement of cerebral CT abnormalities following liver transplantation in a patient with Wilson disease.##Cerebral CT performed in patients with Wilson disease (hepatolenticular degeneration) often reveals abnormalities of the putamen, globus pallidus, thalamocapsular region, cerebral cortex, dentate nucleus, and brain stem. We report a patient with Wilson disease who demonstrated rapid reversal of CT abnormalities following orthotopic liver transplantation.
3050468##1988-1-1##Wilson's disease: yesterday, today, and tomorrow.##
3375049##1988-1-1##[Treatment possibilities in Wilson's disease].##
3233107##1988-1-1##Does CSF copper level in Wilson disease reflect copper accumulation in the brain?##The levels of copper and ceruloplasmin in the cerebrospinal fluid (CSF) of patients with Wilson disease were investigated. Ceruloplasmin concentrations in the CSF of all patients were almost the same but were lower than those of the controls. CSF copper concentrations in patients without neurologic signs were within the normal range, 22 +/- 6 ng/ml. In contrast, CSF copper concentrations in patients with neurologic signs (69-98 ng/ml) were significantly higher than the normal levels before and at the beginning of the treatment with D-penicillamine; it gradually decreased in response to treatment. These results suggest that the appearance of neurologic manifestations in Wilson disease is not related to the CSF ceruloplasmin concentration. The CSF copper concentration in this disease appears to reflect copper accumulation in the brain and may be useful as a marker for monitoring therapy.
3047721##1988-1-1##Disseminated mucormycosis due to Cunninghamella bertholletiae in a liver transplant recipient.##Disseminated mucormycosis occurred in a 19 year old female following orthotopic liver transplantation for fulminant Wilson's disease. The causative organism Cunninghamella bertholletiae has previously been described in ten clinical cases, but never before in this setting.
3399664##1988-1-1##[Control of the therapeutic prevention of copper uptake in the liver in Wilson's disease following oral administration of 64Cu].##
3420353##1988-1-1##[Wilson's disease: demonstration of lesions of the cortex and white matter by MRI].##Lesions of cortex and white matter are present in Wilson's disease in approximately 10 p. cent of cases. Before Magnetic Resonance Imaging (MRI) only post-mortem examination evidenced them. We report the case of a 15 year-old girl in whom Wilson's disease was diagnosed after partial motor epileptic seizures. She later presented with progressive extrapyramidal and pyramidal signs, severe cognitive weakening and disorder of behaviour. MRI clearly showed cortical and subcortical lesions by an enhanced signal (T2 values). It showed as well the classical picture of lesion in the lenticular nuclei. With T1 values it showed an extensive cortical atrophy and a widening of the ventricules.
3289110##1988-1-1##[Dystonia in the child].##A classification of child dystonias is proposed as a guide to etiological diagnosis. The analysis of symptoms and signs provides a distinction between dystonia and other involuntary movements: dystonia is a tonic involuntary movement which appears during voluntary activity as a slow and involuntary movement. Two groups of child dystonic syndromes can be distinguished: 1) dystonic syndromes where dystonia is the main neurologic abnormality; they result mainly from toxic and anoxic disorders and from torsion dystonia; 2) dystonic syndromes with associated dystonia and intellectual impairment; they are often familial neurometabolic disorders. Analysis of child dystonias show some common features: a long interval between the causative brain lesion and the onset of dystonia is possible, and may last several years. In neuro-metabolic disorders also dystonia appears after the first year of life, when psycho-motor impairment has already appeared. Etiologic investigations can provide a diagnosis and sometimes a treatment in several varieties of dystonia, e. g. L-Dopa in torsion dystonia, correction of metabolic disturbance in Wilson disease or glutaric aciduria. Genetic counselling should be provided.
3136594##1988-1-1##[Current experiences and problems with long-term management of patients with Wilson's disease in East Germany].##
2891602##1987-12-1##Localization at a subband level of polymorphic 13q14 DNA probes for diagnosis of hereditary retinoblastoma and Wilson disease.##Two single-copy DNA sequences, pG24E6.8 (D13S21) detecting a low-frequency MspI RFLP and pG14E1.9 (D13S22) detecting a high-frequency Dra I RFLP, have been isolated and cloned from a human chromosome 13-specific phage library and localized at 13q14. Their subband localization was described using a panel of cell lines from patients with different chromosome 13 deletions. A quantitative analysis of hybridization signals was carried out, taking for reference a single-copy DNA sequence from another chromosome. D13S21 and D13S22 were both assigned to q14.1-14.2, which also harbors the genes responsible for retinoblastoma and Wilson disease. The Dra I polymorphism detected by pG14E1.9 is a very suitable one for linkage studies in families with either disease.
3436787##1987-12-1##Wilson's disease: varied manifestations and consequences of non-compliance with treatment.##
3453418##1987-12-1##Wilson's disease with extensive degeneration of cerebral white matter and cortex.##This is a report of an autopsy case of Wilson's disease with widespread degeneration of the cerebral cortex and white matter, the basal ganglia and thalamus and, to a lesser degree, the cerebellum and brain stem. The patient was a 28-year-old man at the time of death with the clinical course of a 20-year duration. The lesions consisted of spongy degeneration leading to a cavity formation with insufficient glia fiber proliferation. We noted the characteristic findings of Alzheimer glia (Types I and II) and Opalski cells and the new formation in capillaries. The distribution of the changes in the hemispheres showed the typical pattern with a tendency of preferential superior and anterior localization and a relative preservation of the hippocampal formation, carcarine areas, amygdaloid nuclei and the hypothalamus. Similar cases in the literature were reviewed.
3332047##1987-12-1##Wilson's disease.##
2968162##1987-12-1##[GFAP immunohistochemical analysis of Alzheimer type II cells in Wilson disease].##
3322832##1987-11-1##Ultrasound findings in childhood chronic liver parenchymal diseases. An analysis of 41 patients.##Forty-one children with liver disease were studied by ultrasound scan at King Khalid University Hospital, Riyadh, Saudi Arabia. Diagnoses were confirmed either by liver biopsy or specific laboratory tests. Sonograms were studied for liver size, beam penetration, echogenicity, vascularity, and biliary tree abnormalities. Different liver diseases, such as chronic hepatitis, biliary cirrhosis, Wilson's disease, familial idiopathic cirrhosis, type III glycogen storage disease, and secondary haemochromatosis revealed non-specific disease patterns. Four cases of biliary cirrhosis and two cases of glycogen storage disease showed periportal fibrosis. Two cases of familial idiopathic cirrhosis and a case of Wilson's disease revealed thickening of the gall bladder wall, which has not been described in the literature.
3679690##1987-11-1##Neuropsychological impairment associated with hepatolenticular degeneration (Wilson's disease) in the absence of overt encephalopathy.##Neuropsychologic tests of cerebral integrity recorded impairments in visuopractic and learning capacity in patients with Wilson's disease. These psychometric findings point to the presence of a subclinical encephalopathy that is not otherwise revealed upon clinical examination.
3681585##1987-11-1##Idiopathic hepatic copper toxicosis in a child.##A 10-year-old Italian boy with chronic liver disease and copper overload is described. Biological and histopathological findings are similar to those described in children with Indian childhood cirrhosis. This report suggests that a disease akin to Indian childhood cirrhosis but different from Wilson disease can be found in non-Indian children probably representing a new, possibly inherited, disease of copper metabolism leading to copper overload in the liver.
3499583##1987-11-1##Wilson's disease studied with FDG and positron emission tomography.##Four patients with Wilson's disease and eight normal controls were studied with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and positron emission tomography (PET). The patients had diffusely reduced glucose metabolism in all brain regions evaluated compared with controls, with the exception of the thalamus. The ratio of the cerebral metabolic rate for glucose in the lenticular nuclei to hemispheres declined from 1.23 (+/- 0.14 SD) in controls to 1.03 (+/- 0.06) (p less than 0.025) in Wilson's disease patients. Compared with Huntington's disease, the PET FDG results in Wilson's disease indicate relatively less focal involvement of the caudate nucleus, more severe focal changes in the lenticular nuclei, and more significant global changes in glucose metabolism.
3478700##1987-11-1##Structural changes and metal binding by proalbumins and other amino-terminal genetic variants of human serum albumin.##Proalbumins are rare genetic variants of human serum albumin containing a basic propeptide that is not removed during post-transcriptional processing because of a mutation in the site of excision, an Arg-Arg sequence. We have identified the amino acid substitutions in three different types of proalbumins designated Gainesville, Taipei, and Takefu. The first two proalbumins are identical to previously described proalbumins of the Christchurch and Lille types, respectively, and exhibit the characteristic properties of susceptibility to tryptic cleavage and of lower metal-binding affinity. Takefu is a third type of proalbumin and resists tryptic cleavage because of the substitution Arg-1----Pro. Each of the first two types of proalbumins has been identified in geographically separate, ethnically diverse populations and therefore must have arisen by independent mutations. There is some tendency for mutations in albumin to cluster in the propeptide sequence. Although the substitution His3----Gln in the genetic variant albumin Nagasaki-3 decreases metal-binding affinity, mutations further down the polypeptide chain have no such effect, nor is there any reduction of copper-binding affinity in albumin from patients with Wilson disease.
2825298##1987-11-1##[MRI of Wilson's disease. Tissue differentiation of intracerebral lesions].##
3685872##1987-11-1##Comparison between serum ferritin and computed tomographic densities of liver, spleen, kidney and pancreas in beta-thalassaemia major.##Thirty-seven children with beta-thalassaemia major, eight children with liver cirrhosis, and 20 matched controls were enrolled in this study. Serum ferritin was determined in each subject by radio-immunoassay and liver enzymes by standard methods. The liver, spleen, kidney and pancreas densities were obtained by computed tomography using a Siemens Somatom 2 Scanner with 8-mm slice thickness. The iron content of liver biopsies from 10 patients was graded by staining. The mean serum ferritin of the thalassaemic patients was significantly higher than that of the control group (p = 0.0001). The ferritin of patients with cirrhosis and Wilson's disease was similar to that of the control group. The liver density of the thalassaemic patients was significantly higher than that of the control group (p less than 0.0001) while that of patients with liver cirrhosis and Wilson's disease was similar to the control group. The liver iron content of patients with liver cirrhosis was within the normal range. The spleen and kidney densities of patients with thalassaemia were higher than that of the control group with p values of 0.02 and 0.056, respectively. The density of the pancreas in patients with thalassaemia was not significantly different from that of the control group, (p = 0.52). There was correlation between the liver density and serum ferritin in patients with thalassaemia (r = 0.432, p less than 0.01) while there was no correlation between spleen, pancreas and kidney densities with serum ferritin.
2889941##1987-10-31##Brain copper in Wilson's disease.##
2441968##1987-10-1##Brain-stem auditory evoked potentials in different types of hepatic diseases.##Brain-stem auditory evoked potentials (BAEPs) were studied in 69 patients with different types of hepatic diseases. BAEPs were normal in viral hepatitis, but the peak V and interpeak I-V latencies were prolonged in liver cirrhosis. Prolongation in peaks III, IV and V and interpeaks I-III, III-V and I-V were observed in both alcoholic liver disease and Wilson's disease with the latter more severely affected. The present data indicate that BAEPs may be used to study the effect of various hepatic diseases on the CNS.
3679310##1987-10-1##Wilson's disease (a study of 12 cases).##
3654978##1987-10-1##Molecular studies of ceruloplasmin deficiency in Wilson's disease.##Deficiency of serum ceruloplasmin is a characteristic biochemical abnormality of Wilson's disease, although the mechanism of this finding is unknown. Ceruloplasmin messenger RNA (mRNA) levels were therefore examined in five patients with Wilson's disease and five controls with other types of hepatic disease. Northern and dot blot hybridizations showed that detectable ceruloplasmin mRNA was present in all of the patients with Wilson's disease, including one patient with no detectable serum ceruloplasmin. However, the ceruloplasmin mRNA levels in the Wilson's disease patients were only 33% that of controls (P less than 0.001). In contrast, albumin mRNA levels in the Wilson's disease patients averaged 161% that of controls. In an attempt to better delineate the level of gene expression responsible for this decrease in ceruloplasmin mRNA, the nuclear run-on assay was used to analyze transcriptional rates. The amount of ceruloplasmin gene transcription in four Wilson's patients was decreased to 44% that of three controls. These results indicate that the diminished serum ceruloplasmin levels in patients with Wilson's disease are due at least in part to a decrease in ceruloplasmin gene transcription.
3312808##1987-10-1##Hepatic copper and metallothionein distribution in Wilson's disease (hepatolenticular degeneration).##Wilson's disease is a rare inherited disorder of copper (Cu) metabolism characterized by the deposition of Cu in the liver, brain, and cornea. The levels of metallothionein (MT), Cu, and zinc (Zn) in the livers of two Wilson's disease patients were analyzed in this study. About 50-fold increase in the Cu levels above normal controls was observed in both patients (160 and 298 micrograms/g of wet tissue). About 73% of subcellular Cu was present in the cytoplasmic fraction and most of it was in association with MT. Analysis of hepatic MT levels showed a 3-fold increase (863 micrograms/g of wet tissue) over control human levels (321 micrograms/g of wet tissue). The two forms of MT (MT-I and MT-II) were isolated from one liver sample. Both forms contained high amounts of Cu (11 to 12 g atoms/mole), indicating saturation of MT which had only 2 to 3 g atoms of zinc. The distribution of MT in the hepatocytes was investigated using an immunohistochemical method. In tissue sections with minimal tissue damage, there was intense cytoplasmic staining for MT in hepatocytes whereas both nuclear and cytoplasmic staining was found in tissue sections with extensive necrosis and fibrosis. These results suggest that MT is the major hepatic Cu-binding protein in Wilson's disease, that it is present in a form saturated with Cu, and that only in degenerating hepatocytes is it found in the nucleus as well as the cytoplasm.
2447466##1987-10-1##Evaluation of histochemical methods for the detection of copper overload in rat liver.##Histochemical methods have invariably shown a good correlation with copper analysis by absorption spectrophotometry in the identification of canine copper storage diseases. But, in Wilson's disease (WD) in humans no such correlation exists and similar discrepancies have also been observed in copper-loaded rats. This study attempts to quantify stainable copper in the livers of copper-loaded rats and relate this to the hepatic copper concentrations. Male rats fed a high copper diet (1500 ppm) for 16 weeks were killed at intervals. The livers were analysed for copper and graded according to stainable copper present in paraffin sections stained with rhodanine and rubeanic acid. Initially there was a good correlation between histochemically demonstrable copper and its total concentration, but subsequently, when high liver levels of the metal were present, copper staining was very variable. This unrealiability has similarities with WD, in which the higher hepatic concentrations of presymptomatic patients are difficult to detect by conventional copper stains. The variation in the binding of copper and its intracellular localisation suggested by these results may have considerable significance in the pathogenesis of copper storage diseases.
3432203##1987-10-1##The interaction of copper (Cu++) with the erythrocyte membrane and 2,3-dimercaptopropanesulphonate in vitro: a source of activated oxygen species.##The therapy of copper poisoning and of Wilson's disease with 2,3-dimercaptopropane-1-sulphonate (DMPS) may increase the copper-induced haemolysis. Some aspects of the mechanism of this effect were investigated. The possible generation of activated oxygen species during the interaction of Cu++ and DMPS was studied using a chemiluminescent method detecting oxygen radicals. It was found that incubation of DMPS with copper ions (free or bond with erythrocyte membranes) is accompanied with generation of oxygen radicals. Activated oxygen species produced via O2- are able to increase the haemolytic effects of cupric salts. Hence DMPS treatment in cases of copper poisonings or Wilson's disease may involve risk of side effects on the basis of activated oxygen species generation.
3440344##1987-10-1##[Defects of antithrombin III, protein C, and plasminogen in Wilson's disease with brainstem infarction].##
2441839##1987-9-15##Histochemical and ultrastructural study of copper-binding protein in hepatocellular carcinoma.##Orcein-positive hepatocellular material (OPHM), found in 18 of 44 hepatocellular carcinomas (HCC), was compared histochemically and ultrastructurally with similar granular materials in other liver diseases. OPHM was not found in 15 control livers, 45 metastatic liver cancers or ten cholangiocellular carcinomas. OPHM in HCC was stained with orcein when the tissue sections were preoxidized. In addition, it was positively stained with rhodanine and rubeanic acid for copper. These findings were identical to the OPHM in Wilson's disease, in primary biliary cirrhosis and in neonatal livers. Seven of 12 resected HCC revealed cytoplasmic dense bodies ultrastructurally in which an x-ray microanalyzer demonstrated copper. OPHM in HCC, a granular accumulation, was concluded to be rich in copper-protein complex, and might correspond to dense bodies derived from lysosome ultrastructurally. The pathogenesis and biologic significance of this copper overload in a number of HCC are also discussed.
2975511##1987-9-1##[3H]spiperone binding to lymphocyte in extrapyramidal disease and in aging.##[3H]Spiperone binding to lymphocytes in Parkinson's disease (PD), Wilson's disease (WD), and age-matched control groups was studied. In the untreated PD group, [3H]spiperone binding was lower than in young controls, but did not differ from elderly healthy persons. After treatment with levodopa, the number of [3H]spiperone binding sites increased. In WD, lower binding of [3H]spiperone compared with age-matched controls was found. However, the magnitude of the differences in [3H]spiperone binding to lymphocytes in PD was too small to permit its use as a routine indicator of the disease state or the adequacy of pharmacological treatment in individual patients. [3H]Spiperone binding to lymphocytes decreases with age. Changes in [3H]spiperone binding to lymphocytes may be a general phenomenon for all states where dopamine is depleted, including normal aging. The nature of [3H]spiperone binding to lymphocytes remains unclear. The possible influence of dopamine on immune reactivity is discussed.
3319968##1987-9-1##[Penicillamine-induced pemphigus].##D-Penicillamine is effective in the treatment of Wilson's disease, cystinuria and rheumatoid arthritis. However, it may have adverse side-effects by inducing a spectrum of diseases such as myasthenia gravis, lupus-like disease, IgA deficiency and pemphigus vulgaris. A case of D-penicillamine-induced pemphigus is presented. The clinical aspects, pathogenesis, immunology and therapy of D-penicillamine-induced diseases are discussed.
3660361##1987-8-10##[Trientin in Wilson's disease. Therapeutic possibilities in patients who cannot tolerate penicillamine].##
2890425##1987-8-1##Anatomy and pathology of the basal ganglia.##Neurotransmitters of the basal ganglia are of three types: I, amino acids; II, amines; and III, peptides. The amino acids generally act ionotropically while the amines and peptides generally act metabotropically. There are many examples of neurotransmitter coexistence in basal ganglia neurons. Diseases of the basal ganglia are characterized by selective neuronal degeneration. Lesions of the caudate, putamen, subthalamus and substantia nigra pars compacta occur, respectively, in chorea, dystonia, hemiballismus and parkinsonism. The differing signs and symptoms of these diseases constitute strong evidence of the functions of these various nuclei. Basal ganglia diseases can be of genetic origin, as in Huntington's chorea and Wilson's disease, of infectious origin as in Sydenham's chorea and postencephalitic parkinsonism, or of toxic origin as in MPTP poisoning. Regardless of the etiology, the pathogenesis is often regionally concentrated for reasons that are poorly understood. From studies on Parkinson and Huntington disease brains, evidence is presented that a common feature may be the expression of HLA-DR antigen on reactive microglia in the region where pathological neuronal dropout is occurring.
3597731##1987-8-1##Wilson's disease, a reversible dementia: case report.##A case of advanced Wilson's disease with clear dementing features is presented. Neuropsychological evaluation before treatment revealed intellectual deterioration particularly in memory and performance tasks. The patient was treated with Penicillamine, a copper-chelating agent, for 7 months, with notable improvement in her dementia and in her motor signs. A second battery of neuropsychological tests demonstrated the improvement in the mental aspects. These findings support the concept of Wilson's disease being a reversible dementia.
3655308##1987-8-1##Copper protects against galactosamine-induced hepatitis.##Although copper is believed to be hepatotoxic in Wilson's disease and Indian Childhood Cirrhosis (ICC), the rat shows only minimal hepatic damage on copper-loading. To investigate the possibility that copper deposition may potentiate the effects of a superimposed hepatitis, D-galactosamine (GalN) was given to copper-loaded and control rats. In the non-copper-dosed rats, GalN 0.85 g/kg i.p. produced elevated serum AST (3731 +/- 545 IU/l; normal 64.8 +/- 2.1), ALT (2090 +/- 190 IU/l; normal 18.0 +/- 0.7), and OCT (16.7 +/- 2.6 mmol/min/ml; normal 0.12 +/- 0), and liver cell necrosis with portal infiltration. In rats whose liver copper was elevated to 1298 +/- 169 micrograms/g (control 18.7 +/- 1.7) by oral copper supplementation, GalN produced much smaller increases in AST (825 +/- 122 IU/l), ALT (103 +/- 15 IU/l) and OCT (0.27 +/- 0.02 mmol/min/ml) and minimal histological damage. Viable bacterial cell counts from faecal homogenates showed that the anaerobically cultured bacteria were reduced on copper-dosing of rats. Therefore the protective effect of copper may be due to a decrease in gut-derived endotoxin acting on the liver, or to an impaired prostaglandin synthesis or perhaps to synthesis of acute phase reactants.
2958567##1987-8-1##Wilson's disease: a genetic disorder of copper metabolism.##This article provides an overview of Wilson's disease, a rare genetic disorder of copper metabolism. The etiology, pathogenesis, clinical manifestations, diagnosis, and treatment of the disease are discussed. A nursing care plan is presented.
3328213##1987-8-1##Reversal of severe neurological manifestations of Wilson's disease following orthotopic liver transplantation.##Experience with liver transplantation for patients with Wilson's disease who have major neurological impairment is limited, and this report describes the results obtained in two such patients. The first was a 30-year-old man with a 14-month history of hepatic and neurological impairment. In spite of treatment with d-penicillamine, he developed increasing dysarthria, dysphagia, akinesia and rigidity of all four limbs, and required continuous nursing care. Following transplantation, liver function was almost normal from four weeks onwards, but recovery of neurological function was much slower and was not seen until two to three months after surgery. By four months he was sufficiently mobile to be discharged, and when he returned for assessment at eight months, no abnormal neurological signs were detectable. The second patient was a 27-year-old woman with worsening liver dysfunction for eight years; one year previously she had developed dysarthria, akinesia, a fine tremor and moderate rigidity of all limbs as well as marked psychological impairment. There was no improvement on treatment with d-penicillamine or trientine, but as liver function returned to normal two months after liver grafting, her neurological and psychological function began to improve so that by three months she could be discharged.
3440405##1987-8-1##[Brainstem auditory evoked potential in patients with Wilson's disease].##
3600712##1987-7-23##The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.##Penicillamine is known to be effective therapy for Wilson's disease. However, the clinical consequences of the abrupt and permanent withdrawal of penicillamine have not been investigated. We studied 11 patients who stopped their own treatment after having been treated successfully with penicillamine (1 to 2 g per day) for periods of 3 to 19 years. Eight died of hepatic decompensation or fulminant hepatitis after an average survival of only 2.6 years. In another 13 patients, penicillamine was discontinued by the physician because of serious adverse reactions. In these patients, penicillamine was replaced with trientine (1 to 1.5 g per day), a newer chelating agent. All but one of these patients (who was killed accidentally) are alive at this writing, from 2 to 15 years later. Our observations suggest that discontinuation of penicillamine in patients with Wilson's disease results in rapid clinical deterioration, which is often fatal. The replacement of penicillamine with trientine appears to prevent this adverse clinical course.
2885586##1987-7-11##Penicillamine may detoxify copper in Wilson's disease.##
3474893##1987-7-1##Mapping the Wilson disease locus to a cluster of linked polymorphic markers on chromosome 13.##Linkage of both several chromosome 13 DNA markers and the locus for the red cell enzyme esterase D (ESD) to Wilson disease (WD), an autosomal recessive disorder affecting copper metabolism, was investigated in five Middle-Eastern kindreds. The single-copy probe 7D2, identifying the polymorphic region D13S10, was demonstrated to lie 7.5 centiMorgans (cM) from the locus, since a maximum lod score of 4.66 at a recombination frequency of .07 (7.5 cM) was found between the locus for WD (WND) and D13S10. Multipoint linkage analysis between several chromosome 13 markers and WND enables us to propose that the order of markers closely linked to WND is as follows: centromere-D13S10-ESD-WND.
3505174##1987-7-1##[Hepatolenticular degeneration (Wilson's disease). 4 cases in brothers].##
3320285##1987-7-1##Importance and significance of liver echotomography in Wilson's disease during childhood.##
3582206##1987-6-5##[Treatment of Wilson's disease].##
3578235##1987-6-1##Wilson's disease presenting in sisters as fulminant hepatitis with hemolytic episodes.##Wilson's disease presenting as fulminant hepatic failure is a rare and poorly recognized disorder. When ophthalmic and neurologic signs are missing and liver biopsy cannot be performed the patients may not be diagnosed and treated specifically. An acute hemolysis only occasionally occurs in Wilson's disease but is considered a distinctive feature in the form of fulminant hepatitis. Two homozygous sisters suffering fatal Wilsonian fulminant hepatitis with hemolytic episodes are presented. Failure or delay in diagnosis seems to be responsible for high mortality in this form of Wilson's disease. Diagnostic value of familial history and laboratory results is discussed.
3322241##1987-6-1##[Hepatolenticular degeneration. Apropos of 102 cases].##The author reports the clinical and laboratory findings in 102 patients of hepatolenticular degeneration (HLD) followed up in the Department of Neurology, University of São Paulo Medical School, since 1946. The problem of the early diagnosis of the relatives is analysed, the pathology of Wilson's disease is reviewed, and the relationship of HLD with other hepatocerebral diseases is examined. Etiopathogenesis is discussed according to current researches, the role of the decreased biliary copper excretion being emphasized. The results of treatment with D-penicillamine in 84 cases are commented.
3611722##1987-6-1##Early diagnosis of presymptomatic Wilson's disease.##
3654552##1987-6-1##Wilson's disease in India: clinical and laboratory manifestations in thirty patients.##
3597821##1987-6-1##Ten-year study of a Wilson's disease dysarthric.##This case study presents a ten-year speech treatment history of a young adult Wilson's disease patient in whom a severe dysarthria persisted despite drug and dietry controls. The patient was initially classified as &quot;100% disabled&quot; and was compensated because of his severe communication disorder. As he progressed, he ultimately secured full-time employment (involving verbal communication) which affords him economic independence. One aspect of therapy that played a critical role in the transfer of intelligible speech to situations outside the clinical setting was the use of a protocol for systematic client self-evaluation and for systematic elicitation and use of listener feedback. Methods that may prove helpful in the study of intelligibility maintenance in other dysarthric clients are presented. This report suggests that in some instances long-term therapy for dysarthria is both beneficial and economically justifiable.
3612170##1987-6-1##CSF copper concentration: a new parameter for diagnosis and monitoring therapy of Wilson's disease with cerebral manifestation.##In five patients with cerebral manifestation of Wilson's disease, copper was measured in CSF, serum, urine and liver, and ceruloplasmin was determined in CSF and serum. CSF copper was found to be elevated in all cases, especially in the four examined before therapy. Two patients were followed up for a period of 3 years, while undergoing therapy with chelating substances. In case 1, the data and the clinical course are presented in detail: prior to therapy, the daily urinary copper excretion had been elevated, and this increased during the initial treatment stages. The serum copper concentration, which was already low, decreased quickly the during the initial stages of therapy, and remained at a low level during further treatment. In contrast to its level in serum, the copper level in the CSF was up to 3-fold the normal range and fell only very slowly as clinical symptoms improved. These findings suggest transport of copper from the CNS to the CSF. The copper concentration in CSF appears to be a valuable parameter for diagnosis and monitoring therapy in patients with cerebral manifestation of Wilson's disease.
3332455##1987-6-1##Treatment of Wilson's disease.##
3579660##1987-5-1##Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy.##We describe a patient with Wilson's disease who presented with neurologic disease, was treated with D-penicillamine, and suffered sudden neurologic deterioration coincident with therapy. Replicate brain magnetic resonance imaging examinations after six weeks and 11 months of penicillamine therapy documented the development of new brain lesions during this period, while liver biopsy specimen data disclosed that excellent hepatic decoppering had occurred. To develop information on the relative rarity or frequency of neurologic worsening with the initiation of penicillamine therapy, we conducted a retrospective survey of 25 additional patients with Wilson's disease who met the criteria of presenting with neurologic disease and having been treated with penicillamine. The replies indicate that, at least from the patient's viewpoint, this syndrome occurs frequently. We suggest that the cause of this distressing syndrome, and ways to mitigate or circumvent it, must be discovered.
3595514##1987-5-1##[Wilson's disease and psychiatry. Apropos of a case].##This work is based on the case of a 24 year old young man sent to a psychiatry department for behaviour troubles, hysterical demonstrations and a neurological syndrome atypical. The first part develops his familial and medical background, the clinical schemes and, finally, the biological elements leading to the Wilson's disease diagnosis. The second part is a clinical and biological summary. Comparing to our case, we can see that it is a relatively typical form. This work ends with the difficulty of determining such a diagnosis regarding a patient whose personal and familial background allowed for a consistent psychopathological explanation and who had been already treated in this sense, with the risk of neglecting the biological check up. But can this Wilson's disease diagnosis be enough to sum up all the psychiatric pathology of this patient? The question remains to be resolved in the absence of any future studies.
3595645##1987-5-1##Presenting symptoms and natural history of Wilson disease.##The presenting symptoms of Wilson disease and its natural history as related to age are described based on 283 cases collected in Japan. The disease presented with a variety of signs and symptoms; the most frequent were in order of frequency jaundice, dysarthria, clumsiness, tremor, drooling, gait disturbance, malaise and arthralgia. The mean age at onset of the disease was 12.0 years. Hepatic and osteoarthral symptoms developed early and neurological symptoms late. Fifty-eight cases developed neurological symptoms only, 28 cases had hepatic symptoms only, and in 26 cases hepatic symptoms were followed by neurological symptoms. A higher mortality rate was observed in hepatic, hepato-haematological and hepato-renal cases mainly due to acute hepatic failure resulting in death only a few weeks after onset. Cases having only neurological symptoms showed a more favourable prognosis with a longer survival.
3570171##1987-5-1##Unmeasurable serum alkaline phosphatase activity in Wilson's disease associated with fulminant hepatic failure and hemolysis.##
3570170##1987-5-1##Treatment of Wilson's disease: in D-penicillamine we trust--what about zinc?##
3570163##1987-5-1##Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens.##The standard therapy for preventing copper accumulation in Wilson's disease, D-penicillamine, has been a life-saving drug, but it has many side effects and some patients are completely intolerant. We have been using oral zinc as another approach to the therapy for Wilson's disease, with copper balance studies as the key initial assessment of the adequacy of a given dose or regimen of zinc therapy. We earlier reported that an intensive regimen of zinc (zinc taken every 4 hr) was effective in controlling copper balance. We have now shown with balance studies that a simplified zinc therapy regimen of 50 mg zinc taken 3 times per day is effective in controlling copper balance. Preliminary work presented here with other simplified regimens also indicate their effectiveness. These studies increase the data base, in terms of copper balance, for zinc therapy of Wilson's disease, and expand the dose range and regimens of zinc which have been shown to control copper balance.
3679489##1987-5-1##Hepatic presentation of Wilson's disease.##
3572199##1987-5-1##Treatment of Wilson's disease with zinc: III. Prevention of reaccumulation of hepatic copper.##Twelve patients with Wilson's disease, most of whom had received intensive treatment with penicillamine, were given zinc therapy as their sole medication for copper control. Serial liver biopsies were performed during a 12- to 20-month follow-up period to determine whether hepatic copper reaccumulates during zinc therapy. Mean baseline liver copper concentration was 255 micrograms/gm dry weight, whereas the mean value after therapy was 239 micrograms. No patient demonstrated hepatic reaccumulation of copper during zinc therapy. Copper balance, 24-hour urinary copper excretion, and nonceruloplasmin plasma copper concentration all indicated good copper control during zinc therapy. Hepatic zinc concentration increased twofold to threefold over baseline values but no toxicity was seen. Hepatic zinc concentrations appeared to reach a plateau after 12 to 18 months of zinc therapy. We conclude that oral zinc as the sole maintenance therapy in patients with Wilson's disease prevents hepatic reaccumulation of copper.
3572198##1987-5-1##Zinc-copper interaction provides a novel and apparently effective alternative therapy for Wilson's disease.##
3586738##1987-4-4##[Systemic lupus erythematosus induced by d-penicillamine in Wilson's disease: apropos of a case].##
3827691##1987-4-1##Clinical assessment of 31 patients with Wilson's disease. Correlations with structural changes on magnetic resonance imaging.##Thirty-one patients with Wilson's disease were evaluated with detailed neurologic and medical examinations. Mean age (+/- SD) at onset was 21 +/- 5 years and at examination was 28 +/- 6 years. Of the 90% of patients who were first treated with penicillamine, 31% deteriorated initially despite therapy, and half never recovered to pretherapy baseline. At the time of our evaluations, the most common neurologic findings were dysarthria (97%), dystonia (65%), dysdiadochokinesia (58%), rigidity (52%), gait and postural abnormalities (42%), and tremor (32%). Chorea and dementia were rare. Twenty-two patients underwent magnetic resonance imaging. All but one of the 19 symptomatic patients had abnormal scans. The three asymptomatic patients had normal scans. Most lesions were seen in the caudate, putamen, subcortical white matter, midbrain, and pons. Generalized brain atrophy was also common. Lesions were less common in the thalamus, cerebellar vermis, midbrain tegmentum, globus pallidus, red nucleus, and dentate nucleus. Dystonia and bradykinesia correlated with putamen lesions, and dysarthria correlated with both putamen and caudate lesions.
3829752##1987-4-1##Cardiac Wilson's disease.##Wilson's disease is a multisystem disorder. Heart involvement in Wilson's disease, however, has rarely been recognized. A prospective study was undertaken of 53 consecutive patients (28 men and 25 women, mean age of 21.4 years) with Wilson's disease. Electrocardiographic abnormalities occurred in 18 of 53 patients (34 percent), including left ventricular hypertrophy, biventricular hypertrophy, early repolarization, ST depression and T inversion, premature atrial or ventricular contractions, atrial fibrillation, sino-atrial block, Mobitz type 1 atrioventricular block, and tremor artifact. In contrast, 26 medical students and 14 carriers of Wilson's disease as control subjects (mean age of 22.6 years) all showed normal ECG. Eight out of 43 patients (19 percent) demonstrated asymptomatic orthostatic hypotension. An abnormal response to the Valsalva maneuver occurred in six of 18 patients (33 percent). There were two cardiac deaths; one died of repeated ventricular fibrillation (the copper content in the myocardium was 2.28 micrograms/g, and in the bundle of His 1.21 micrograms/g wet weight in the autopsy specimen); and the other, of dilated cardiomyopathy. It is concluded that four modes of cardiac manifestations in Wilson's disease include arrhythmias, cardiomyopathy, cardiac death, and autonomic dysfunction. Such possible cardiac involvement should be added to the clinical picture of Wilson's disease involving the hepatic and central nervous system.
3581846##1987-4-1##High-field magnetic resonance imaging of Wilson's disease.##A single case of Wilson's hepatolenticular degeneration was imaged by computed tomography and magnetic resonance (1.5 Tesla). Findings included generalized cerebral atrophy seen both on computed tomography and magnetic resonance images. T1-weighted images revealed a slight symmetric hypointensity in the lentiform nuclei and thalamus. T2-weighted images demonstrated marked symmetric hypointensity in the lentiform nuclei. These hypointensities are ascribed to the deposition of intracellular hemosiderin (and perhaps copper), which produce heterogeneous magnetic susceptibility and preferential T2-proton relaxation. Areas of increased signal activity on T2-weighted images were also seen in areas of presumed demyelination known to occur in Wilson's disease.
2952930##1987-4-1##Daily release of copper from dental alloy restorations in a patient with Wilson's disease.##Wilson's disease is a rare genetic disorder in which copper accumulates in tissues. Its victims must adhere to a strict dietary regimen yielding less than 2 mg of copper per day. Three major variables have been identified as being of critical importance in the treatment of these patients: the amount of copper naturally occurring in foods, the amount of copper introduced during the preparation of foods, and the amount of copper in the environment. An environmental variable that rarely has been addressed is the amount of copper in dental restorations. A case report is presented to discuss the possible consequences of copper-containing dental restorations for the patient with Wilson's disease.
3562454##1987-4-1##The treatment of Wilson's disease with zinc. IV. Efficacy monitoring using urine and plasma copper.##Progress has been made in establishing the efficacy and safety of oral zinc as a maintenance therapy for Wilson's disease. It is important to develop simple, noninvasive monitoring methods to assure the adequacy of zinc therapy in individual patients. In this paper we report the use of 24-hr urine copper and plasma copper measurements to monitor efficacy of zinc maintenance therapy in 30 Wilson's disease patients. In examples of therapeutic inadequacy such as noncompliance, these values increase. With continued long-term adequate therapy, they remain stable or decrease. These two simple monitoring tools appear to be very useful in monitoring Wilson's disease patients receiving zinc therapy.
3577684##1987-3-1##Subacute necrotizing encephalomyelopathy (Leigh's disease): clinical correlations with computerized tomography in the diagnosis of the juvenile and adult forms.##A computerized tomography (CT) scan was performed on 6 surviving patients with a suspected diagnosis of subacute necrotizing encephalomyelopathy of the juvenile and adult forms. Bilateral low density areas were observed in the putamina in all cases. This CT pattern conformed with the characteristic pathological changes of the disease. Once the possibility of Wilson's disease or an earlier episode of acute cerebral hypoxia, syndromes which both display a similar appearance in CT, is excluded, a diagnosis of subacute necrotizing encephalomyelopathy may be considered in cases showing bilateral low density areas in the basal ganglia, especially in the putamina, and with a consistent clinical history.
3033976##1987-3-1##Viral IgM antibodies in serum and cerebrospinal fluid in patients with multiple sclerosis and controls.##Serum and cerebrospinal fluid (CSF) from 28 patients with multiple sclerosis (MS), 14 with other neurological diseases (OND) and 31 control subjects with tension headache were analysed for presence of IgM antibodies against measles, mumps and varicellae zoster by a specific enzyme-linked immunosorbent assay (ELISA). This technique excluded false positive reaction due to possible presence of rheumatoid factor. Twelve of the 28 patients with MS had IgM antibodies in serum and 4 in CSF, the latter always being accompanied by presence of corresponding IgM antibodies in serum. Six patients had mumps specific IgM, 5 had measles specific IgM and 3 varicellae specific IgM. In 2 patients, viral IgM antibodies were demonstrated in serum against 2 different viruses. Among the 14 OND patients, one with Wilson's disease had demonstrable serum IgM varicellae antibodies and one with radicultis had elevated serum and CSF measles and varicellae IgM antibodies. Among 31 controls, 2 had IgM antibodies in serum, one against varicellae and one against mumps. No correlations were found between viral IgM antibodies and CSF IgM index, serum IgM levels or blood-brain barrier state. Our data show that MS may be accompanied by a systemic IgM response against the 3 viruses tested, occasionally against 2 of the 3 different viruses simultaneously. The occurrence in MS of virus-specific IgM may be a reflection of viral reactivation and/or polyclonal B cell activation.
3622989##1987-3-1##[Hemolytic anemia in a patient with Wilson's disease. Clinical case].##
3609950##1987-3-1##[Generalized pruritus as a presenting symptom of Kimmelstiel-Wilson disease and central hypothyroidism].##
3694353##1987-3-1##Kinetics of copper absorption in zinc-overload states and following the withdrawal of zinc supplement: the role of endogenous zinc status.##Zinc (Zn), in therapeutic dosages, has been used to inhibit copper (Cu) absorption in patients with Wilson's disease. A series of experiments were conducted to substantiate the effects of high dosages of Zn on Cu absorption using the experimental animal model. In the first experiment, five groups of mice were fed five different levels of Zn: 6 ppm (basal diet), 30 ppm (control), 750 ppm, 1,000 ppm, and 2,400 ppm, for a period of 35 days. 64Cu-loading test was conducted to measure whole body retention (WBR) of 64Cu at the 10th, 14th, 21st, and 35th day. Results showed that the inhibition of 64Cu absorption by Zn is dose- and time-dependent. However, maximum inhibition occurred in mice fed 1,000 ppm of Zn, and no additional effect was observed in mice fed 2,400 ppm of Zn. In the second experiment, the distribution between the gastrointestinal tract (GIT) and gut-free carcass, of the retained dose of 64Cu, was measured in controls and in the group fed 750 ppm of Zn. While WBR of 64Cu was significantly lower (p less than 0.01) in mice fed 750 ppm of Zn, the distribution of the retained dose was not affected. In the third experiment, a group of mice was fed 30 ppm of Zn for a period of 70 days (control), and a second group was fed 1,000 ppm of Zn for the first 35 days (repletion), after which they were switched to the basal diet (6 ppm) for the following 35 days (depletion). WBR of 64Cu was conducted in intervals throughout the experimental period.(ABSTRACT TRUNCATED AT 250 WORDS)
3495740##1987-3-1##[Epidemiologic study of Wilson's disease in West Germany].##
2957087##1987-3-1##[The relationship of astrocyte activation and fibrous gliosis to the development of Alzheimer type I cells in Wilson disease].##
3817173##1987-2-1##Endocrine studies of the ovulatory disturbances in Wilson's disease (hepatolenticular degeneration).##Women with Wilson's disease may have severe oligomenorrhea or amenorrhea whose cause is unknown. The endocrine profile of four such cases was investigated by measuring basal values and the response to dynamic tests of hypothalamic, pituitary, thyroid, and adrenal function, which all proved normal. Ovarian function was disturbed, as witnessed by low estradiol, high total testosterone (T) levels with normal free T, and mildly elevated androstenedione. An interference of ovarian follicular aromatase activity possibly due to copper intoxication could explain these findings as the cause of the ovulatory disturbances of Wilson's disease.
3819764##1987-2-1##Management of Wilson's disease with zinc sulphate. Experience in a series of 27 patients.##Evaluation of the literature concerning the various approaches for the treatment of Wilson's disease led to the conclusion that zinc sulphate might be a good choice because it is effective and relatively safe. Twenty seven patients were managed with zinc sulphate for a total period of 142 patients-years. The drug was administered in doses varying from 300 to 1200 mg/day. Of the 9 patients who were treated with zinc from the start, 8 improved and one died from severe cirrhosis. All 8 patients who were placed on zinc after intolerance to penicillamine did well on zinc therapy. Ten patients were changed to zinc after they had first been treated with penicillamine without developing signs of intolerance. Of this group 8 patients were kept on long-term zinc therapy, 2 were changed back to penicillamine because of personal preference. Signs of intolerance to zinc were not observed. All patients kept a diet containing about 1.2 mg of copper a day. Our experience supports the idea that zinc sulphate is a good choice for the treatment of Wilson's disease: the drug is effective, safe and cheap.
3561699##1987-2-1##Neurological abnormalities in Wilson's disease are reversible.##The therapeutic responses of seven children with Wilson's disease who presented with neurological disease were evaluated. Neurological abnormalities comprised intellectual deterioration in 7, conduct disorder in five, dystonia in three, choreoathetosis in three, seizures in one and hemiparesis in one. Lethargy and weight loss were present for several months in 6 children. Four children had clinically demonstrable liver disease which was fatal in two. Electroencephalography performed in two children was normal. Computed tomography (CT) of the brain in three children showed cerebral atrophy in all and areas of low attenuation in the basal ganglia which resolved on treatment in one. All patients were treated with penicillamine but, in four, triethylene tetramine (TETA) was substituted because of adverse effects. Neurological abnormalities in these patients were reversible.
3541580##1987-1-1##Spontaneous bacterial peritonitis in Wilson's disease.##Spontaneous bacterial peritonitis associated with Wilson's disease has been previously reported in only one case. We report two cases where this infection developed and seriously complicated the course of illness. As with spontaneous bacterial peritonitis occurring with other underlying diseases, early diagnosis and treatment are critical to improved outcome. Recognition that it can occur with Wilson's disease is important, and paracentesis should be performed without delay when suspicious features are present.
3814517##1987-1-1##Systemic sclerosis-like lesions during long-term penicillamine therapy for Wilson's disease.##Systemic sclerosis-like lesions developed in a 14-year-old boy with Wilson's disease who had been treated with D-penicillamine for 11 years. Clinical and laboratory manifestations included proximal scleroderma, pulmonary restrictive defects, positive antinuclear antibodies, and the deposition of C3 at the dermal-epidermal junction of the lesional skin. This is the first case reported in which long-term administration of penicillamine was followed by the development of systemic sclerosis-like lesions.
3652508##1987-1-1##D-penicillamine induced dermopathy in Wilson's disease.##
2957133##1987-1-1##Preferential activation of helper/inducer T lymphocytes in autoimmune chronic active hepatitis.##We found a significant increase of activated circulating T lymphocytes expressing interleukin 2 receptor (IL-2r) (mean +/- s.e.m. 11.0 +/- 1.1%) or DR antigen (5.0 +/- 0.49%) in patients with autoimmune chronic active hepatitis (CAH) starting in childhood when compared to healthy controls (0.14 +/- 0.09%, P less than 0.001 and 2.8 +/- 0.06%, P less than 0.01). Patients with liver disorders due to Wilson's disease (IL-2r 0.64 +/- 0.25%, DR 3.5 +/- 0.22%) or alpha-1-antitrypsin deficiency (IL-2r 0.1 +/- 0.06%, DR 2.8 +/- 0.35%) had levels similar to controls. Levels of both IL-2r and DR positive T lymphocytes were higher in patients with uncontrolled CAH (IL-2r 18.0 +/- 1.01%; DR 6.3 +/- 0.78%) than in patients with inactive disease (IL-2r 3.2 +/- 1.4%, P less than 0.001; DR 3.0 +/- 0.13%, P less than 0.01). In patients with active disease levels of IL-2r positive cells were higher than DR positive cells (P less than 0.001). Only 21% of activated T cells coexpressed the two markers of activation. Sixty-seven percent of IL-2r positive T lymphocytes were helper/inducer and 25% suppressor/cytotoxic, while 66% of the DR positive T cells were suppressor/cytotoxic and 31% helper/inducer. The finding that the highest levels of activated T lymphocytes are present in patients with uncontrolled CAH suggests that these cells are involved in its pathogenesis. The preferential increase of activated helper/inducer cells might explain the enhanced immune reactivity characteristic of autoimmune CAH.
3624829##1987-1-1##Factors modifying the prognosis of Wilson's disease in childhood.##The prognosis of Wilson's disease was investigated in 96 patients, in whom the disease had presented before 15 years of age and had begun between 1965 and 1983 (when D-penicillamine was widely available in Japan). In the activities of daily living, the prognosis was poor in those patients presenting with neurological symptoms. Interruption of D-penicillamine treatment was seen in one third of the patients, and it worsened the prognosis. Toxic side effects were seen in about half of the patients, being more frequent in the patients with initial neurological symptoms. A disappointing 17% of patients with slight or no side effects discontinued the drug. Death occurred in eight patients of whom seven had had initial hepatic symptoms. Not only early diagnosis and treatment before the appearance of hepatic failure or neurological symptoms, but also treatment throughout life without interruption is important for improving the prognosis of Wilson's disease.
3326939##1987-1-1##Studying biological vulnerability and heterogeneity--a long way ahead.##Common diseases are usually the consequence of a variety of etiologies. This rule applies, for example, to mental retardation and epilepsy. There is evidence that genetic factors influence the propensity to utilize alcohol on an addictive basis at two levels of interaction between the drug and the body. It is doubtful that psychiatric symptoms are specific for defined etiologies. Individuals who are heterozygous for autosomal-recessive alleles may show slight deviations toward the homozygous genotype. These findings are applied to a polygenic concept of psychiatric disorders. Data are presented that would be compatible with a slightly increased incidence of heterozygotes for Wilson's disease and metachromatic leucodystrophy in psychiatric patients.
3669114##1987-1-1##Arsenicosis in India.##Consumption of the hepatotoxin arsenic is very common in certain geographical areas of India and occurs as a result of the intake of arsenic contaminated water, vegetables, adultered opium, ayurvedic and indigenous medicines, and &quot;home made brew&quot;. Arsenic levels were estimated in livers obtained after autopsy from patients of idiopathic cirrhosis, alcoholic cirrhosis, Indian childhood cirrhosis, non-cirrhotic portal fibrosis, fulminant hepatitis and Wilson's disease. Significantly increased levels of arsenic were found in all diseased livers investigated when compared with values obtained from control groups. The study suggests that elevated levels of arsenic may be associated with liver disease.
3504266##1987-1-1##Young onset Parkinson's disease.##We describe a personal series of 60 cases of parkinsonism with onset under the age of 40 years. Known causes for early onset of secondary parkinsonism, such as Wilson's disease or encephalitis, were excluded in every case. Two groups were identified: those with onset after the age of 21 in whom no hereditary factors could be ascertained (56 cases), and those with onset before 21 years all of whom had familial parkinsonism. In neither group have we found any association with prematurely grey hair, hypertension, diabetes, pernicious anaemia, or thyroid disorder. Among their families, we have not found any association with diabetes, pernicious anaemia, or thyroid disorder. We propose that cases of apparent idiopathic Parkinson's disease beginning between age 21-40 years should be called &quot;young onset Parkinson's disease.&quot; Twenty percent of such patients in our series had at least one first- or second-degree relative in the same or antecedent generations with parkinsonism, but only 1.5% of their relatives at risk had parkinsonism, which is similar to the prevalence in the general population. Ten percent of these patients had at least one relative with essential tremor, but only 1.6% of their relatives at risk had tremor, which again was similar to the prevalence in the population in general. These patients with young onset Parkinson's disease responded well to levodopa therapy. However, dyskinesias and response fluctuations occurred early and frequently. The prevalence of dyskinesias and response fluctuations was strongly correlated with the duration of levodopa treatment, but not with the duration (or probably the severity) of the disease before levodopa therapy was commenced. The involuntary movements often were severe and frequently were diphasic. Despite long disease duration, the incidence of dementia in young onset patients aged less than 65 years was negligible. We believe that most, if not all, patients in this group have degenerative Lewy body idiopathic Parkinson's disease, representing the lower end of a skewed deviation for age of onset of this disease. We have so far failed to identify any additional environmental factor which may have accelerated disease onset in these patients. In contrast, cases of parkinsonism beginning before age 21 years were invariably familial. We proposed that they should be called &quot;juvenile parkinsonism.&quot; All affected relatives with parkinsonism also had young disease onset, and all but one were siblings. None of four such patients seen by us has demented, and computed tomography (CT) scan has been normal in all four. We believe that most such patients have some form of genetically determined secondary parkinsonism.
3541288##1986-12-15##Thiomolybdates: mediators of molybdenum toxicity and enzyme inhibitors.##The evidence for a role for thiomolybdates in the important ruminant disease syndromes of molybdenosis and Mo-induced hypocuprosis is outlined and present knowledge of their chemistry and metabolism in vivo is reviewed in an attempt to provide a less empirical basis for their toxicology. The compounds are novel enzyme inhibitors in vitro and have also been used therapeutically, apparently successfully, in the treatment of Wilson's disease. While the changes which occur in vivo are complex they can be best understood in terms of an alteration in the affinities for copper of some of the competing ligands, including albumin, which leads to a change in the distribution of copper between the different systemic pools and an overall depletion.
3799705##1986-12-1##Treatment of Wilson's disease with zinc. II. Validation of oral 64copper with copper balance.##The efficacy of zinc as a therapeutic agent to control copper balance in Wilson's disease patients has been previously documented with balance studies. In an attempt to develop a simpler and faster tool for evaluating the adequacy of zinc therapy, a technique that measures the uptake into blood of a small oral dose of 64copper was studied in conjunction with copper balance. The mean peak 64copper uptake into blood of nine Wilson's disease patients on D-penicillamine, trien, or no medication was 6.04 +/- 2.74%, comparable with normal controls. Seven patients on zinc therapy had a markedly and significantly reduced mean uptake of 0.79 +/- 1.05% after treatment. The data demonstrate that the prevention of copper uptake into blood in Wilson's disease patients by zinc therapy can be evaluated by 64copper uptake and that peak uptakes of less than 1% occur in patients with neutral or negative copper balance.
3569749##1986-12-1##A copper-sulfur complex in the liver of a patient with Wilson's disease.##An asymptomatic 16-year-old boy was found to have Wilson's disease without Kayser-Fleischer rings. Liver biopsy showed chronic active hepatitis with 1025 micrograms copper/g dry weight. After 19 months of d-penicillamine therapy, the liver histology became almost normal and the copper content decreased to 238 micrograms/g dry weight. The liver specimens obtained before and after treatment were studied by X-ray probe microanalysis. After treatment, both copper and sulfur decreased in hepatocellular lysosomes. The estimated molar ratio of the decreased copper to the decreased sulfur was 32/100. These figures suggest that lysosomal copper exists in the form of metallothionein.
3773810##1986-11-17##Wilson's disease in childhood. A plea for increased awareness.##Wilson's disease, a hepatic-based metabolic disease, is treatable with a relatively good prognosis if diagnosed before severe complications occur. It has been diagnosed in eight children (five boys, three girls) in 11 years at our institution. The presenting symptoms were hepatic in four children, neurological in one and non-specific in one, whereas two children were asymptomatic siblings of index patients. The mean age at diagnosis was 8.9 years (range, 4.7-11.7 years). Two boys died soon after diagnosis: one had fulminating hepatic failure and the other, who had neurological disease, died of aspiration pneumonia. Six children are well, with regression of clinical disease, two to 10 years after the initiation of chelation therapy by mouth. The diagnosis was delayed for all symptomatic patients because of the disease's rarity, its nonspecific early manifestations and a low index of suspicion for the disease on the part of physicians.
3777013##1986-11-1##Oral zinc therapy normalizes serum uric acid level in Wilson's disease patients.##The authors investigated changes in the serum uric acid (s-UrA) level seen in a Wilson's disease patient who had to undergo oral zinc therapy because of the occurrence of D-penicillamine-induced acute sensitivity reactions, including neutrophilic agranulocytosis, thrombocytopenia, and skin eruptions. Although s-UrA levels were low before oral zinc therapy (mean +/- SD, 1.60 +/- 0.20), they increased (mean +/- SD, 2.63 +/- 0.32) to within normal range (2.8-8.0 mg/dl) after therapy. There were no significant changes in the renal tubular reabsorption of UrA during oral zinc therapy. This therapy also produced an improvement of the decreased cholinesterase (ChE) values usually seen in Wilson's disease. These results suggest that oral zinc therapy can normalize UrA metabolism in Wilson's disease by improving liver dysfunction and increasing UrA synthesis.
3792921##1986-11-1##Wilson's disease: clinical presentation and use of prognostic index.##As the results of treatment in Wilson's disease are so dependent on the stage at which penicillamine therapy is started, the antecedent history in 34 patients with Wilson's disease was analysed with particular respect to the earliest manifestations of the disease. Lethargy and anorexia (70%) jaundice (56%) and abdominal pain (48%) were the commonest symptoms and less common were intellectual deterioration (22%) and recurrent epistaxes (22%). The duration of symptoms before diagnosis ranged from five days to three years (mean 10.5 months) and in only five of the patients was the diagnosis established before referral. Analysis of the physical signs at presentation showed hepatomegaly (81%) and splenomegaly (70%) to be common and the only signs which were significantly more common in the 13 fatal cases were jaundice and ascites. In three of these and in one other patient who survived the clinical course was exceptionally severe and was indistinguishable from fulminant hepatic failure. Based on the severity of abnormality of serum aspartate aminotransferase, bilirubin, and prothrombin time on admission a prognostic index was derived which enabled complete separation of fatal and nonfatal cases and when subsequently used in a further nine index cases correctly predicted the outcome. Two further cases found to have indices in the fatal category did well after liver transplantation, which needs to be considered as soon as the diagnosis is established in cases with such severe liver damage.
3820209##1986-10-1##Penicillamine associated pulmonary hemorrhage.##Penicillamine is the drug of choice in Wilson's disease and a therapeutic alternative in rheumatoid arthritis. Autoimmune complications associated with penicillamine include cases resembling systemic lupus erythematosus and Goodpasture's syndrome. We report a case of diffuse pulmonary hemorrhage associated with prolonged penicillamine use in a patient with Wilson's disease with evidence of circulating immune complexes and complement activation, but without serologic or morphologic evidence of systemic lupus erythematosus, Goodpasture's syndrome or renal disease.
3790358##1986-10-1##[Copper-binding proteins in liver, kidney and brain tissue from a Wilson's disease patient].##Copper-binding proteins (Cu-PBs) in the liver, kidney, and brain tissues from a Wilson's disease patient, who was 19-year-old woman and died of hemolytic crisis, were examined with Sephadex G-75 gel chromatography and SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Copper contents, which were determined by flameless atomic absorption spectrophotometry in the liver, kidney, and cerebral tissues from the patient, were 28-, 38-, and 3.5-fold, respectively, as compared to those of control subject, who was 5-year-old girl and died of cerebral palsy. Each tissue was homogenized in 3 volumes of 50 mM Tris-HCl buffer, pH 8.6, and the homogenate was centrifuged at 105,000 g for 60 min to obtain cytosol fraction. Sephadex G-75 gel chromatography of cytosols from Wilson's liver and kidney showed that most of increased copper existed as Cu-thionein (Cu-Th), in contrast to a much lower Cu-Th level in control liver cytosol and to no detectable amount of Cu-Th in control kidney cytosol. In addition, Zn-Th was also increased in Wilson's kidney cytosol, while it was decreased in Wilson's liver cytosol. Gel chromatography of Wilson's cerebral cytosol revealed that the increased copper bound mainly to two proteins with apparent molecular mass of 10 kDa (Cu-BP 1) and 20 kDa (Cu-BP 2), respectively, both of which showed no absorption at 280 nm and were not observed in control cerebral cytosol even after addition of excess copper (50 micrograms/ml) as CuSO4.(ABSTRACT TRUNCATED AT 250 WORDS)
3538693##1986-10-1##Zuelzer-Wilson's syndrome and absence of the enteric nervous system. Two rare forms of anomalies of the enteric nervous system with identical clinical symptoms.##47 children have been treated in Basel for aganglionosis (Hirschsprung's disease) during the last 25 years. Six children presented severe vomiting and an ileus as leading symptoms instead of chronic constipation, the classical leading symptom of Hirschsprung's disease. Clinical, radiological and intraoperative findings were virtually identical in these 6 patients. However, enzyme histochemical and immunocytochemical investigations disclosed an aganglionosis of the entire colon (Zuelzer-Wilson's disease) in 3 patients, absence of the enteric nervous system in the small and large intestine in 2 patients, and a combination of both in 1 patient. In contrast to children suffering from aganglionosis of the entire colon, the chance of survival for patients with an absence of the enteric nervous system is extremely small. It is therefore necessary in presence of severe vomiting and an ileus to take intraoperative biopsies from the large and the small intestine. The precise diagnosis can be made only by using enzyme histochemical and immunocytochemical techniques.
3752071##1986-9-1##Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive systemic sclerosis: successful treatment of two patients and a review of the literature.##Although D-penicillamine has been used effectively in the management of a variety of diseases such as cystinuria, Wilson's disease, rheumatoid arthritis, and progressive systemic sclerosis, several toxic drug reactions have been observed with prolonged administration of this agent. One of the most serious side effects is the renal changes that occur following several months of use. We now report two patients with scleroderma who developed serologic evidence of lupus and crescentic glomerulonephritis during treatment with D-penicillamine. Both patients responded to pulse methylprednisolone and subsequent daily steroids. We also review the current information available on the variety of penicillamine nephropathies.
2427312##1986-9-1##An EEG study of Wilson's disease. Findings in patients and heterozygous relatives.##The correlation of clinical and EEG findings was studied in 40 patients with Wilson's disease and their 57 heterozygous relations (25 children, 30 parents and 2 siblings). EEG changes in Wilson's disease were found in 84% (50% mild, 34% moderate) with but a slight predominance in patients with neurological involvement. The relatively high rate of pathological EEG findings in the hepatic or asymptomatic forms suggested the presence of subclinical CNS damage even in these cases. Diffuse episodic abnormalities were a dominant feature in all the groups under observation. As for the heterozygous relatives, a significant increase in pathological EEG findings (80-28% mild, 52% moderate to severe) was found in the heterozygous children. The changes often correlated with the clinical detection of minimal brain damage. The grossest EEG changes were seen in the youngest age group (under 10 years of age) with a subsequent tendency to abatement. In 2 cases there was an extinction of specific epileptic graphoelements which may have been the result of long-term penicillamine administration. In the adult heterozygous population (parents and siblings) there was no significant increase in the rate of pathological EEG findings compared with our control group. The authors discuss the problem of control mechanisms which have a role to play in the normalization of biochemical and probably also clinical and EEG findings in the heterozygotes.
3758940##1986-9-1##Low serum alkaline phosphatase activity in Wilson's disease.##Low values for serum alkaline phosphatase activity were observed early in the course of two patients with Wilson's disease presenting with the combination of severe liver disease and Coombs' negative acute hemolytic anemia. A review of other cases of Wilson's disease revealed that 11 of 12 patients presenting with hemolytic anemia had values for serum alkaline phosphatase less than their respective sex- and age-adjusted mean values; in eight, serum alkaline phosphatase activity was less than the lower value for the normal range of the test. Low values for serum alkaline phosphatase were much less common in Wilson's disease patients with more chronic forms of presentation. Copper added in high concentration to serum in vitro did not have an important effect on serum alkaline phosphatase activity. The mechanism responsible for the decrease in serum alkaline phosphatase activity in patients is uncertain.
3771686##1986-9-1##Wilson's disease in an adolescent displaying an adjustment reaction to a series of life stressors: a case study.##The case is presented of a 13 year old boy suffering from Wilson's disease. Initially, his medical condition was, to a large degree, masked by a range of behavioural and emotional problems which followed directly in the wake of a series of major life stresses.
3462698##1986-9-1##Molecular cloning of the human esterase D gene, a genetic marker of retinoblastoma.##Retinoblastoma, the most common intraocular tumor, represents one of the prototypes of inheritable cancers. To elucidate the mechanisms that give rise to this tumor, the retinoblastoma gene (RB) must be molecularly cloned. The difficulty encountered in cloning the gene is that little of its function or structure is known. The human esterase D gene, on the other hand, has been localized cytogenetically to the same sub-band of chromosome 13q14:11 as the RB gene. The esterase D gene thus provides a convenient starting point for cloning the RB gene. In this communication, we describe the isolation of the esterase D cDNA clone. Its identification is based on three lines of evidence. This cDNA encodes a protein immunologically related to the esterase D protein. The deduced amino acid sequences of this clone contain sequences identical to the three CNBr-cleaved peptides of the esterase D protein. This clone is mapped to the chromosome 13q14 region by Southern genomic blotting using different deletion mutants. The availability of this clone should allow for the cloning of the RB gene by chromosome walking; the diagnosis of genetic defects such as retinoblastomas and Wilson disease, whose genes are closely linked to the esterase D gene; and the exploration of the large family of human esterase genes.
3532572##1986-8-29##[Liver cirrhosis in childhood--etiology, diagnosis and conservative therapy].##Liver cirrhosis is relatively rare in children as compared to adults; frequently it is diagnosed too late. Biliary cirrhosis of early childhood is often the result of neonatal cholestatic syndromes. Beyond infancy, cirrhosis as a consequence of chronic active autoimmune hepatitis or of Wilson's disease may be prevented, if causal therapy is begun in time. Hence paediatricians should exclude both diseases in all children with elevated transaminases and clinical features of a liver disorder.
3766920##1986-8-1##Penicillamine-induced elastosis perforans serpiginosa. Tip of the iceberg?##Elastosis perforans serpiginosa (EPS) is now a well-recognized potential complication of long-term penicillamine therapy. By itself, EPS appears to be a relatively innocuous cutaneous side effect of penicillamine. However, suspicion has been raised in recent literature that EPS may represent only a superficial manifestation of more serious penicillamine-induced systemic elastic tissue damage, particularly involving blood vessels. This is a report of a patient with Wilson's disease who was treated with penicillamine for 14 years. She developed EPS, and histologic examination of the skin revealed the characteristic penicillamine-induced &quot;lumpy-bumpy&quot; elastic fibers in the dermis. More important, nonlesional skin showed the same elastic fiber changes. Of greatest significance was the finding of identical elastic fiber alterations in an artery.
2873435##1986-7-19##Compliance in Wilson's disease and in copper toxicosis of Bedlington terriers.##
3724656##1986-7-4##Trientine for Wilson's disease.##
2872502##1986-6-14##Compliance and Wilson's disease.##
3729321##1986-6-1##Wilson's disease and Kayser-Fleischer rings.##
3718912##1986-6-1##Unilateral Kayser-Fleischer ring.##A patient is presented who had unrecognised Wilson's disease. He had developed a clinically obvious Kayser-Fleischer ring in only one eye. The eye without the corneal ring had been injured in childhood and had a low intraocular pressure. Possible mechanisms for formation of a Kayser-Fleischer ring are reviewed and the lack of Kayser-Fleischer ring in this case is discussed.
3719287##1986-6-1##Sensory evoked potentials in Wilson's disease.##Somatosensory, brainstem auditory and pattern-reversal visual evoked potentials (SEP, BAEP and VEP) were studied in 16 patients with Wilson's disease and 16 family members. In 13 patients with neurological manifestations, median nerve stimulation elicited cervical potentials with normal N13 latency. Scalp-recorded components of the median and tibial SEPs were absent bilaterally in 1 patient and unilaterally in another. The median conduction time (N13 to N20 peaks) was bilaterally prolonged in 3 patients and unilaterally prolonged in 5. In the tibial SEPs from 9 patients with neurological symptoms, the N22 latency of the lumbar evoked responses was within normal limits, but conduction time from N22 to P40 peaks was unilaterally prolonged in 5. Overall, 9 of 13 patients with neurological manifestations had SEP abnormalities. The BAEPs were bilaterally abnormal in 12 of 13 patients with neurological symptoms, mainly due to prolongation in the III-V and I-V intervals. In the VEPs from 8 patients with the neurological form, the P100 latency was delayed bilaterally in 2 patients and unilaterally in 1. Abnormalities in evoked potentials were not observed in 3 patients with other forms of Wilson's disease and in the family members. The present study indicates that the majority of the patients with neurological manifestations had subclinical dysfunction in three major sensory pathways. They are consistent with neuropathological and neuroradiological findings of widespread degeneration of the brain in Wilson's disease.
3516787##1986-6-1##Fulminant Wilson's disease treated with postdilution hemofiltration and orthotopic liver transplantation.##A 22-yr-old woman presented with fulminant Wilson's disease. The diagnosis was suspected clinically and was later confirmed with chemical and pathologic studies. She presented with acute hepatic failure, hemolysis, and acute anuric renal failure. Postdilution hemofiltration and continuous arteriovenous hemofiltration with oral D-penicillamine allowed removal of a total of 95,700 micrograms of copper; 78,665 micrograms of the total were removed via postdilution hemofiltration alone. On the 57th day, the patient received successful liver and renal transplants. We found that the determination of serum copper was instrumental in the diagnosis of fulminant Wilson's disease, that postdilution hemofiltration allowed a rapid removal of copper in the presence of renal failure, and that, finally, orthotopic liver transplantation should be performed early in the clinical course of these patients. This patient is the longest survivor of this serious condition.
3769313##1986-6-1##[Wilson's disease with peculiar MR-CT imaging].##
3520895##1986-6-1##Indications for liver transplantation in the cyclosporine era.##One hundred seventy orthotopic liver transplants were performed under conventional immunosuppression with azathioprine and steroids with 1- and 5-year survivals of 32.9 per cent and 20.0 per cent, respectively. Since the introduction of cyclosporine-prednisone therapy in March 1980, 313 primary orthotopic liver transplants have been performed. Actuarial survivals at 1 and 5 years have improved to 69.7 per cent and 62.8 per cent, respectively. Biliary atresia is now the most common indication for liver replacement. In adults, primary biliary cirrhosis and sclerosing cholangitis have become more common indications for transplantation, and alcoholic cirrhosis and primary liver malignancy as indications have declined. Early enthusiasm for liver transplantation in patients with hepatic cancer has been tempered by the finding that recurrence is both common and rapid. An increasing number of patients with inborn errors of metabolism originating in the liver are receiving transplants, including patients with Wilson's disease, tyrosinemia, alpha-1-antitrypsin deficiency, glycogen storage disease, familial hypercholesterolemia, and hemochromatosis. Survival in this group of patients has been excellent (74.4 per cent at 1 and 5 years). A hemophiliac who received a transplant for postnecrotic cirrhosis has survived and may have been cured of his hemophilia. About 20 per cent of patients require retransplantation for rejection, technical failure, or primary graft failure. Only four of the patients receiving retransplants under conventional immunosuppression survived beyond 6 months, and all died within 14 months of retransplantation. Sixty-eight patients have received retransplants under cyclosporine-prednisone. Thirty-one patients are surviving, all for at least 1 year. Six of the twelve patients requiring a third transplant are alive 2 to 3 years after the primary operation. An aggressive approach to retransplantation in the patient with a failed graft is justified.
3710431##1986-5-1##The ontogeny of liver copper metabolism in the guinea pig: clues to the etiology of Wilson's disease.##The normal human neonate has a copper profile indistinguishable from Wilson's disease, and we have previously postulated that this disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism. This study validates the developing guinea pig as a suitable animal in which to study copper ontogeny. At birth, liver copper concentrations are 7 times higher than in adults and serum copper and ceruloplasmin are 27 and 21% of adult values, respectively. A 53% fall in liver copper occurs in the 4 days after birth. This is associated with a marked increase in bile copper output, which does not parallel increasing bile flow. Liver copper falls, and serum copper and ceruloplasmin increase to near adult levels in the 30 days after birth. Until the sixtieth day of gestation, liver copper was significantly increased in copper-stressed littermates, although paradoxically at birth, concentrations were significantly lower. In copper-stressed fetal animals, bile copper output increased markedly before birth. Metallothionein was the dominant copper-binding protein in the fetal liver but a minor component in the adult. Superoxide dismutase activity only developed after birth. We conclude that the postnatal switch from the fetal to adult mode of copper metabolism involves activation of biliary excretion and ceruloplasmin export as well as changes in the association of copper with hepatic copper proteins. Similarities between the fetus and Wilson's disease suggest that this disease is caused by failure of this postnatal adaptation process.
3738398##1986-5-1##[Joint involvement in Wilson's disease].##
3529410##1986-5-1##Fulminant and subfulminant liver failure: definitions and causes.##Fulminant or subfulminant liver failure, complicated by encephalopathy and in many cases by death is seen to be a syndrome that may result from numerous causes. Although viral hepatitis, drug-induced hepatitis, and hepatitis due to various types of poisonings, in decreasing frequency, account for 90% of all cases, a variety of miscellaneous conditions account for the remainder. Consideration of the possibility of these less common etiologies by the clinician is of considerable importance, since some, including massive malignant involvement (such as leukemia) or acute fulminant Wilson's disease, may respond to specific treatment measures. Thus, unless hepatic transplantation proves to be applicable in FHF of many etiologic diagnosis may continue to have important therapeutic indications in at least some cases with this syndrome.
3029930##1986-5-1##[Vitamin-resistant rickets preceding Wilson's disease].##
3737464##1986-4-28##[Fulminant hepatitis and acute hemolysis as the symptoms of Wilson's disease].##
3719623##1986-4-18##[An EEG study of Wilson's disease].##
2870324##1986-4-12##Dangers of non-compliance in Wilson's disease.##A patient who presented with severe hepatic Wilson's disease at age 14 responded well to treatment with penicillamine and remained in good health for a further 20 years, although she became somewhat careless about her medication towards the end of this period. Finally she abandoned treatment altogether and died of hepatic failure 2 1/2 years later. Abdominal computed tomography showed that the main structural damage to the liver occurred in this relatively short period of non-compliance after over 20 years of normal health on maintenance penicillamine therapy.
3752894##1986-4-1##Wilson's disease revisited in the tropics.##The clinical features and investigations of 17 patients were analysed. Thirteen of them were Chinese and the rest Indians. Their ages at presentation ranged from 8 to 63 years (mean 18.35 years). Thirteen patients (76%) were symptomatic; 8 with predominantly hepatic manifestations and 5 with neurological features. Four were asymptomatic siblings. At diagnosis, however, 10(59%) had features of liver involvement singly, 3 (18%) had neurological involvement alone and 4 (27%) had mixed presentations. Family histories were available in 15 patients; 26.9% of siblings had Wilson's Disease. Serum ceruloplasmin was low in 82% of the patients. 24-hour urinary copper was measured in 16 patients and was raised in all of them. About half the patients (41%) had evidence of concomittant renal tubular dysfunction with hypouricaemia and aminoaciduria. Three patients (18%) had joint involvement at presentation. All 17 patients were treated with Penicillamine. Complications due to therapy included pemphigus in one and toxic epidermal necrolysis and later a lupus like syndrome in another. The features of clinical improvement included fading of K-F rings, improvement of neurological signs and the normalisation of serum transaminases. One patient developed primary hepatocellular carcinoma 5 years after presentation. Delay in diagnosis was encountered in half of the patients reviewed. Being a treatable condition, Wilson's Disease, although rare, should always be thought of in patients with haemolysis, liver diseases or extrapyramidal disorders.
3519972##1986-4-1##Of mice and men, metals and mutations.##Several mutations affecting the transport of copper and zinc in humans and in mice have been discovered over the last 15 years, joining the long known disturbance of copper transport in Wilson's disease. Menkes' disease (classical and mild variant forms) and X linked Ehlers-Danlos syndrome (type IX, X linked cutis laxa) have features in common with one another and with the brindled (Mobr) and blotchy (Moblo) mouse mutants, respectively. There may be one allelic series of mutants in each species or two loci may be involved in each. The toxic milk mutant (tx) in the mouse may be homologous to Wilson's disease in man. The defect of intestinal absorption of zinc in acrodermatitis enteropathica has no homologue yet in the mouse. However, the lethal milk (lm) mutant in the mouse may be homologous to a condition of zinc deficiency described in a few breastfed, low birth weight infants. Many more genetic defects of transport of copper and of zinc may await discovery. Conversely, these mutants are valuable in elucidating the normal processes of copper and zinc transport.
3094875##1986-4-1##[Effect of oral ZnSO4 on urine copper and blood trace elements in 60 patients with Wilson's disease].##
3751986##1986-3-1##Ultrastructural features in active chronic hepatitis with changes resembling Wilson's disease.##A case of chronic hepatitis with ultrastructural changes resembling alterations usually occurring in Wilson's disease is presented in an elderly man. At the time of the diagnosis, the patient did not show clinical and laboratory data consistent with the diagnosis of Wilson's disease. Subsequently, the patient developed neurologic symptoms similar to that resulting from hepatolenticular degeneration. The possibility that such lesions are caused by an abnormal copper metabolism in consequence of acquired liver disease is considered.
3948959##1986-3-1##Effects of copper on dopaminergic function in the rat corpus striatum.##Copper-loading was produced in rats by administration of 0.125% CuSO4 in the drinking water for a period of 11 months from weaning. At conclusion of the treatment the animals had significant increases in liver (552%) and brain (26%) copper content relative to age-matched controls. Whereas the concentration of dopamine was unaffected, the concentration of 3,4-dihydroxyphenylacetic acid in the corpus striatum was found to be lower (25% decrease) in the copper-treated group. Saturation studies of the striatal D-2 dopamine receptors using [3H]spiperone indicated that in copper-loaded animals the affinity was significantly increased threefold, whereas there was a trend for the number of receptors to decrease. When included in the radioligand binding assay, copper salts (Cu2+) inhibited specific [3H]spiperone binding to untreated corpora striata. The inhibition produced by copper was competitive with a significant decrease in affinity, the 50% effective concentration of Cu2+ was 21 to 24 microM, and the potency of dopamine agonists was also decreased. These results are discussed in relation to the mechanism by which copper affects dopaminergic function and to the use of copper-loaded rats as a model of Wilson's disease.
2978898##1986-3-1##[D-penicillamine and cutaneous lesions in Wilson's disease].##
3522961##1986-3-1##[A case of Wilson disease with a nodular lesion in the liver].##
3961914##1986-3-1##Wilson's disease in the Commonwealth of Dominica, a case report.##The first case reported in Dominica of Wilson's disease is described. This is possibly the first successfully treated case in the West Indies. Wilson's disease, though rare, may occur in an unexpected setting.
3721331##1986-2-16##[Triethylene tetramine in Wilson's disease].##
3943210##1986-2-1##Detection of Wilson's disease in sibs of a patient with Wilson's disease.##
3711011##1986-2-1##Wilson's disease (report of three cases).##
3950647##1986-2-1##Coincidence of Wilson's disease with other movement disorders in the same family.##
3712863##1986-2-1##Pregnancy and penicillamine treatment in a patient with Wilson's disease.##A 22-year-old female with Wilson's disease became pregnant and subsequently delivered a normal infant. At the age of 17 the patient presented evidence of liver cirrhosis and was diagnosed as having Wilson's disease. A regimen of d-penicillamine was started at this time and continued, although irregularly for the 10 months prior to her 9th week of pregnancy. At the 14th week of pregnancy she was started on 500 mg of D-penicillamine a day. She was stable during the remainder of her pregnancy and after delivery. Fetal development was normal and a normal infant was delivered at 35 weeks. It is suggested that pregnancy is not contraindicated in well treated Wilson's disease, and that a regimen of D-penicillamine during pregnancy can control the illness without harming the fetus.
3523546##1986-2-1##[The detection of antibodies against D-penicillamine. 3. Detection of antibodies against D-penicillamine in the serum of patients with Wilson's disease treated with D-penicillamine--preliminary results].##121 serum samples from 54 patients with Wilson's disease were tested for antibodies against D-penicillamine by indirect immunofluorescence (DASS-system). IgG antibodies were found in 44 serum samples from 16 patients (31% of all patients). The incidence of serum antibodies was higher in patients with side effects during therapy with D-penicillamine (10 of 13 patients 77%) compared to 6 of 39 15% in patients without side effects. The titre of antibodies was higher in patients with side effects. The antibodies bound complement demonstrated by double immunofluorescence. These observations indicate that complement binding IgG antibodies to D-penicillamine are involved in pathogenesis of side effects during therapy with D-penicillamine.
3456572##1986-2-1##A sialic acid-specific O-acetylesterase in human erythrocytes: possible identity with esterase D, the genetic marker of retinoblastomas and Wilson disease.##The &quot;nonspecific&quot; esterases are a family of enzymes that were originally identified because of their reaction with synthetic O-acetyl ester substrates. While the electrophoretic polymorphisms of these enzymes have been extremely useful for genetic studies, their biological functions have remained completely unknown. Esterase D is characterized by its reactivity with 4-methylumbelliferyl acetate. This enzyme has recently been of particular interest because of its tight linkage to the putative recessive gene causing retinoblastomas, and to the recessive gene causing Wilson disease. We describe here the partial purification of a human erythrocyte esterase that appears to be highly specific for O-acetylated sialic acids. We next present evidence that suggests that esterase D is identical to this sialic acid-specific O-acetylesterase. First, both activities copurify from human erythrocyte lysates through several different purification steps, each of which use different principles of separation. Second, both activities show a remarkably similar profile of inhibition with a variety of different agents. Third, they both show a nearly identical heat-inactivation profile. This cytosolic sialic acid-specific O-acetylesterase appears to be involved in the &quot;recycling&quot; of O-acetylated sialic acid molecules. Thus, esterase D may be the first nonspecific esterase for which a specific biological role can be predicted.
3520716##1986-2-1##[Hepatic transplant in Wilson's disease].##
3495088##1986-1-1##[The value of the Pi system phenotype in alpha 1-antitrypsin deficiency].##One-hundred-and-ten children between the ages of two months and 14 years with the following liver diseases were studied: 16 with acute viral hepatitis, 8 with persistent chronic hepatitis, 31 with active chronic hepatitis, 5 with hepatic steatosis, 11 with cirrhosis of the liver, 24 with newborn cholestasis, 3 with Wilson's disease, 2 with congenital hepatic fibrosis, 5 with metabolic diseases and 5 due to other causes. These children presented Pi system phenotypes in isoelectric focus using ultrafine polyacrylamide gels according to Kuepper's method, with modifications incorporated to determine Alpha-1-antitrypsin (A1-AT) serum level deficiencies in those presenting the Pi ZZ phenotype, a liver biopsy with P.A.S. coloration on digestion of diastase and a family history of the phenotype. Four (3.6%) of the children with Pi ZZ phenotypes showed a decrease of serum A1-AT and the presence of positive P.A.S. inclusions resistant to diastase in the cytoplasm of hepatocytes. Three had a history of postnatal icterus and the fourth presented hepatomegaly. The phenotypic study of the parents showed their being heterozygous (MZ), while siblings were normal (MM). The importance of the diagnosis of A1-AT deficiency and the diagnostic value of detecting Pi system phenotypes in every case of liver disease in children and adolescents is stressed.
2958986##1986-1-1##[Hepatic laparoscopy and biopsy in the diagnosis of hepatic cirrhosis].##316 cases of proved hepatic cirrhosis (HC) which underwent Laparoscopy (L) were analysed. In 94 cases, hepatic biopsy by needle (HBN) was also practised under laparoscopic view, 96 cases were controlled until death, with a follow-up of almost 90 months. In 54 of these, there is a complete necropsy study. The performance in diagnosis of cirrhosis, L and HBN are compared separately. L gave the exact result of 96.6% and HBN 74.7%. HBN commonly practised with a Menghini needle (1.2 or 1.4 mm) as it is one that produces less complications, gives and insufficient sample, which determines that in 25.3% of the cases under biopsy, the HC diagnosis could not be proved, while L only fails in this aspect, in 3.38%. To this disadvantage of HBN, we must add another negative factor, the frequency which HBN can not be practised due to prothrombin under 50%, which nevertheless is not an obstacle for practising an L. In this series we have not reported any deaths with this two techniques. L has the additional advantage to contribute other useful data which can not be obtained with HBN alone. as revealing signs of portal hypertension, and hepatobiliary or peritoneal pathology which can coexist with HC. Due to this reasons, in the study of HC, we preferred as the first method of diagnosis, L, instead of HBN. When through this endoscopy we obtain the typical aspect, we omit adding HBN, which we only practised in doubtful cases of not very nodular livers (glabra cirrhosis) or when a probable post-hepatis, Wilson disease or hemochromatosis is being investigated. In the present conditions, we believe that the new methods of diagnosis &quot;of non invasive images&quot; can not substitute L or HBN in precising the diagnosis of HC.
3706007##1986-1-1##Wilson's disease in two siblings--one with fatal outcome.##The clinical and biochemical findings in two siblings with Wilson's disease are described. One of them, an 11-year-old girl, developed acute liver failure terminating in death within a few weeks. Prior to her terminal illness she had been in good health without symptoms suggestive of Wilson's disease. Copper contents of urine, liver, kidney and brain were 20-100 times above the upper normal limits. The liver showed extensive micronodular cirrhosis with nonbile pigment deposits. Her 15-year-old brother had abnormal liver function tests with urinary copper excretion 20 times above the upper normal limit. Treatment with penicillamine was started. Following a short period of deterioration his condition has steadily improved.
3727931##1986-1-1##Glial fibrillary acidic protein and S-100 protein in human hepatic encephalopathy: immunocytochemical demonstration of dissociation of two glia-associated proteins.##Immunocytochemical staining patterns for glial fibrillary acidic protein (GFAP) and S-100 protein (S100P) were compared in cerebral cortex, basal ganglia and white matter of eight cases with hepatic encephalopathy (HE), including four cases of Wilson's disease and four of liver cirrhosis, and of eight age-matched controls, using the peroxidase-antiperoxidase method on adjacent paraffin sections. The majority of Alzheimer type II glia (Alzg II) showed prominent immunoreactivity for S100P but not for GFAP, resembling normal astrocytes of protoplasmic type; Alzg II might be interpreted as being peculiar types of reactive astrocytes retaining characteristics of protoplasmic astrocytes. A small number of Alzg II cells showed slight perinuclear immunoreactivity for GFAP; some lacked both markers. This suggests a spectrum of metabolic changes in these two proteins in Alzg II. GFAP-positive Alzg II cells were restricted to basal ganglia and white matter adjacent to grey matter, indicating that expression of GFAP in Alzg II might be modulated by local factors. Alzheimer type I cells and Opalski cells in Wilson's disease were immunoreactive for both proteins, confirming their astroglial origin and different character from that of Alzg II. In morphometric comparison, the proportion of GFAP-positive glial cells decreased in the cortex (P less than 0.001) but not significantly in the white matter (0.05 less than P less than 0.1), confirming earlier data that the prominent reduction of GFAP in HE brains is restricted to the grey matter.(ABSTRACT TRUNCATED AT 250 WORDS)
3776618##1986-1-1##The treatment of Wilson's disease in paediatrics: oral zinc therapy versus penicillamine.##
3776570##1986-1-1##Wilson's disease and liver failure in childhood.##
3535379##1986-1-1##Synergistic neurotoxicity of carbon tetrachloride/carbon disulfide (80/20 fumigants) and other pesticides in grain storage workers.##Neurophysiologic, neurobehavioral, and neuropsychologic profiles in 17 grain storage workers, 1 grain inspector, and 4 malting laboratory workers are described. The effects of CS2 toxicity as seen in viscose rayon workers as well as in experimental animals is remarkably similar to the clinical profile of our grain storage workers. CS2 use explains the dysfunction of peripheral axons, auditory nerve, the optic nerve, and the extrapyramidal system, as well as altered behavior and cognition changes. The signs and symptoms in these workers seem to be dose-related and we note that workers separated out from the areas where fumigation took place reported improvement not seen by fellow workers who continued the fumigant treatment routine. Likewise, malting laboratory workers exposed only to the grain dust from 3 to 7 years showed only minimal symptoms. Though a number of mechanism have been suggested for the alteration of neuropsychological function, the chelating ability of DDC derived from CS2 and its ability to markedly increase copper and zinc within the central nervous system suggests a mechanism of toxicity analogous to copper intoxication as in Wilson's Disease and may explain the production of extrapyramidal symptoms in these patients. Chelation of copper might prove therapeutic in CS2 poisoning. It is obvious that both basic and clinical research will be necessary to sort out the questions raised. We applaud the EPA's decision to ban the use of 80/20 fumigants and also methyl bromide, and trust that similar toxic substances be carefully studied before their selection for replacing these previous toxic agents. We further decry the technique of re-introducing grain dust into the food chain rather than destroying it, since the dust contains very high residues of fumigant material. We speculate on the possible role of CS2 and other pesticides in the food chain and the incidence of Parkinsonian symptoms in these patients and the general public.
3538948##1986-1-1##[D-penicillamine and collagen].##D-penicillamin is widely used for the treatment of various diseases, such as cystinuria. Wilson's disease or rheumatoid arthritis. It is an osteolathyrogenic agent. This effect may explain some side-effects such as fetal dysplasias, wound healing defects, skin lesions, obliterative bronchiolitis, auto-immune abnormalities. Conversely the collagen effects of D-Penicillamin explain its use in various fibrosis states such as progressive systemic sclerosis, liver or lung fibrosis.
3706665##1986-1-1##Increased cadmium resistance of skin fibroblasts from Menkes disease patients.##Cultured skin fibroblasts from patients with Menkes disease and Wilson disease were analyzed as to their sensitivities to copper and cadmium by means of a colony-forming ability and cell growth study. All the Menkes strains exhibited about 3-fold higher levels of resistance to cadmium, whereas the cytotoxicity of copper did not differ among the Menkes, Wilson and normal fibroblast strains. The resistance to cadmium of Menkes skin fibroblasts may provide a diagnostic marker of Menkes disease and useful or valuable model for the understanding of detoxification system against heavy metals.
3082542##1986-1-1##Chronic active hepatitis and related disorders.##Chronic hepatitis in children should be suspected if clinical features and abnormal liver function tests persist for over one month following an episode of acute hepatitis, in children who present with relapsing hepatitis, or those presenting coincidentally with features of chronic liver disease. Specific investigation must be undertaken to define aetiology. For example, hepatitis B, Wilson's disease and alpha 1-antitrypsin deficiency must be excluded. Early histological diagnosis by an experienced histopathologist is mandatory. Chronic persistent hepatitis requires no therapy, but careful follow-up is desirable, especially for hepatitis B-positive cases. If the histological appearances are those of chronic active hepatitis, distinction between HBV-associated and autoimmune varieties is necessary. Autoimmune CAH in children differs from that in adults in that the onset is often acute, response to immunosuppressants usually favourable, and withdrawal of therapy may be successful, especially if diagnosis is established early before serious liver damage occurs. Evidence is presented to suggest that autoimmune CAH is associated with a genetic predisposition to autoimmune disease, characterized by both antigen-specific and antigen-independent T suppressor cell defects. An antibody-dependent non-T cell cytotoxicity operates against liver cell surface antigens. HBV CAH, on the other hand, may respond poorly to immunosuppressants and appropriate therapeutic regimens are not defined. There is some evidence to suggest that early diagnosis and institution of therapy in autoimmune CAH may lessen the incidence of cirrhosis on follow-up. Further studies to understand the interaction between hepatocytes, inflammatory cells and non-parenchymal cells in the process of hepatic fibrosis may provide the means of active intervention in this area in the future.
3780108##1986-1-1##Plasma and erythrocyte copper, zinc, manganese and magnesium concentrations in Wilson's disease.##Plasma copper was significantly reduced in Wilson's disease with decreased ceruloplasmin levels, while there was no significant difference in erythrocyte copper levels between Wilson's disease and controls. Mean zinc and manganese levels in plasma were increased in Wilson's disease, but these differences were not significant. Mean magnesium level in plasma was normal. The levels of these metals in erythrocytes showed no difference between Wilson's disease and controls. Our results suggest that the abnormal copper level in plasma is not due to the primary metabolic defects, but is probanly due to the level of the binding proteins in plasma to this metal, ceruloplasmin, in Wilson's disease.
3514056##1986-1-1##Genetic diseases of copper metabolism.##There are several known examples of mutations which influence copper homeostasis in humans and animals. Pleiotropic effects are observed when the mutant gene disturbs copper flux. In some cases, the mutation alters the level of a specific copper ligand (enzyme) and the clinical consequences are unique. The two most widely studied genetic maladies in humans are Menkes' and Wilson's diseases. Menkes' disease is an X-linked fatal disorder in which copper accumulates in some organs (intestine and kidney) and is low in others (liver and brain). Wilson's disease is an autosomal recessive disorder in which copper accumulates, if untreated, in liver and subsequently in brain and kidney. Pathophysiological consequences of copper deficiency and toxicity characterize these two disorders. Specific mutations of human cuproenzymes include overproduction of copper-zinc superoxide dismutase in Down's syndrome, absence of tyrosinase in albinism, hereditary mitochondrial myopathy due to reduction in cytochrome c oxidase, and altered lysyl oxidase in X-linked forms of cutis laxa and Ehlers-Danlos syndrome. Mutations altering copper metabolism are also known in animals. Several murine mutants have been studied. The most extensively investigated mutants are the mottled mice, in particular brindled mice, which have a mutation analogous to that of Menkes' disease. Another recently described murine mutation is toxic milk (tx) an autosomal recessive disorder that is characterized by copper accumulation in liver. Two other mutants, crinkled and quaking, were once thought to exhibit abnormal copper metabolism. Recent data has not confirmed this. A mutation in Bedlington terriers has been described which is very similar to Wilson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
3459695##1986-1-1##Evidence for linkage between Wilson disease and esterase D in three kindreds: detection of linkage for an autosomal recessive disorder by the family study method.##Wilson disease (WD) is an inherited disorder of copper metabolism that affects the brain, liver, and other organs. Our group recently reported close linkage between the locus for WD and a polymorphic red cell enzyme, esterase D (EsD), in a large inbred Israeli-Arab lineage. We have subsequently studied two unrelated Druze kindreds in order to confirm this linkage and more precisely define the distance between the two loci. The maximum likelihood estimate of recombination was determined to be zero with lod scores of 1.48 and 1.06 in each Druze family, respectively. The combined maximum lod score based on pooled results from the Israeli-Arab and Druze kindreds is 5.49 at theta = 0.03. WD is one of a few autosomal recessive disorders that has been mapped by classical family study methods. In this paper, the merits for using large, inbred families in linkage studies of rare recessive disorders are discussed. Major considerations for pedigree selection are size and number of constituent nuclear families, number and distribution of affected individuals, and pedigree structure that may provide information for determination of phase between the disease and marker loci.
3949188##1986-1-1##The Kayser-Fleischer ring during long-term treatment in Wilson's disease (hepatolenticular degeneration). A follow-up study.##The role of Kayser-Fleischer rings is described in 67 patients with Wilson's disease, both in the asymptomatic and symptomatic stage of the disease during life-long therapy, which lasted up to 22 years. The rings were missing in 60% of patients in the presymptomatic stage and in 2% of those in the symptomatic stage at the time of diagnosis. The Kayser-Fleischer rings disappeared in 81% of the patients (completely in 41% and incompletely in 59%). In 2 of the 6 asymptomatic patients the rings did not reabsorb even after therapy of more than 10 years. The fading of Kayser-Fleischer rings seems to be independent not only of the stage of the disease but also of the effectiveness of the decopperizing treatment.
3759507##1986-1-1##A highly sensitive method for the histochemical demonstration of copper in normal rat tissues.##Earlier, widely used histochemical methods for the demonstration of copper are capable of detecting only extremely high tissue levels of this metal (generally only in pathological states, e.g. Wilson's disease, or in cases of copper intoxication), because of their low sensitivity. The specificity of these methods has also proved to be unsatisfactory. We present a new method based on the release of bound (unreactive) copper by trichloroacetic acid, its primary precipitation using magnesium dithizonate, and intensification of the staining (secondary precipitation) using silver nitrate. Using this method, copper is demonstrable in various tissues of normal rats (brain, stomach, liver, small intestine, spleen, pancreas, kidneys) in the form of reddish to pink staining. This method can also be applied to locate pathologically high levels of copper.
3958727##1986-1-1##Generalized dystonia, whispering dysphonia and Wilson's disease in members of the same family.##
3504238##1986-1-1##Long-term followup computed tomography and magnetic resonance imaging findings in hepatolenticular degeneration: case report and summary of the literature.##Pretreatment and long-term followup computed tomography (CT) findings were reported in a patient with successfully treated Wilson's disease. Results of magnetic resonance imaging (MRI) are correlated with followup CT findings, with MRI being more specifically sensitive than CT. The literature of CT and MRI findings in Wilson's disease is reviewed and summarized.
3561797##1986-1-1##Glial fibrillary acidic protein and S100 protein in abnormal astrocytes in Wilson's disease.##
3952248##1986-1-1##Psychosis in Wilson's disease.##
3704107##1986-1-1##The management of pregnancy in Wilson's disease treated with trientine.##Seven patients with Wilson's disease, treated with trientine, have been followed during 11 pregnancies. Eight of these resulted in the delivery of normal infants, whilst one was very premature (31 weeks) and was later shown to have a chromosomal defect, isochromosome X. There was one therapeutic termination and one miscarriage associated with a contraceptive coil. The eight children are progressing satisfactorily and have been studied for periods varying from three months to nine years; all mothers are also doing well. The child with the isochromosome X is developing slowly; she shows no morphological abnormalities at this stage. The normal-for-age caeruloplasmin values found in the cord blood indicates that there was no significant copper depletion in the foetuses, as a result of treatment.
3538594##1986-1-1##Renal parenchymal disease: histopathologic-sonographic correlation.##Retrospective study of 60 patients with histologically confirmed renal parenchymal disease and ultrasound examination of kidneys was conducted at King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. The various renal parenchymal abnormalities were: proliferative glomerulonephritis (26 cases), glomerulosclerosis and focal segmental glomerulonephritis (5 cases), membranous glomerulonephritis (7 cases), minimal changes (12 cases), sclerosing glomerulonephritis (3 cases), chronic interstitial nephritis (2 cases), mesangiocapillary glomerulonephritis (2 cases), amyloidosis (1 case), Wilson's disease (1 case), and medullary cystic disease (1 case). Ultrasound examination was normal in 31 cases (51% of 60 cases) and abnormal in the rest of the cases. Thus, there was no correlation among the specific type of renal disease, cortical echogenicity and corticomedullary definition.
3830328##1985-12-1##Psychiatric aspects of Wilson's disease.##A variety of psychiatric symptoms have been described in relation to Wilson's disease, an inherited disorder of copper metabolism. At least four symptom clusters can be identified: affective, behavioural/personality, schizophrenia-like, and cognitive; the first two groups appear to be the commonest. Four cases (three newly reported) are described, and current approaches to the psychiatric management of Wilson's disease discussed.
3910522##1985-12-1##Clinical course of cirrhosis in young adults and therapeutic potential of liver transplantation.##The lack of information on survival in young adults with cirrhosis and the increasing use of liver transplantation in this age group have led us to carry out a retrospective analysis of the clinical course and survival in 83 young adults aged between 15 and 30 years presenting to the Liver Unit between 1970 and 1983. Fifty four (65%) patients had cirrhosis at initial presentation and in the remaining 29 (35%) this developed within the study period. The overall five year survival of the group, excluding 14 cases treated by transplantation, was 70%. When considered according to aetiological groups this was 83% in those with chronic active hepatitis, 60% in those with cryptogenic cirrhosis and 37% in Wilson's disease. When considered in relation to Child's grading, only three deaths occurred in the 45 patients with well-compensated liver disease (Child's grade A and B). Of the 38 patients with Child's grade C, 20 (83%) of the 24 patients not undergoing transplantation have died, whereas eight (57%) of the 14 receiving liver grafts are alive and well.
3870513##1985-12-1##[Neurologic manifestations in Wilson's disease. Clinical, biological, x-ray computed tomographic and developmental study of 11 cases].##
4056786##1985-11-1##Penicillamine therapy for schizophreniform psychosis in Wilson's disease.##A hospitalized 22-year-old woman had suffered from Wilson's disease for the past 11 years. The diagnosis was confirmed by hepatic nonspecific changes, high copper urine excretion, and low to zero serum ceruloplasmin, but psychiatric symptomatology was the main manifestation of the disease. The history of treatment modalities and a controlled trial with penicillamine revealed a clear priority of this drug over phenothiazines in abolishing the psychotic features of the disease. The effective dose in this case was found to be over 1650 mg/day. The mental state, as measured by the Brief Psychiatric Rating Scale, was clearly correlated to the dose of penicillamine. In addition, there was a tendency to increased copper excretion with penicillamine treatment. This case suggests a connection between copper brain poisoning and the related acute psychotic features, which responded well to penicillamine treatment.
4084421##1985-11-1##[Effects of high-dosage trihexyphenidyl on symptomatic dystonia in a case of Wilson disease].##
3835045##1985-11-1##[Long-term follow-up study of seventeen cases with Wilson's disease].##
3939211##1985-11-1##[Ophthalmologic findings in Wilson's disease--analysis of 18 cases].##
3907891##1985-10-1##Somatosensory evoked potentials: monitoring cerebral functions following liver transplantation.##Serial somatosensory evoked potentials (SEPs) were obtained from a patient with Wilson's disease who had had liver transplantation. Correlating with recovery of hepatic encephalopathy and liver functions following the surgery, SEPs showed progressive normalization of peak latencies and waveforms. The data indicate that SEP may be a useful objective method in assessing recovery of cerebral functions following liver transplantation.
4045603##1985-10-1##Peritoneal dialysis with D-penicillamine in Wilson disease.##
3900322##1985-10-1##Orthotopic liver transplantation for acute fulminant Wilson disease.##
4034959##1985-10-1##Wilson disease of the brain: MR imaging.##Twenty-three patients with biochemically proved Wilson disease underwent magnetic resonance (MR) imaging of the brain. Positive findings, believed secondary to this condition, were found in 15 subjects. Findings varied among patients, but there were striking similarities between certain groups of patients. Areas of abnormal signal were seen in the lenticular, thalamic, caudate, and dentate nuclei, as well as in the brain stem; in these areas, the abnormalities were bilaterally symmetric. A smaller number of patients had asymmetric focal white-matter lesions. Correlation of the MR findings with clinical symptoms was generally good. Repeat imaging was performed on five patients at intervals ranging from 4 to 8 months; none showed significant interval change.
4091735##1985-9-1##[Hepatolenticular degeneration: critical evaluation of the diagnostic criteria in 95 cases].##Ninety-five cases of hepatolenticular degeneration have been studied, focusing particularly the clinical and laboratory characterization of the disease. On the clinical viewpoint the variability of the starting symptoms and the frequency of the Kayser-Fleischer rings were analyzed. As regards the laboratory findings the ceruloplasmin, blood and urinary copper, and aminoaciduria levels have been evaluated, as well as the radiological and scintillographic study of joints and bones, cranial computerized tomography and liver biopsy. In 54.4% of the cases the opening clinical picture was neurological, in 31.1% hepatic, in 14.4% psychiatric, in 7.8% osteoarticular, in 2.2% ophtalmologic (Kayser-Fleischer rings), in 1.1% hematologic (hemolytic anemia), and in 1.1% cardiac. Kayser-Fleischer rings were present in 84 of the 92 cases in which they have been searched for (91.3%). Concerning the laboratory findings, hypoceruloplasminemia was found in 98.8% of the cases in which it was investigated, hyperaminoaciduria in 94.7%, hypocupremia in 87.0%, increased cupruresis in 78.2%, osteoporosis in 79.4%, scintillographic changes of the joints in 67.6%; the CT-scan, performed in 11 cases, showed low attenuation areas in the basal ganglia of 2 patients. The significance of the mentioned laboratory findings and the presence of the Kayser-Fleischer rings for the diagnosis of Wilson's disease is discussed.
4041939##1985-9-1##[A syndrome similar to systemic lupus erythematosus caused by penicillamine in patients with Wilson's disease].##
4053496##1985-9-1##[Nuclear magnetic resonance tomography and computed tomography of the brain for detection of Wilson's disease].##The authors report on two woman patients with confirmed Wilson's disease (hepatolenticular degeneration) who had neurological deficits and showed typical changes evident from laboratory data. Both computed tomography and magnetic resonance tomography revealed degenerative changes in the basal ganglia, especially of the lenticular nucleus, MR showing these defects more clearly than CT. There was a noticeable symmetrical enhancement of signals in the lenticular nucleus which was particularly evident on the image basing on the T2 (spin-spin relaxation time constant) values. MR could be superior to CT with regard to showing up pathological changes in the basal ganglia. The future indication of MR could be the establishment of an exact correlation between clinical signs and symptoms on the one hand, and morphological findings on the other. Over and above this, it should be explored to what extent MR can already detect degenerative changes in the brain in primarily hepatic types of the disease even without prior neurological examination.
4056754##1985-9-1##[Teratogenic risk during treatment of Wilson disease].##Untreated Wilson's disease usually causes infertility or abortion, as a result of increased intrauterine copper level. Therefore, a chelation treatment is necessary during the whole pregnancy. The most used is D-Penicillamine whose teratogenic risks such as cutis laxa, dermatopathy or complex mesenchyme abnormalities are paradoxically rare in the new borns of treated Wilson's disease mothers, perhaps owing to hypercupremia that protects the foetus from excessive copper deficiency. Yet, it's wise to reduce chelation treatment about a quarter fold and to add 50 mg vitamin B6 weekly as we did in our case whose child was born normal.
3834206##1985-9-1##An expected decrease in incidence of Wilson's disease due to decrease in consanguinity.##
4052057##1985-8-1##Low content of hepatic reduced glutathione in patients with Wilson's disease.##In five of six patients with symptomatic Wilson's disease (WD) with increased hepatic copper content, increased renal copper excretion, and decreased serum concentrations of ceruloplasmin, significantly low levels of hepatic reduced glutathione (GSH) were found. Three of these patients showed increased levels of oxidized glutathione which in part could account for the missing GSH. These changes may result from increased lipid peroxidation due to the rise of intracellular copper concentration. Furthermore, WD patients showed a 50% decrease in the activity of hepatic GSH S-transferases. From these results we conclude that the disturbance in the hepatic glutathione system of patients with symptomatic WD may contribute to the perpetuation of liver damage. These patients, additionally, may be predisposed to an increased sensitivity to drugs interacting with glutathione.
3905081##1985-8-1##Inborn errors of trace element metabolism.##Genetic disorders of trace element transport are now known in humans, mice, dogs and cattle. Those involving copper have been known longest and are best known clinically. Effects due to copper deficiency are seen in Menkes' disease, in X-linked cutis laxa and in the X-linked series of mottled mutants in the mouse. Copper accumulation is also harmful, causing damage initially to the liver and later to the kidneys and brain in Wilson's disease, in some Bedlington terriers and in toxic milk mice. Zinc deficiency is seen in acrodermatitis enteropathica and in premature babies born to women who seem to secrete milk that is zinc-deficient, as is seen in lethal milk mice. Study of animal mutants, especially mutant mice, is helpful in understanding the human diseases and identification of the basic defects in trace element transport in these diseases is improving knowledge relevant to trace element nutrition.
3905080##1985-8-1##Clinical, endocrinological and biochemical effects of zinc deficiency.##The essentiality of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, chronic renal disease, certain diuretics, the use of chelating agents such as penicillamine for Wilson's disease, and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. The requirement of zinc is increased in pregnancy and during the growing age period. The clinical manifestations in severe cases of zinc deficiency included bullous-pustular dermatitis, alopecia, diarrhoea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males and it is fatal if untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss and hyperammonaemia. Zinc is a growth factor. As a result of its deficiency, growth is affected adversely in many animal species and in man. Inasmuch as zinc is needed for protein and DNA synthesis and cell division, it is believed that the growth effect of zinc is related to its effect on protein synthesis. Testicular functions are affected adversely as a result of zinc deficiency in both humans and experimental animals. This effect of zinc is at the end organ level and the hypothalamic--pituitary axis is intact in zinc-deficient subjects. Inasmuch as zinc is intimately involved in a cell division, its deficiency may adversely affect testicular size and thus its function. In mice, the incidence of degenerate oocytes, and hypohaploidy and hyperhaploidy in metaphase II oocytes were increased due to zinc deficiency. Zinc at physiological concentrations reduced prolactin secretion from the pituitary in vitro and it has been suggested that this trace element may have a role in the in vivo regulation of prolactin release. Thymopoietin, a hormone needed for T-cell maturation, has also been shown to be zinc dependent. It is clear that zinc may have several roles in biochemical and hormonal functions of various endocrine organs. Future research in this area is very much needed.
4007418##1985-8-1##Abnormalities in tests of copper metabolism in primary sclerosing cholangitis.##Primary sclerosing cholangitis is a chronic, cholestatic syndrome characterized by fibrosing inflammation of the bile ducts that may lead to cirrhosis and death from liver failure. Previous reports have suggested abnormal hepatic copper metabolism in this disease. Therefore, in 70 patients, we prospectively determined the levels of hepatic copper, serum copper, and serum ceruloplasmin, and the rate of urinary copper excretion to assess the diagnostic and prognostic usefulness of these tests. Virtually all patients had at least one abnormal copper test. Hepatic copper levels were elevated in 87% of patients [292 +/- 38 micrograms/g dry wt (mean +/- SE)] and 24-h urinary copper levels in 64% of patients [135 +/- 15 micrograms/24 h (mean +/- SE)] to values comparable to those seen in Wilson's disease or primary biliary cirrhosis. In advanced histologic stages of primary sclerosing cholangitis, progressively higher mean levels of hepatic and urinary copper were found. In the liver, mean copper content (in micrograms per gram dry weight) in disease stages I and II was 147 +/- 36 (mean +/- SE); in stage III (fibrosis), 302 +/- 68; and in stage IV (cirrhosis), 379 +/- 69. In the urine, mean copper excretion (in micrograms per 24 h) in stages I and II was 72 +/- 14 (mean +/- SE); in stage III, 100 +/- 14; and in stage IV, 207 +/- 30. Higher hepatic and urinary copper levels at initial evaluation were associated with decreased survival during a median follow-up period of 2.6 yr: patients with hepatic copper greater than 250 micrograms/g dry wt and urinary copper excretion greater than 200 micrograms/24 h at initial evaluation had an 18-mo survival of less than 60%. We conclude that abnormal copper metabolism is a universal feature of primary sclerosing cholangitis, that hepatic copper accumulates and urinary copper excretion increases as the disease progresses, and that the hepatic copper concentration and the 24-h urinary copper determination are useful prognostic indicators in this disease.
3011292##1985-8-1##[Studies on the content of trace elements in the hair of patients with Wilson's disease and healthy individuals].##
4000228##1985-7-4##Unusual digestive lesions in a patient with Wilson's disease treated with long-term penicillamine.##
3876678##1985-7-1##Epidemiologic study of hepatolenticular degeneration (Wilson's disease) in Sardinia (1902-1983).##From 1902 to 1983, 68 cases of hepatolenticular degeneration (HLD) were discovered in Sardinia, with a mean frequency, in reference to number of live births, of 27.7 and a sex ratio of 1.83. The prevalence of the disease was seen to be higher over the last few decades. With regard to the geographic distribution of the disease, 3 high-frequency areas were evident, in Barbagia, in Campidano, and in the area surrounding the city of Sassari. In 38.23% of cases, the clinical picture was of hepatoneurologic type; hepatic forms have become more frequent over the last decades. The first symptoms were observed at mean age of 15 years 8 months. The number of asymptomatic cases was fairly consistent (22.05%). The median survival rate in subjects who received inadequate therapy was 6 years 4 months. Only 3 patients of the 45 treated with adequate therapy died. The gene frequency, calculated by the application of Dahlberg's formula, was extremely high.
4026362##1985-7-1##Oral zinc sulphate for Wilson's disease.##After initial promotion of copper excretion with D-penicillamine, the effect of oral zinc sulphate (3 X 150 mg/day, loading dose; 3 X 100 mg/day, maintenance dose) in two children with clinically stable Wilson's disease was evaluated after completion of three years' treatment. The course, judged by clinical, biochemical, and histological parameters was satisfactory in both. The urinary copper concentration reverted to less than 1.26 mumol/24 hours; and the serum copper concentration decreased further during zinc sulphate treatment. In one child the rise in 24 hour urinary copper excretion observed after a challenge dose of D-penicillamine (+/- 20 mg/kg) remained constant throughout the period of observation while the liver copper content fell from 1460 micrograms/g dry weight to 890 micrograms/g dry weight. In the other patient, however, the liver copper content as well as the 24 hour urinary copper excretion increased after D-penicillamine challenge during the third year of treatment. We conclude that zinc sulphate is a low toxic and well tolerated alternative for D-penicillamine. The dosage depends, however, on individual factors not yet well understood, and we recommend restriction of its use to patients who do not tolerate D-penicillamine well. We suggest monitoring of treatment with yearly D-penicillamine challenge and a liver biopsy if liver function deteriorates.
4026361##1985-7-1##Wilson's disease: assessment of D-penicillamine treatment.##Serum copper and zinc concentrations and 24 hour urinary copper and zinc excretion were determined serially from the beginning of treatment with D-penicillamine in four children with Wilson's disease. The data show a progressive decrease in both serum copper and zinc concentrations in all. Urinary copper excretion gradually levelled off to approximately 50% of initial values, but zinc excretion increased. Urinary zinc:copper ratios therefore increased with the duration of treatment. Copper elimination was considered adequate as soon as challenge with a test dose of D-penicillamine did not result in an increase in copper excretion. Urinary zinc excretion was increased further by the test dose. Zinc depletion was suspected clinically in one patient on D-penicillamine maintenance treatment. Lowering the dose alleviated the symptoms, urinary zinc loss decreased from 64 to 34 mumol/24 hours, and copper excretion remained largely unchanged. Data obtained indicate that D-penicillamine alters the metabolism of both copper and zinc. The extent of this is not only dose dependent but is also related to the efficacy of copper elimination. Both copper and zinc concentrations must by monitored to assess the benefits of treatment and the risks of inducing manifest or subclinical zinc deficiency.
4007843##1985-7-1##Copper-binding protein in liver cells.##The patterns and incidences of orcein-positive granules of copper-binding protein (CBP) in 2,531 liver biopsy specimens from children and adults with a large variety of liver diseases are reported. Fetal and neonatal livers have high physiologic levels of copper and CBP, which fall to within the adult range by the third to the sixth month of life. Therefore, in liver specimens from children less than 6 months of age, it was not possible to determine whether the orcein-positive granules present represented physiologic or pathologic deposits of CBP. In adults and in children older than 6 months of age, CBP granules were found almost exclusively in association with four main groups of liver diseases: Wilson's disease, chronic biliary disorders, cirrhosis/extensive fibrosis, and primary liver tumors. Orcein-positive granules were never found in patients with acute liver disease. The granules were extremely helpful in distinguishing chronic biliary diseases from acute cholestatic and hepatic disorders, primary biliary cirrhosis from chronic active hepatitis, and primary liver tumors from metastatic tumor deposits.
4033073##1985-7-1##Determination of triethylenetetramine dihydrochloride in aqueous solution by reversed-phase ion-pairing high performance liquid chromatography and conductivity detection.##Triethylenetetramine dihydrochloride (TETA) has been used for the treatment of Wilson's disease which is a metabolic disorder that prevents its victims from eliminating excess copper. TETA was scheduled for toxicological evaluation because of a deficiency of such information. Analytical chemical procedures to determine the purity of the drug as well as the proper concentration and stability of the drug in dosed water were prerequisites for the toxicological tests. A high performance liquid chromatography (HPLC) procedure employing ion-pairing and conductivity detection has been developed for the analysis of TETA in dosed water at levels as low as 10 micrograms/mL and for the determination of drug purity. The conductivity detector response was linear over the concentration range of 10 to 100 micrograms/mL. Data are presented concerning the stability of the drug in water during ambient storage and after autoclaving. An ancillary colorimetric procedure for the analysis of aqueous TETA solutions is also presented which is based on measuring the absorbance of the colored TETA copper chelate at 599 nm. The HPLC procedure is applicable to the analysis of TETA and the chemically similar polyamines spermidine and spermine in admixture.
4051676##1985-6-1##[Maintenance treatment of Wilson's disease with oral zinc. Apropos of a child treated for 4 years].##A 13 year-old boy with Wilson's disease was treated with zinc sulphate per os for 4 years. This treatment, which was effective and non toxic, could substitute for penicillamine as long term treatment of Wilson's disease.
4095001##1985-6-1##Wilson's disease in a patient presenting with skeletal abnormalities.##We present a case with extensive bone and joint involvement in the form of bone fragmentation and osteochondritis dessecans. The case was subsequently documented to be that of Wilson's disease. Biochemical screening was also carried out on the family members and the results of the findings are presented.
4035036##1985-6-1##[Acute liver failure and Wilson's disease].##
4019049##1985-5-1##Neuropsychological and electrophysiological examination of a patient with Wilson's disease.##A patient with Wilson's disease underwent neuropsychological and electrophysiological examination 4 months following symptom onset. Although motor deficits were more severe, there was considerable impairment of cognitive and intellectual function. Auditory evoked responses were also abnormal in this patient. This case is unusual because of the early severe cognitive deficits.
3921780##1985-5-1##Fulminant hepatitis: Mayo Clinic experience with 34 cases.##From 1974 through 1982, fulminant hepatitis was diagnosed in 34 patients at our institution. Of these patients, only two survived (survival rate, 6%). This syndrome was caused by viruses (B and non-B hepatitis and herpes simplex) in 23 patients, hepatotoxic drug in 6, Wilson's disease (hepatolenticular degeneration) in 3, and industrial poisons in 2. Most of the patients died within 10 days after the onset of encephalopathy. The poor prognosis in our group of patients was probably related to the preponderance of older patients and cases caused by non-B hepatitis virus. In our patients, the clinical course was complicated by renal failure, ascites, bleeding, sepsis, pancreatitis, and seizures. The major cause of death was hepatic failure.
3921157##1985-4-20##Unithiol in Wilson's disease.##
4004163##1985-4-1##Late-onset Wilson's disease with neurological involvement in the absence of Kayser-Fleischer rings.##We report a patient with Wilson's disease whose case is unusual in two respects. First, the patient was 58 years of age when the diagnosis was made based on urinary, serum, and hepatic copper studies, as well as liver histological investigation. Second, despite the patient's neurological impairment, Kayser-Fleischer rings had not developed. We conclude that in patients with chronic, degenerative neurological disease, particularly when associated with hepatic dysfunction, the diagnosis of Wilson's disease should be considered regardless of age at onset or the absence of Kayser-Fleischer rings on slit lamp examination.
3886537##1985-4-1##Wilson's disease and copper metabolism--a review.##
3981256##1985-4-1##Disparate hepatic imaging with technetium-99m sulfur colloid and disofenin in Wilson's disease.##A 10-yr-old boy presented with fulminant hepatic failure. Technetium-99m sulfur colloid images showed absent reticuloendothelial function in the liver. A [99mTc]-disofenin hepatobiliary scan visualized liver parenchyma and biliary excretion. Disparate appearance of the liver may be seen in other hepatic diseases, but should be remembered as a possible pattern in Wilson's disease.
2582331##1985-4-1##Diabetic choroidopathy. Light and electron microscopic observations of seven cases.##The choroid of seven young patients (ages 20-29 years), who had had diabetes mellitus for many years (14-23 years) was studied by light and electron microscopy. The eight enucleated eyes were blind and painful as a complication of diabetes mellitus. Histopathologically, the choriocapillaris and other small choroidal blood vessels disclosed marked basement membrane thickening of their walls. Periodic acid-Schiff-positive homogeneous acellular nodules were present and resembled those of diabetic glomerulosclerosis (Kimmelsteil-Wilson disease). Some choroidal arteries were arteriosclerotic. Choroidal compromise was suggested by luminal narrowing of the capillaries, capillary dropout, and focal scarring. Choroidal neovascularization with subretinal fibrovascular membranes occurred in two patients at the midperiphery and periphery, and resembled those of retinitis proliferans. Leakage of proteinaceous fluid into the choroidal stroma and beneath the focally detached pigment epithelium was suggested by the electron microscopic observations. Choroidal vasculopathy in diabetes mellitus is similar to much of what has been described in other tissues of the eye and body, and suggests an important role in the pathogenesis of diabetic retinopathy since the outer retinal layers are largely dependent on the choroid for their nutrition and oxygenation.
2991870##1985-4-1##Primary hepatocellular carcinoma associated with Wilson's disease in a young woman.##A 27 year old woman with hepato-lenticular degeneration (Wilson's disease) was found to have primary hepatocellular carcinoma (PHC) three and a half years after she was started on treatment with D-penicillamine. The tumour was resected since when she has remained well. Her liver function tests were normal throughout the course of her disease. The available literature is reviewed and possible mechanisms for this association proposed.
2989971##1985-4-1##An unusual case of Wilson's disease.##A man of 61 with a 26-year history of progressive cerebellar ataxia was admitted to hospital. He was found to have chronic liver disease and died 22 days after admission. A diagnosis of hepatolenticular degeneration (Wilson's disease) was supported by clinical investigations and confirmed at autopsy, when tissue copper studies were performed. Several unusual features were present, including a unilateral Kayser-Fleischer ring, a hepatocellular carcinoma, peripheral neuropathy, pontine demyelination and calcification of neurones in the medulla. The significance of these findings is discussed with a review of the relevant literature.
3160555##1985-4-1##[CT in the evaluation of Wilson's disease].##
3974639##1985-3-7##Case 44-1984: Wilson's disease.##
3918711##1985-3-2##Unithiol in Wilson's disease.##
3156966##1985-3-1##Hereditary whispering dysphonia.##An Australian family group is described where at least twenty members have inherited torsion dystonia and two siblings with an affected mother have similar clinical manifestations, but have also the biochemical and pathological changes found in Wilson's disease. Whispering dysphonia was the commonest presenting symptom, and a diagnosis of hysteria was invariably made if the family history was not known. This group emphasises the enormously varied ways in which torsion dystonia may be manifested in one family, and raises the possibility of a disturbance in copper transport in diseases of the basal ganglia other than Wilson's disease.
3856863##1985-3-1##Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus.##Wilson disease (WD) is an autosomal recessively inherited disorder of copper metabolism for which the basic defect is still unknown. Twenty-seven autosomal markers were investigated for linkage in a large inbred kindred with affected individuals in two generations. Also, serum copper and ceruloplasmin were measured on all available members. Close linkage (theta = 0.06) with a logarithm of odds (lod) score of 3.21 was found between the gene for WD and the esterase D locus. Efficient detection of linkage was made possible by the use of a multisibship inbred pedigree. The discovery of a polymorphic marker genetically linked to the WD locus has profound implications both for investigation of the primary gene defect and for clinical services.
3980656##1985-1-11##Analysis of D-penicillamine by gas chromatography utilizing nitrogen--phosphorus detection.##A method is presented for the analysis of the &quot;orphan&quot; drug D-penicillamine (D-Pa), which is used for the treatment of the inherited rare copper metabolism dysfunction known as Wilson's disease, by assaying a derivative of the compound by gas chromatography employing a rubidium sensitized nitrogen--phosphorus detector. Analytical procedures are described for the analyses of residues of D-Pa X HCl salt in animal feed and for the analyses of the salt or free base from aqueous solutions by utilizing a single-step double derivatization with diazomethane--acetone. Stability data for D-Pa X HCl in animal feed and for the free base in water are presented. An ancillary fluorescence derivatization procedure for the analysis of D-Pa in water is also reported.
3843748##1985-1-1##Low molecular weight copper binding proteins in Wilson disease.##Cultured fibroblasts deriving from Wilson disease patients were compared with the control ones in respect of copper accumulation and low molecular weight copper binding protein (metallothionein) properties. No evidence was obtained that metallothionein abnormality could be a primary cause of copper metabolism disturbances in Wilson disease. The determination of radioactivity, present in serum low molecular weight fraction 24 hours after intravenous injection of 64Cu, has been suggested as an additional tool in Wilson disease diagnosis in doubtful cases.
3896271##1985-1-1##Clinical manifestations of zinc deficiency.##The essentiality of zinc for humans was recognized in the early 1960s. The causes of zinc deficiency include malnutrition, alcoholism, malabsorption, extensive burns, chronic debilitating disorders, chronic renal diseases, following uses of certain drugs such as penicillamine for Wilson's disease and diuretics in some cases, and genetic disorders such as acrodermatitis enteropathica and sickle cell disease. In pregnancy and during periods of growth the requirement of zinc is increased. The clinical manifestations in severe cases of zinc deficiency include bullous-pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections, hypogonadism in males; it is fatal if unrecognized and untreated. A moderate deficiency of zinc is characterized by growth retardation and delayed puberty in adolescents, hypogonadism in males, rough skin, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, and abnormal dark adaptation. In mild cases of zinc deficiency in human subjects, we have observed oligospermia, slight weight loss, and hyperammonemia. Zinc is a growth factor. Its deficiency adversely affects growth in many animal species and humans. Inasmuch as zinc is needed for protein and DNA synthesis and for cell division, it is believed that the growth effect of zinc is related to its effect on protein synthesis. Whether or not zinc is required for the metabolism of somatomedin needs to be investigated in the future. Testicular functions are affected adversely as a result of zinc deficiency in both humans and experimental animals. This effect of zinc is at the end organ level; the hypothalamic-pituitary axis is intact in zinc-deficient subjects. Inasmuch as zinc is intimately involved in cell division, its deficiency may adversely affect testicular size and thus affect its functions. Zinc is required for the functions of several enzymes and whether or not it has an enzymatic role in steroidogenesis is not known at present. Thymopoeitin, a hormone needed for T-cell maturation, has also been shown to be zinc dependent. Zinc deficiency affects T-cell functions and chemotaxis adversely. Disorders of cell-mediated immune functions are commonly observed in patients with zinc deficiency. Zinc is beneficial for wound healing in zinc-deficient subjects. In certain zinc-deficient subjects, abnormal taste and abnormal dark adaptation have been noted to reverse with zinc supplementation.
3912072##1985-1-1##[Liver transplantation in children].##Liver transplantation has become a clinical therapeutic modality for end stage liver diseases. The results achieved in children are better than in adults: in T.E. Starzl unique experience in Pittsburgh, USA, the survival rate at one and four years are 75 and 70% respectively. Complete rehabilitation of these children can nowadays be expected. Between March 1984 and June 1985, 8 children received an orthotopic liver transplantation at the University of Louvain Medical School in Brussels, Belgium; one child received two transplantations after acute and irreversible rejection of a first ABO incompatible graft. The indications were biliary atresia in five (polysplenia in one), biliary hypoplasia in one, alpha-1-antitrypsine deficiency in one and Crigler-Najjar syndrome type I in one. The age of the patients at the time of liver replacement was 12 to 18 months in four, 8 to 13 years in four. Six patients are alive after 17, 14, 12, 10, 3 and 3 months; the two youngest children deceased during the first postoperative month. The Kaplan-Meyer one year survival rate is 75%; all surviving children are in excellent clinical condition with a normal liver function. The 9 transplanted livers were harvested from multiorgan cerebral death donors with the exception of one neonate whose liver alone was removed; 4 were retrieved locally, the five others were offered by foreign hospitals through the organ procurement agencies (Eurotransplant, France-Transplant, U.K. Transplant). Due to appropriate logistics with air flight transportation of the harvesting team when indicated, the total ischaemia time was kept below 6 hours in every case. Two small children underwent a left lobe orthotopic transplantation after ex vivo right trisegmentectomy of the liver retrieved from an older donor with one long term survival. The indications for liver transplantation in children are end-stage liver diseases consisting of a) cholestatic diseases among which the most frequent is biliary atresia after unsuccessful Kasai procedure followed by familial cholestasis (Byler syndrome) and the paucity of the intrahepatic bile ducts of the syndromatic (Alagille syndrome) or non syndromatic type. b) the metabolic diseases resulting either in cirrhosis with liver failure (alpha-1-antitrypsin deficiency, Wilson disease, glycogen storage disease type I and IV, protoporphyria) or in extrahepatic complications of enzymatic deficiency of an otherwise normally functioning liver (Crigler-Najjar syndrome type I, familial hypercholesterolemia and perhaps oxalosis). c) the hepatocellular diseases either chronic with cirrhosis of various origin or acute, eg. toxic hepatitis.(ABSTRACT TRUNCATED AT 400 WORDS)
4054179##1985-1-1##Successful pregnancy in Wilson's disease: a case report and review of the literature.##Pregnancy in patients with Wilson's disease can be successfully managed. A case of successful pregnancy in a patient with Wilson's disease is presented. The pathophysiology, protean clinical manifestations and treatment modalities are described.
4007736##1985-1-1##[Visually evoked potentials in Wilson's disease].##
3886759##1985-1-1##Interactions of trace elements: clinical significance.##We examined interaction of the trace element zinc with copper and lead. In sickle cell anemia, the usual situation is one of mild to moderate zinc deficiency owing to renal loss of zinc. Zinc deficiency seems to produce a mild overburden of copper and an increased ceruloplasmin level, probably by enhancing copper absorption. With zinc therapy, this process is reversed. Pharmacological doses of zinc, when administered in a way to ensure effectiveness (without food) will usually lead to copper deficiency. We have taken advantage of the copper-depleting effect of zinc to design a new therapy for Wilson's disease. Zinc, by inducing intestinal metallothionein, inhibits absorption of copper from food, and inhibits reabsorption of endogenously secreted copper, thereby producing a negative copper balance in Wilson's disease. Once we are certain that zinc blocks accumulation of copper in the liver of Wilson's disease patients, zinc therapy will be available as one approach for treating this fatal disease. The animal literature indicates that zinc protects against lead toxicity when both elements are given orally, no doubt through the intestinal metallothionein mechanism. In preliminary experiments in rats, we have not been able to show that toxicity from lead that arrives into the body through a nonoral route is affected by oral zinc supplements.
3998770##1985-1-1##Wilson's disease: evoked potentials and computed tomography.##Multi-modality evoked potentials and computed cranial tomography (CT) were performed in ten patients with Wilson's disease to determine if any of these studies would correlate reliably with neurologic status. While all four patients with CT abnormality had neurologic signs, two additional patients with neurologic findings had normal scans. Evoked responses were normal in nine patients. The remaining patient displayed abnormal visual, brainstem, and somatosensory evoked potentials, and follow-up studies after clinical deterioration revealed worsening of the brainstem and visual evoked potentials. This patient died unexpectedly from a subdural hematoma, and postmortem examination confirmed the radiographic findings of cortical atrophy of the cerebrum and cerebellum and bilateral cystic degeneration of the basal ganglia. However, localized demyelination in the visual, auditory, and sensory pathways was not present. We conclude that the clinical neurologic status of patients with Wilson's disease cannot be reliably predicted by either CT or multi-modality evoked potentials.
4088468##1985-1-1##[Extensive damage of the brain stem structures in a case of the acute form of Wilson's disease].##
4095037##1985-1-1##Case 4. Wilson's disease.##
3841762##1985-1-1##Splenic growth rates in cirrhotic and other splenomegalic diseases of childhood.##The weights of the spleens of series of patients with various disorders of children dating from birth or early infancy and causing splenomegaly, with or without cirrhosis of the liver, were analyzed. The linear regression equation for spleen weight versus age in months for each disease was derived, and the rate constants from these equations were adjusted for the age range of the patients in each group. The original data of Coppoletta and Wolbach were used for normal values. The rates of splenic growth of appropriate entities for which the regression equation could be computed fell into three groups, with adjusted rate constants (growth of spleen in grams per month) of 6.53-6.95 (biliary atresia, thalassemia, and cirrhosis following neonatal hepatitis), 2.30-2.62 (cirrhosis of alpha-1-antitrypsin deficiency, infantile polycystic disease, and spherocytosis), and 1.06-1.11 (cystic fibrosis and idiopathic thrombocytopenic purpura). These classes of splenic growth rates are approximately 10, 3.7, and 1.6 times the normal growth rate (0.67 g/mo). Rate constants could not be computed for the categories cirrhosis following viral hepatitis and hemolytic anemia other than spherocytosis and sickle cell anemia, and the numbers of patients with splenic vein obstruction, cirrhosis with the cholestatic syndrome of parenteral alimentation, hypoplastic anemia with hemosiderosis, tyrosinemia, Byler's disease, congenital hepatic fibrosis, and Wilson's disease were too few for analysis. The significance of the finding of classes or &quot;quantum groups&quot; of splenic growth rates in disorders of children, dating from birth or early infancy and causing splenomegaly, is uncertain. Comparable data on adequate series of patients with other appropriate disorders will be necessary.
4070288##1985-1-1##Zinc as a treatment for Wilson's disease--an orphan among orphans.##
3975658##1985-1-1##Radiologic study of 42 cases of Wilson disease.##This paper reports 42 cases of bone and joint radiographic changes in hepatolenticular degeneration. The cases were proven clinically by ophthalmologic and laboratory study, and their radiographic and joint changes were divided into five groups: no abnormal findings, osteoporosis, osteomalacia (rickets), distinct changes, and miscellaneous. Distinct changes include marginal bone fragments, angulation of carpal bones, squaring of metacarpal heads, and calcification of the joint capsule or tendon insertion. The mechanism causing the bone changes in hepatolenticular degeneration is also discussed.
4060799##1985-1-1##[Oral zinc in Wilson disease--an alternative to D-penicillamine].##Recently Brewer et al. reported the possibility of an oral zinc therapy in Wilson's Disease. We treated a 19 years old patient with decompensated liver cirrhosis due to Wilson's disease with zinc-sulphate. D-Penicillamine had to be withdrawn since proteinuria occurred under treatment. After the discontinuation of D-Penicillamine an increase of serum copper almost up to normal range was observed; concomitantly urinary copper elimination decreased. Under oral zinc sulphate therapy (145 mg/day) a drop of serum copper level was achieved and liver function improved: serum albumin, gamma globulins and prothrombin time reached normal values. The patient did not complain any side effects during oral zinc sulphate therapy. Oral zinc therapy in Wilson's Disease may be regarded as an alternative to D-Penicillamine treatment when this drug has to be discontinued because of side effects.
6532922##1984-12-16##[Wilson's disease with hepatic manifestations in a child].##
6535556##1984-12-1##[Myasthenia gravis induced by D-penicillamine in a patient with progressive systemic sclerosis].##The development of autoimmune diseases in some patients treated with D-penicillamine (DPA) suggests that the reported occurrence of a conduction disorder at the neuromuscular junction and the development of a reversible myasthenia gravis in rheumatoid disease, progressive systemic sclerosis or Wilson's disease after the use of DPA are part of a general predisposition for autoimmune disease related to DPA therapy. The case reported is an example. The DPA- induced myasthenia gravis (MG) is similar to the spontaneous MG clinically and electrophysiologically, though ocular signs prevail in the former. Antibodies to acetylcholine receptor have been demonstrated and thymic hyperplasia also has been formed. Regarding the onset of myasthenic manifestations the duration of the treatment with DPA varies from 6 to 10 months. The action of DPA on the neuromuscular junction is different from that occurring in spontaneous MG. The pathogenesis of the DPA induced MG is still obscure. The chemical properties of DPA permit it to react with many proteins and some alteration of proteins may appear, with structural changes in the composition and antigenicity of the collagen fibers. In vitro DPA causes disorder of acetylcholine receptor bridges to alpha, beta, gamma sub-units with reduction of the S-S bridges in the gamma-subunit. This decreases the linkage of high affinity and abolishes its positive cooperative system, reducing the S-S connection in the alpha-unit near the acetylcholine linkage. The interaction between DPA and receptor may induce antigenic alteration in this latter, starting the autoimmune phenomena. The other possibility is the stimulation of prostaglandin E-1 synthesis by DPA may fill the allosteric place of ACh receptor, interfering on the neuromuscular junction.
6518737##1984-12-1##Wilson's disease: a 1984 perspective.##
6521614##1984-12-1##Fulminant hepatic and renal failure complicating Wilson's disease.##We report a case of fatal fulminant liver failure complicating Wilson's disease that is unique in several respects. The illness supervened after several years of medical noncompliance in a patient who had been previously diagnosed and successfully treated with penicillamine. Re-institution of penicillamine therapy 2 weeks prior to the fulminant decompensation failed to prevent it. Renal failure in this patient was apparently secondary to rhabdomyolysis. Addition of penicillamine to a peritoneal dialysis solution allowed chelation and removal of over 14 mg per day of copper but without apparent benefit. Exchange transfusion and high dose dexamethasone therapy (24 mg/day) were equally ineffective in reversing the liver failure. Other reported cases have also been fatal. The best treatment for fulminant Wilson's disease is prevention by diagnosis in a pre-symptomatic stage and institution of carefully supervised life-long therapy with penicillamine.
6241658##1984-12-1##Neurotoxic effects of copper: inhibition of glycolysis and glycolytic enzymes.##The effects of Cu2+ on glycolysis and several glycolytic enzymes were studied in rat brain extracts in vitro. At concentrations reportedly found in Wilson's disease, Cu2+ significantly inhibited lactate production from glucose or glucose-6-phosphate in rat brain postnuclear supernatant with an IC50 of about 3 microM. Cu2+ also inhibited several glycolytic enzymes. Amongst the latter, Cu2+ was most effective in inhibiting hexokinase (IC50 for Cu2+ = 7 microM), moderately effective in inhibiting pyruvate kinase (IC50 for Cu2+ = 56 microM), but least effective in inhibiting lactate dehydrogenase (IC50 for Cu2+ = 300 microM). These results suggest that inhibition of brain glycolysis may have pathophysiological importance in copper poisoning and in Wilson's disease.
6239210##1984-11-3##[Diagnosis of Wilson's disease. 15 cases].##
6488663##1984-11-1##Fatal fulminant hepatitis with hemolysis in Wilson's disease. Criteria for diagnosis.##We report a child with the presentation of Wilson's disease as acute fulminant hepatic failure and severe hemolysis. Our review of the literature suggests the following criteria for considering this diagnosis in the child with acute liver failure: discordance between mildly elevated serum transaminases and extremely elevated bilirubin levels; anemia associated with hemolysis (increased reticulocytes in the absence of bleeding); elevated hepatic copper; and other copper metabolic abnormalities (elevated serum copper, excessive 24-hour urine copper excretion, and reduced serum ceruloplasmin). Establishing the correct diagnosis enhances the possibility of detecting asymptomatic siblings or other family members in whom early inauguration preventive therapy should be successful.
6510441##1984-11-1##Effective D-penicillamine treatment of an early diagnosed patient with Wilson's disease.##
6492760##1984-11-1##Electron probe X-ray analysis on human hepatocellular lysosomes with copper deposits: copper binding to a thiol-protein in lysosomes.##Livers of eight patients with chronic liver diseases were investigated by energy dispersive x-ray analysis. First, three kinds of preparations (osmium-Epon sections, glutaraldehyde-frozen sections, and unfixed-frozen sections) were compared for element detectability at a subcellular level. The glutaraldehyde-frozen sections were satisfactory as far as copper, sulfur, and phosphorus were concerned. Five patients (one patient with Wilson's disease, one chronic cholestasis, one chronic hepatitis, and two asymptomatic primary biliary cirrhosis) yielded x-ray images of copper and sulfur consistent with hepatocellular lysosomes. Second, the glutaraldehyde-frozen sections were utilized for a study of copper deposits in the patients' livers. There was a significant correlation between copper and sulfur contents in the lysosomes of all patients studied but no correlation in the remainder of the cytoplasm. Zinc was not detected in the lysosomes. Whatever the content of copper in the lysosomes, the ratio of delta copper to phosphorus (weight/weight) to delta sulfur to phosphorus was 0.60. These data indicate that most lysosomal copper binds to a thiol protein, probably metallothionein, in the liver.
6525319##1984-11-1##[Copper level and metallothionein-like Cu-binding protein in cultured skin fibroblasts from patients with Menkes' disease and Wilson's disease].##Copper concentration, intracellular copper distribution, and inducibility of metallothionein-like metal-binding protein (MLP) by copper or cadmium addition to culture medium were compared among three types of skin fibroblasts derived from patients with Menkes' disease and Wilson's disease, both exhibiting genetic defects of copper metabolism, and from normal subjects (control). Skin fibroblasts were cultivated in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum and antibiotics in 5% CO2 at 37 degrees C. Cells were harvested with rubber-policeman, washed twice with phosphate-buffered saline, pH 7.2, suspended in deionized water, and homogenized. The homogenate from each cell type was used to determine the concentration of copper by atomic absorption spectrophotometry employing graphite-rod atomizer after lyophilization, ashing in HNO3, and coprecipitation with zirconium. Intracellular copper concentration was elevated in Menkes' cells (420 ng Cu/mg of protein) and Wilson's cells (217 ng Cu/mg of protein) than in control cells (90.0 ng Cu/mg of protein), although one of four Wilson's strains showed normal copper level (70.5 ng Cu/mg of protein). Cytosol copper concentration was 5.8-fold higher in Menkes' cells but only 1.3-fold in Wilson's cells than in control cells, and cytosol copper accounted for only 35% of total intracellular copper in Wilson's cells as compared with 68% and 52% in Menkes' and control cells, respectively. These suggest that accumulated copper in each cell type is differently distributed within cells; in Menkes' cells exclusively into cytosol, but in Wilson's cells into particulates rather than cytosol. Elution profiles from Sephadex G-75 columns indicated that most of copper had bound to MLP in Menkes' cells, though no Cu-MLP was detectable in Wilson's or control cells under these experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
6504223##1984-10-1##[Computer tomographic studies in Wilson disease].##5 patients with proven Wilson's disease had clinical examinations and follow-up scans up to 6 years while being under penicillamine treatment. Severe neurological deficits were associated with marked CT abnormalities. In all other cases clinical condition and CT finding was only loosely correlated. Under therapy, some hypodense areas normalized their attenuation partially or completely. In primarily normal CT's, cupruresis did not induce alterations. As there is no firm correlation between CT findings and clinical involvement the CT examination is of limited value in prognosis.
6520516##1984-10-1##[A case of Wilson's disease with a high density lesion in hepatic computerized tomography scan and abnormal secretion of pituitary hormones].##
6432188##1984-9-1##Treatment of Wilson's disease with zinc sulphate.##
6468217##1984-9-1##Antemortem diagnosis and short-term survival of a patient with Wilson's disease presenting as fulminant hepatic failure.##When Wilson's disease presents as fulminant hepatic failure, it may be extremely difficult to differentiate from other causes of hepatic insufficiency. A recently described diagnostic biochemical profile (elevated serum and urine copper levels, mild transaminase elevation, very high bilirubin levels, and low hemoglobin with intravascular hemolysis) was employed to diagnose this form of Wilson's disease prior to death in a young woman without Kayer-Fleischer rings and with a normal serum ceruloplasmin level. Since hepatic transplantation now offers a possible cure for this previously uniformly fatal form of Wilson's disease, it should be considered the treatment of choice for this disease entity. Combined with the availability of hepatic transplantation, this patient's temporary improvement and unusually long survival of four months further emphasizes the importance of this diagnostic profile in recognizing Wilson's disease quickly and accurately when it presents as fulminant hepatic failure.
6436606##1984-9-1##[Therapy of chronic non-A, non-B hepatitis].##Before establishing the diagnosis of chronic active hepatitis (CAH) non-A-non-B other diseases have to be excluded, like toxic hepatitis (alcohol, drugs), immunological forms (autoimmune hepatitis, primary biliary cirrhosis), and metabolically caused hepatitis (hemochromatosis, Wilson's disease), since for some of these patients specific therapeutic procedures are available. History of the disease and repeated evaluation of control biopsies performed about every 9 to 12 months help in deciding about therapy. Chronic persisting hepatitis non-A-non-B and the mild form of CAH non-A-non-B do not need treatment but only diagnostic follow-up. Patients with apparent clinical disease, increased transaminases and histologically typical findings in at least two biopsies may be looked at as suitable for drug treatment. Since this disease is probably caused by virus, immunosuppressive therapy in this small group of patients described above has to be temporarily limited and should not be used as long term treatment.
6514866##1984-9-1##[Acoustically evoked brain stem potential in Wilson disease].##By 48 patients with Wilson's disease the brainstem acoustic evoked potentials were stated. There were 35 pathological findings (73%), 13 were normal (27%). The waves, determined by the middle and upper brainstem (Pons and Mesencephalon) showed most of all pathological changes. Those patients with forms of Wilson's disease called Pseudoskelerose and Pseudoparkinson showed the most pathological findings. But one could watch these findings by about 30% of patients in preclinical stage. This method can possibly be used for early detection of disorders of brainstem functions and in the same way it can be used for control of treatment by patients in preclinical stage.
6515070##1984-8-15##[Wilson's disease. Diagnostic clues of a rare but treatable process].##
6430436##1984-8-4##Effective treatment of Wilson's disease with oral zinc sulphate: two case reports.##Most patients with Wilson's disease are treated with the potentially toxic cupriuretic agent penicillamine. The toxicity of zinc taken by mouth is low, and long term administration induces a negative copper balance. Two patients with severe neurological symptoms were given zinc sulphate by mouth three times daily in doses of 200 mg, later increased to 300 mg. One patient, a 21 year old man, started to receive zinc sulphate after his condition had deteriorated during treatment with cupriuretic drugs. The other, a 27 year old woman, was treated from the start with zinc sulphate. The conditions of both patients improved appreciably, and they were still receiving treatment with zinc sulphate roughly two years later. Effective depletion of body copper stores was shown by an intravenous radiocopper loading test and liver biopsy. No side effects were found. Wilson's disease may effectively be treated with zinc sulphate alone.
6235797##1984-8-1##Subcortical dementia. Review of an emerging concept.##Subcortical dementia is a clinical syndrome characterized by slowness of mental processing, forgetfulness, impaired cognition, apathy, and depression. First recognized in progressive supranuclear palsy and Huntington's disease, the concept has been extended to account for the intellectual impairment of Parkinson's disease, Wilson's disease, spinocerebellar degenerations, idiopathic basal ganglia calcification, the lacunar state, and the dementia syndrome of depression. Disorders manifesting subcortical dementia have pathologic changes that involve primarily the thalamus, basal ganglia, and related brain-stem nuclei with relative sparing of the cerebral cortex. Recent studies of neuropsychologic deficits following focal subcortical lesions also support a role for these structures in arousal, attention, mood, motivation, language, memory, abstraction, and visuospatial skills. The clinical characteristics of subcortical dementia differ from those of dementia of Alzheimer's type where prominent cerebral cortical involvement produces aphasia, amnesia, agnosia, and apraxia.
6092189##1984-8-1##[Hepatocellular carcinoma in Wilson's disease].##
6238709##1984-8-1##[Copper excretion in 37 cases of Wilson's disease treated with &quot;anti-hepatolenticular degeneration decoction&quot;].##
6741909##1984-7-1##Acute Wilson's disease and thalassemia minor: a case report.##The case of a 17-year-old Italian girl with thalassemia minor and fatal acute Wilson's disease together with severe hemolysis is reported. The fortuitous(?) occurrence of both genetically determined conditions in the same patient was the source of delayed diagnosis of the metabolic disorder.
6732083##1984-7-1##Zinc treatment of Wilson's disease.##
21965993##2011-10-4##Wilson'S disease presenting with schizophrenia like psychosis : a case report.##
6547147##1984-7-1##Serum vitamin D metabolites and their binding protein in patients with liver cirrhosis.##Serum parameters of calcium metabolism were measured in 32 consecutive patients with biopsy-proven cirrhosis due to either hepatitis (n = 13), alcohol abuse (n = 11), Wilson's disease (n = 3), or primary or secondary biliary cirrhosis (n = 5). All measurements were normal in the small group of patients with Wilson's disease. The serum concentrations of albumin, vitamin D-binding protein, total calcium, phosphorus, and 1,25-dihydroxyvitamin D3 (1,25-(OH2)D3) were decreased in the other patients with cirrhosis, but their mean serum concentrations of ionized calcium, 25-hydroxyvitamin D3 (25-OHD3) and free 1,25-(OH2)D3 index were normal. A slight but significant increase in the serum PTH measured using a carboxyl-terminal antiserum was found. A significant correlation was found between the serum concentration of either albumin or vitamin D-binding protein and the serum concentrations of total calcium, 25-OHD3, 1,25-(OH2)D3, and PTH but not with ionized calcium or free 1,25-(OH2)D3 index. The observed abnormalities of calcium metabolism in unselected patients with cirrhosis were mainly due to decreased protein synthesis. Only the patients with severe cirrhosis had decreased concentrations of 25-OHD3 but they were nevertheless able to maintain a normal ionized serum calcium and free 1,25-(OH2)D3 level, possibly by means of compensatory hyperparathyroidism.
6428604##1984-6-23##Wilson's disease.##
6381924##1984-6-9##[Wilson's disease (hepatolenticular degeneration)].##
6426690##1984-6-2##Wilson's disease.##
6734469##1984-6-1##Chronic hepatitis. Aetiology and current management.##The entity of chronic hepatitis has long been an enigma, and its treatment confusing. Recent studies have indicated the importance of excluding causes such as drugs, Wilson's disease and alpha 1-antitrypsin deficiency. After excluding such causes, there are 3 major groups--'autoimmune', hepatitis B, and non-A, non-B (NANB) in all of which an immunological basis for pathogenesis exists. The autoimmune group has been subdivided into a milder type (chronic persistent hepatitis) and a more severe type (chronic active hepatitis) on histological grounds. Corticosteroids are indicated in chronic active hepatitis if cirrhosis or bridging necrosis is present. However, corticosteroids are contraindicated in disease due to the hepatitis B virus where chronic active hepatitis correlates with the presence of replicating virus (serum positive for e antigen, DNA polymerase and HBV-DNA), and in such cases antiviral agents and immunomodulation are being studied. Very little is known about NANB hepatitis in the absence of an assay and there may be more than a single agent. In hepatitis B, the development of serological markers, molecular probes (HBV-DNA), natural animal hepatitis with near-identical viruses, and delta antigen (a virus requiring co-infection with hepatitis B) have all extended our knowledge so dramatically that it is hoped that the enigma of chronic hepatitis will be solved when an assay for NANB hepatitis becomes available.
6233326##1984-6-1##Optic neuropathy associated with penicillamine therapy in a patient with rheumatoid arthritis.##Optic neuropathy developed in a patient with rheumatoid arthritis who had been receiving D-penicillamine for about 1 year. An associated finding included a 2+ positive antinuclear antibody test with a titer of 1:320. Optic disc swelling was resolved on high doses of intravenous steroids. The case resembles two previously reported cases of optic neuropathy which occurred in patients with Wilson's disease who were receiving penicillamine.
6464668##1984-5-1##Reduced binding of 3H-spiroperidol to lymphocyte in Wilson's disease.##Biochemical studies of CSF from patients with Wilson's disease (WD) have increased that alterations in the state of dopaminergic and serotoninergic systems are similar to those manifested in Parkinson's disease. Recently, the density of dopaminergic receptors on lymphocytes has been found to be diminished in Parkinson's disease. In the present study, 3H-spiroperidol binding was evaluated in lymphocytes acquired from 12 patients suffering from WD, as compared to blood donors. A significant decrease in the number of binding sites (Bmax) was observed in the lymphocytes of the WD patients. There was no clear relationship between clinical status, age and duration of the disease and the alterations in receptor density. The mechanism underlying the decrease in lymphocyte 3H-spiroperidol binding sites in WD demands clarification.
6373070##1984-5-1##Clinical consequences of heterozygosity for autosomal-recessive diseases.##Heterozygotes of autosomal-recessive diseases can often be recognized by special heterozygote tests, since enzyme activities are normally reduced in comparison with the normal homozygote state. In Drosophila, the majority of recessive lethal mutations shows a reduction of fitness in heterozygotes, whereas in a strong minority fitness of heterozygotes is increased. This review will be devoted to a consideration of the extent to which heterozygotes for a wide variety of nominally recessive diseases are subject either to an increased liability for common diseases or slight shifts of behavioral characteristics. The available evidence has been collected and will be discussed in three steps: Most studies are available for phenylketonuria. For this group of diseases, a slight reduction of average--especially verbal--I.Q. in heterozygotes has been reported together with signs of a slightly increased cerebral irritability, a possible slight increase of risk for mental disease, and an increase of blood phenylalanine levels in stress situations. The PKU example is used to discuss methodological problems involved in such studies. Other conditions for which relevant deviations in heterozygotes are possible or even likely include among others lipid storage diseases, microcephaly, myoclonus epilepsy, Wilson's disease, galaktokinase deficiency, homocystinuria, recessive myotonia and ataxia- teleangiectasia (increased cancer risk). Since heterozygotes for autosomal recessive diseases are common, it is possible that an appreciable fraction of &quot;multifactorial&quot; genetic liabilities for common, &quot;constitutional&quot; or mental disease might simply be due to heterozygosity for genes whose homozygous affects are already well known. By the same token, much of the &quot;normal&quot; genetic variability influencing cognitive performance (I.Q.)--especially in the lower range--and personality characteristics could also be caused by recessive genes in the heterozygous state.
6147299##1984-5-1##Decreased platelet aggregation, Ca2+ and Mg2+ ATPase and platelet factor 3 activities in patients with Wilson disease.##
6504245##1984-5-1##[A case of the abdominal form of Wilson's disease with atypical clinical symptoms in a 19-year-old man].##A case of the abdominal form of Wilson's disease is described in a male patient aged 19 years. The case progressed rapidly and presented rarely observed signs of central nervous system damage. Morphological examination of the brain demonstrated well developed picture of tissue damage characteristic of this disease entity.
6377131##1984-5-1##Oral zinc therapy for Wilson's disease.##
6424779##1984-4-21##Wilson's disease.##
6717566##1984-4-19##Release of endogenous Zn2+ from brain tissue during activity.##The role of divalent transition metal ions in neural function is poorly understood. In excess, these ions are associated with neurological disorders such as Wilson's disease, Pick's disease and epileptic seizures. We suggest that zinc ions, which are contained in nerve terminals, are extruded into the extracellular space during neuronal activity. Excessive levels of zinc may be released during intense neuronal activation, and contribute to the paroxysm and toxic damage observed. Zinc ions are contained in high concentrations in mossy fibres of the hippocampal formation, and it is the postsynaptic neurones of these fibres which are most susceptible to the toxic effects of kainic acid, a potent convulsant, or to chronic exposure to organometallic compounds. Here we demonstrate for the first time that Zn2+ is released into the extracellular space during excitation of hippocampal slices.
6730985##1984-4-1##Haemolytic activity of copper as influenced by chelating agents, albumine and chromium.##The haemolytic activity of CuSO4 (0.3 mM) in vitro was reduced in the presence of albumine (5-20 g/l). The presence of D-penicillamine, triethylene tetramine or dimercaptosuccinic acid (0.3 mM) also reduced the copper-induced haemolysis, whereas 2,3-dimercaptopropane-1-sulphonate increased the cytolysis. N-ethylmaleimide (NEM) in appropriate concentrations (1 mM), as well as chromic chloride (0.3 mM), reduced the copper-induced haemolysis. Higher concentrations of NEM (2 mM) were ineffective. The results may provide helpful suggestions as regarding the clinical treatment of copper poisoning and Wilson's disease. The results may also be helpful for the understanding of the mechanisms of haemolysis associated with copper intoxication in vivo.
6742703##1984-4-1##[Association of an uncombable hair syndrome and Wilson's disease].##
6697632##1984-4-1##Idiopathic torsion dystonia associated with lesions of the basal ganglia.##We report two siblings who are suffering from a dystonic syndrome, clinically indistinguishable from idiopathic torsion dystonia (dystonia musculorum deformans) but with cranial computerized tomographic scan findings of basal ganglia lesions, similar to that reported in Wilson's disease. The occurrence of the disorder in the same sibship suggests an autosomal recessive mode of inheritance and may represent another variety of the syndrome of idiopathic torsion dystonia.
6232196##1984-4-1##Movement disorders in the psychiatric patient.##Abnormal movements or postures often present a diagnostic and therapeutic challenge to the psychiatrist or neurologist. The authors review pertinent anatomy and physiology of disorders of the extrapyramidal system, suggest aspects of the clinical history and examination particularly important for diagnosis, and describe a range of abnormal movements. They review several syndromes in which abnormalities of behavior and movement may occur together, including Huntington's chorea, Wilson's disease, Parkinson's disease, and tardive dyskinesia.
6746555##1984-4-1##Wilson's disease: report of two cases.##
6700655##1984-3-15##Hypoparathyroidism in Wilson's disease.##
6324360##1984-3-8##[Febrile reaction to D-penicillamine].##Two personal observations of febrile reaction to D-penicillamine in patients with rheumatoid arthritis provide the opportunity for recalling the clinical presentation which is fairly uniform. The physiopathological mechanism is still unknown. In Wilson disease, progressive reintroduction of the drug may be successful.
6370090##1984-3-1##Ultrastructure of the liver and biliary tract in health and disease.##Ultrastructural studies with the transmission (TEM) and scanning (SEM) electron microscopes have added greatly to our knowledge of cellular structure and function in the liver. The normal polyhedral hepatocyte has numerous subcellular organelles, such as mitochondria, peroxisomes, lysosomes and complex rough (rer) and smooth (ser) endoplasmic reticulum. The normal hepatocyte stores glycogen, and sometimes lipid droplets, and secretes bile through the bile canaliculi between adjacent liver cells. It receives nutrients from the sinusoidal lumen across a fenestrated endothelium which is separated by the Space of Disse' from the plasma membrane. The Space of Disse' contains a scant network of reticulin fibers but no basal lamina. Two types of parasinusoidal cells are found in Disse's space: the fat storing cells of Ito, and the Pit cells which may have an endocrine function. The diseased liver has yielded much information in studies with TEM and SEM. The studies with TEM have been most helpful in studying the etiology of infectious diseases such as hepatitis B; have revealed organelle changes such as megamitochondria in cirrhosis and the fibrillar nature of alcoholic hyaline; have led to the identification of specific deposits in metabolic and storage diseases such as hemochromatosis (iron). Wilson's disease (copper), and alpha-1-antitrypsin deficiency (glycoprotein) have proven useful in identifying drug induced liver cell changes such as proliferation of SER and cholestasis, and are useful for identifying specific cell types in inflammatory and neoplastic diseases. In the future, both TEM and SEM coupled with histochemical, cytochemical, immunohistochemical and other analytic techniques will continue to add greatly to our understanding of the liver in health and disease.
6433587##1984-3-1##Acute hepatic failure in children.##Many diseases may present as acute hepatic failure in the pediatric age group, including viral hepatitis A and B, adverse drug reactions, both toxic and &quot;hepatitic,&quot; and inherited metabolic disorders such as tyrosinemia, alpha 1 antitrypsin deficiency, and Wilson's disease. Management is primarily supportive, with care taken to anticipate the known complications of hepatic failure. Few &quot;curative&quot; therapies are known, although attempts at stimulating hepatic regeneration may be helpful.
6690523##1984-2-1##Computed tomography of the liver in Wilson disease.##Computed tomography (CT) of the upper abdomen was performed in 24 patients with Wilson disease. Hepatic attenuation (range 44.7 to 69.3, mean 58.4 Hounsfield units) was found to be within normal limits, even for those patients known to have a markedly elevated liver copper content at the time of the CT study. In some patients the liver had a rather broad distribution of attenuation values (as measured by the standard deviation around the mean density and seen as mild nodularity). However, such a nodular appearance can be seen in many forms of liver disease. It appears that CT of the liver has little to offer in the diagnosis or management of Wilson disease.
6717401##1984-1-31##[Diagnosis of Wilson's disease in children. Personal cases].##
6424415##1984-1-1##Therapy for chronic active hepatitis.##As is apparent from the foregoing, there is only one etiologic variant of CAH for which specific therapy is available, namely, that associated with Wilson's disease. However, Wilson's disease is responsible for only a minute portion of the total cases of CAH. Drug-induced CAH also seems highly responsive to appropriate management--in this instance, removal of an offending agent rather than administration of a therapeutic drug. However, as stated, it too is an infrequent contributor to the CAH pool. Among the remaining forms of CAH, a reasonably consistent response to treatment can be expected only from patients with autoimmune CAH. This entity is a serious disorder with unequivocally high morbidity and mortality and thus clearly warrants treatment. Despite the considerable side effects that invariably result from the long-term use of corticosteroids--the only available, although nonspecific, form of treatment--corticosteroid use is justified and indeed recommended. Current evidence, derived from the Mayo Clinic data, suggests that the best therapeutic approach is to use both corticosteroids and azathioprine, a combination that offers the highest therapeutic index with the lowest rate of side effects. Using this regimen, complete remission is reported to result in 65% of cases within 2-3 years, although a considerable proportion of these individuals relapse and require retreatment. Much publicity has surrounded the Mayo Clinic and Royal Free Hospital treatment trials; however, it is probable that autoimmune CAH represents far less than 20% of all cases, and that severe disease requiring corticosteroid therapy comprises but a minor fraction of these. Thus, the bulk of cases of CAH in the United States occur in patients with either established or inferred viral-related disease, the group for which clearly effective therapy is not yet available. Most of these persons are asymptomatic, their disease having been detected through routine screening programs or at the time of evaluation of other disorders. Much interest is evoked, at present, by the new experimental forms of treatment, but none has proved to be consistently effective, and for some, toxicity is high. All appear to reduce levels of replicating virus, but none clearly affects HBsAg or disease activity. Research in this area continues, with highest expectations of success for the use of combination therapy.(ABSTRACT TRUNCATED AT 400 WORDS)
6380333##1984-1-1##[Current problems in Wilson's disease].##
6241440##1984-1-1##[Skin manifestations observed during treatment with penicillamine and its derivatives].##Many forms of toxidermia are observed during D-penicillamine therapy. The exact type seems to depend on the pathology for which the drug was prescribed; pemphigus during rheumatoid arthritis, perforating serpiginous elastoma in Wilson's disease, cystinuria... The two physiopathogenic mechanisms discussed, an autoimmune reaction and a direct action of D-penicillamine on the skin, would seem to be complementary.
6712099##1984-1-1##[Persistent hypertransaminasemia manifesting Wilson's disease. Apropos of 3 cases].##
6723129##1984-1-1##Bio-inorganic effects of D-penicillamine in children and in the elderly.##The principle mechanisms of action of dimethylcysteine (D-penicillamine) are thiazolidine formation, sulphhydryl -disulphide exchange, chelation and superoxide dismutase-like activity; as a consequence, it can enter into many varied biological interactions. Thiazolidine formation with maturing collagen makes D-penicillamine potentially teratogenic; sulphhydryl -disulphide exchange allows the formation of a mixed disulphide with L-cysteine from the L-cystine dimer; chelation permits it to bind metals such as copper; and superoxide scavenging makes it theoretically capable of influencing the inflammatory response of specific cell systems. Not surprising, D-penicillamine is of value in the treatment of cystinuria, Wilson's disease, juvenile rheumatism, rheumatoid arthritis and various other conditions.
6714120##1984-1-1##[Rupture of a splenic artery aneurysm in a woman suffering from Wilson's disease].##
6714278##1984-1-1##Computerized cranial tomography in presymptomatic and hepatic form of Wilson's disease.##Computerized cranial tomography was performed in 14 patients affected with hepatolenticular degeneration (4 presymptomatic and 10 with a hepatic form). 1 case showed brain stem atrophy with atypically located hypodense areas and another subject showed frontal atrophy with prevalence to the right side. The abnormalities found in another 7 cases were slight. In 5 patients, CT was normal.
6363255##1984-1-1##Wilson's disease: indications for liver transplants.##The clinical course of certain patients with Wilson's disease resembles that of patients with viral or drug-induced fulminant hepatitis lasting only few weeks from recognition of symptoms to severe hepatic insufficiency and death. The disease is complicated by hemolysis and is characterized by hypercupremia. Routine laboratory findings may underestimate the severity of the disease. These patients, as well as patients with decompensated Wilsonian cirrhosis who are not responding to therapy, should be considered as candidates for liver transplants.
6429441##1984-1-1##Biochemical and clinical changes in Wilson's disease heterozygotes.##This paper reports on a study of the heterozygous children of patients with Wilson's disease. A total of 16 children of 10 patients with the disease were followed up. Detailed biochemical, clinical and EEG tests were done. Nearly all the children were found to have reduced serum copper and caeruloplasmin levels and high rates of urine copper excretion following exposure to penicillamine. These findings were different from the results obtained in adult heterozygous carriers. Thirty per cent of the children had pathological neurological findings, and EEG abnormalities were found in 75%.
6689792##1984-1-1##Cerebral abnormalities: use of calculated T1 and T2 magnetic resonance images for diagnosis.##The potential clinical importance of T1 and T2 relaxation times in distinguishing normal and pathologic tissue with magnetic resonance (MR) is discussed and clinical examples of cerebral abnormalities are given. T1 and T2 values may be used in three ways: (a) Relative values, obtained by an analysis of intensity images with varying dependence on T1 and T2, may be used if absolute values for T1 and T2 are not required for diagnosis. (b) If an absolute value is desired, the numerical values for the relaxation times may be generated using a region of interest on the intensity images. (c) In cases in which both T1 and T2 change may require a calculated image to indicate the contribution of each to the signal intensity, the numerical value may be used to generate analogue images of T1 or T2 calculations. Five patients with cerebral infarction, 15 with multiple sclerosis, two with Wilson disease, and four with tumors were imaged. Hemorrhagic and ischemic cerebrovascular accidents were distinguished using the spin echo technique. In the patients with multiple sclerosis, lesions had prolonged T1 and T2 times, but the definition of plaque was limited by spatial resolution. No abnormalities in signal intensity were seen in the patient with Wilson disease who was no longer severely disabled; abnormal increased signal intensity in the basal ganglia was found in the second patient with Wilson disease. Four tumors produced abnormal T1 and T2 relaxation times but these values alone were not sufficient for tumor characterization.
6718959##1984-1-1##[Trazodone in involuntary pathologic movements].##The authors report an experiment undertaken with trazodone in the treatment of different forms of pathological involuntary movements. Forty-five subjects were treated for two months; 15 were affected with L-DOPA + decarboxylase inhibitor induced dyskinesias, 9 with choreic or choreoathetosic syndromes, 6 with primary buccolingual dyskinesias, 4 with ticks, 9 with tremors--3 of whom had delirium tremens--and 1 case of Wilson's disease with severe postural dystonia. At the end of treatment there was a considerable improvement in 40 cases (88.9%), 17 of whom (37.8%) had a reduction of over 65% of symptoms. The results were good in all the groups considered; particularly interesting were those obtained in delirium tremens, alcoholic induced tremor, primary buccolingual dyskinesias, L-DOPA + decarboxylase inhibitor induced dyskinesias. Emphasis is placed on the efficacy of the drug in inhibiting postural dystonia in the one case of Wilson's disease. The good tolerance of the drug was confirmed.
6485485##1984-1-1##[The question of a false-structured ceruloplasmin in Wilson's disease].##
6363337##1983-12-1##[Unusual complications in Wilson's disease].##
6665351##1983-12-1##[Gonadotropin-resistant ovary syndrome and Wilson's disease. A case].##
6605066##1983-11-1##Nuclear magnetic resonance of iron and copper disease states.##The tissue levels of paramagnetic ions are an important factor in the determination of T1 values as observed by nuclear magnetic resonance (NMR) imaging. The increased levels of iron present in human disease states such as hemochromatosis lead to decreased T1 values. The mean liver T1 of three patients with iron storage disease was determined to be 130 msec, significantly different from the value of 154 msec, the mean for 14 normal controls. Whether NMR will be able to detect the increased copper levels in liver and brain in Wilson disease remains for further clinical trials to evaluate. NMR imaging, however, does serve as a noninvasive method for the diagnosis of states of iron overload and as a technique to follow progression of disease or response to medical therapy.
6428817##1983-11-1##Wilson's disease. An electroencephalographic study.##
6617055##1983-11-1##Wilson's disease in childhood. Variability of clinical presentation.##Although Wilson's Disease is a treatable disorder, 9 of 15 cases referred with undiagnosed liver disease in the present series died in 3 to 53 days of admission. We have reviewed these cases to identify features that would allow earlier diagnosis and improvement in management. The presenting symptoms were lethargy and malaise (11 cases), jaundice (11), abdominal pain (9), and deteriorating school performance (4). At diagnosis, all fatal cases had jaundice and ascites, while only one of the 6 survivors had ascites and two had jaundice. Evidence of hemolysis was found in 3 fatal cases and 5 survivors. Serum bilirubin concentrations, aspartate transaminase, and prolongation of prothrombin time were significantly more abnormal in the fatal cases (p less than 0.01) as compared with the survivors. Cirrhosis was present in all fatal cases and in 2 of the 6 survivors. Wilson's Disease must be excluded in children presenting with frank liver disease as well as those with hemolytic anemia, persisting lethargy, abdominal pain, or deteriorating school performance.
6641205##1983-11-1##Computed tomography in hepatolenticular degeneration (Wilson's disease).##Fifteen cases of hepatolenticular degeneration have been studied by means of computerized cranial tomography (CT). The common abnormalities were hypodense areas in the regions of the basal ganglia, in 9 cases; ventricular dilatation, in 7 cases; cortical atrophy, in 5 cases and brain-stem atrophy, in 4 cases. CT abnormalities were most common and most marked in patients with neurological presentations, but 1 of 3 asymptomatic patients discovered by the genetic screening of the affected family had hypodense areas in bilateral lenticular nuclei.
6678448##1983-11-1##[Wilson's disease].##
6888480##1983-10-13##Hypoparathyroidism in Wilson's disease.##An 11-year-old girl with Wilson's disease presented with mild hypocalcemia (8.0 mg per deciliter), hypophosphatemia (2.7 mg per deciliter), hypercalciuria (569 mg per day), and hyperphosphaturia (tubular reabsorption of phosphate, 67 per cent). The hyperphosphaturia and hypercalciuria were attributed to the Fanconi syndrome, a known component of Wilson's disease. Circulating immunoreactive parathyroid hormone was usually undetectable or, occasionally, detectable at minimal levels in the presence of depressed blood levels of ionized calcium. Normal levels of ionized calcium were not maintained throughout a 24-hour monitoring period. The patient had tetany during a period of rapid reduction in ionized calcium levels, and an appropriate rise in circulating immunoreactive parathyroid levels was never demonstrated. Induced hypocalcemia during citrate infusion did not stimulate parathyroid secretion, nor did infusion of magnesium. We conclude that parathyroid insufficiency may be associated with Wilson's disease. We speculate that it is due to deposition of copper in the parathyroid glands.
6659902##1983-10-1##Hepatolenticular degeneration: histological study of conjunctiva and observation of chalazii during D-penicillamine treatment.##Three patients with hepatolenticular degeneration (Wilson's disease) are described. Bilateral blepharoconjunctivitis and Kayser-Fleischer ring was observed in all 3 patients. In 2 patients, long-lasting, bilateral chalazii appeared during chronic treatment with D-penicillamine. Histochemical and ultrastructural studies of pre-treatment conjunctival biopsies showed no copper storage in the tissue thus supporting the hypothesis that copper storage in Descemet's membrane derives from the anterior chamber.
6688520##1983-10-1##Copper distribution in Wilson's disease.##
6639990##1983-10-1##[Isolation and physico-chemical properties of rat ceruloplasmin].##Ceruloplasmin was isolated and purified from albino rat blood serum. Relative molecular mass of the protein is 130 000. Electrophoresis of the protein preparations leads to a formation of the apo-protein devoid of the oxidase activity and migrating slower than the holo-protein. Leucine was found to be the N-terminal amino acid of the ceruloplasmin polypeptide chain. The amino acid composition and carbohydrate content of the protein were determined. The tryptic peptide maps of rat ceruloplasmin were compared to those of human protein. The properties of rat and human ceruloplasmin are discussed with respect to copper metabolism in animal body as well as in normal humans and patients with Wilson's disease.
6647936##1983-9-15##[Tubule function in Wilson's disease].##
6614689##1983-9-1##Treatment of Wilson's disease.##
6614680##1983-9-1##Oral zinc therapy for Wilson's disease.##Wilson's disease is an inherited disorder of copper accumulation that is fatal if untreated. Because penicillamine, the established treatment, is toxic in a substantial number of patients, we studied the efficacy of zinc treatment. We induced a negative or neutral copper balance in five out of five patients with Wilson's disease who were receiving no therapy other than zinc. Zinc acetate was given every 4 hours during the day, and the patient was not allowed to eat for 1 hour before and 1 hour after each dose. Oral zinc therapy, used according to our regimen, may now be considered in the treatment of patients with penicillamine intolerance. However, it is premature to convert patients to zinc therapy if they tolerate penicillamine well. The efficacy of zinc therapy in the initial removal of the copper burden in acutely ill patients with Wilson's disease has not yet been evaluated.
6618439##1983-9-1##Hypouricemia and hyperuricosuria as expressions of renal tubular damage in primary biliary cirrhosis.##Renal tubular damage, in particular, renal tubular acidosis is associated with primary biliary cirrhosis (PBC), but hypouricemia has not been described. We studied four patients with PBC whose serum uric acid levels were 1.4 to 1.8 mg per dl, and compared their renal and liver functions with those of 11 patients with PBC whose serum uric acid levels were normal. In the patients with PBC and hypouricemia, uric acid clearance (Cua) and the ratio of Cua and creatinine clearance (Cua/Ccr) were high enough to cause hypouricemia. Elevated Cua/Ccr was suppressed by administration of pyrazinamide, a blocker of tubular secretion of uric acid, but was not affected by probenecid; the effects of drugs on Cua/Ccr were similar to those reported in Wilson's disease. Elevation in Cua/Ccr was associated with increased serum bilirubin and urinary copper excretion. These observations indicate that hypouricemia and hyperuricosuria, which may be caused by defective postsecretory reabsorption of uric acid, are additional indicators of renal tubular damage in PBC.
6643000##1983-9-1##CT scan in a case of progressive generalized dystonia with amyotrophic paraplegia.##In a case characterized by progressive generalized dystonic paraplegia with amyotrophy and mental deficiency, CT scanning shows a bilateral lenticular nucleus hypodensity. A similar picture can be found in Wilson disease. However, this patient presented no biochemical, hepatic or ocular abnormalities.
6632716##1983-9-1##[Acute hemolysis and liver cirrhosis as leading symptoms of Wilson's disease in childhood].##Acute hemolytic anemia and the development of liver cirrhosis with ascites 3 month thereafter suggested Wilson's disease in a 12 years old child, which was confirmed by inappropriate copper metabolism. In addition, neurological symptoms and renal tubular insufficiency characterized the early stage of the disease.
6616879##1983-8-31##Isolation and purification of ceruloplasmin in oculocutaneous albinism, Menkes' disease, Wilson's disease and pregnant women.##A method is reported for isolation and purification of human ceruloplasmin and apoceruloplasmin from serum. It involves a rapid and mild procedure by ion exchange chromatography on DEAE-Sephacel using a pH and ionic strength concave gradient. It was applied to serum of patients with oculocutaneous albinism, Wilson's disease, Menkes' disease and pregnant women. The ceruloplasmin obtained by this method is undegraded, and homogeneous by physico-chemical and immunochemical analysis.
6354212##1983-8-30##[Comparison between immunofluorescent aspects of chronic HBsAG+, HBAG-hepatitis and some cases of chronic toxic-dismetabolic liver diseases].##In the study the aspects noticed on hepatic biopsies by I.F. in HBsAg+ and HBsAg- chronic hepatitis and in some cases of hepatitis on dismetabolic basis in Wilson's disease are compared. Great differences occurred between HBsAg+, HBsAg- and the Hepatitis in Wilson disease. In fact in the first case reactivity is often present due to immunological phenomena (presence of IgG immunocomplexes and autoantibodies) while in Wilson's disease these aspects are not found confirming the hypothesis that in the latter case is a question of an exclusively toxic damage.
6307837##1983-8-1##Wilson's disease and hepatocellular carcinoma: possible protective role of copper.##A male patient with Wilson's disease developed a hepatocellular carcinoma after treatment for nine years with D-penicillamine. Examination at necropsy showed that excess liver copper had been effectively removed. As copper has been shown to protect against chemically induced hepatocellular carcinoma in rats, this may be the reason for the extreme rarity of hepatocellular carcinoma in patients with Wilson's disease and possibly in other liver diseases with hepatic copper overload.
6620327##1983-8-1##Evaluation of segregation ratio in Wilson's disease.##Two problems relating to segregation analysis for Wilson's disease are discussed and a practical solution is presented. A problem in the ascertainment of families with Wilson's disease is illustrated by comparing segregation ratios calculated by the single selection, complete truncate, and multiple incomplete selection methods. The effect on the segregation ratio of exclusion from the analysis of those sibs who had died of other diseases at a young age is also discussed and a method of adjustment of the number of the affected using the data on age at onset is proposed. The segregation ratio by multiple incomplete selection (Weinberg proband method) after adjustment for those sibs who had died of other diseases was 0.243, consistent with the theoretical value for autosomal recessive inheritance. The segregation ratio calculated by the single selection method tended to give a lower value, while that calculated by the complete truncate method was greater than the theoretical value. Recessive inheritance is, however, supported. The actual effect of exclusion of those sibs who had died of other diseases on gene frequency estimation is shown to be very small.
6409288##1983-7-30##Wilson's disease: a diagnostic dilemma.##A 13 year old boy presented with headache, sore throat, myalgia, and fever and subsequently developed haemolytic anaemia and acute liver failure. Wilson's disease, a rare cause of acute liver failure, was diagnosed at necropsy. In such cases Wilson's disease must be diagnosed at an early stage for treatment to be effective. The most reliable indications are increased urinary and hepatic copper concentrations.
6134912##1983-7-2##Pancreatic distortion due to splenomegaly in Wilson's disease.##
6306058##1983-7-1##Calcium pyrophosphate dihydrate deposition in the intervertebral discs in a case of Wilson's disease.##The vertebral column from a known case of Wilson's disease (hepatolenticular degeneration) was examined by radiological, histological, histochemical and x-ray microanalytical techniques which demonstrated the presence of focal depositions of calcium pyrophosphate dihydrate (CPPD) in the intervertebral discs. These deposits were present in both the annulus fibrosus and the nucleus pulposus but in certain discs the deposits were concentrated near the interface between disc and vertebral body bone endplates. At these sites there was new bone formation with narrowing of the discs, irregularity and sclerosis of the bone endplates and exostosis.
6196633##1983-7-1##Studies in pancreatic secretion: VIII. Pancreatic function in patients with Wilson's disease.##
6612070##1983-7-1##[Wilson's disease: an unusual case].##
6409733##1983-7-1##[The cerebral lesions in Wilson's disease on computer tomography].##M. Wilson is often being mistaken as such for several years and kept for psychosis or another extrapyramidal disease. When the disease causes neuro-psychiatric symptoms a certain part of cases shows typical lesions in CT mainly affecting the Nucleus lentiformis and frontal cortex. From our own material two cases of M. Wilson are shown and compared with two other cases with identical patterns of lesions following toxic and hypoxic brain damage.
6613522##1983-6-1##3 years of continuous oral zinc therapy in 4 patients with Wilson's disease.##A competitive relationship exists between copper and zinc: among other effects, excessive dietary zinc is known to decrease the absorption of copper from the gastro-intestinal tract. The purpose of this study is to investigate the effectiveness of oral zinc therapy in 4 patients with Wilson's disease, who, during a 3-year period, took zinc as their only medication to influence their copper metabolism. Physical examinations, oral 64Cu loading tests, plasma concentrations of copper, zinc and ceruloplasmin, and the urinary copper excretion were used to monitor the effect of therapy. The dosages used ranged from 3 x 100 to 3 x 400 mg zinc sulphate per day. The clinical and biochemical results of the oral zinc therapy were good in all 4 patients and no toxic side-effects were seen. Our conclusion from this study is that oral zinc may well be a low toxic alternative to D-penicillamine in the treatment of Wilson's disease.
6621130##1983-5-14##[Acute hemolytic anemia in a case of Wilson's disease without other symptoms].##
6306820##1983-5-5##[Chronic hepatic encephalopathies. Acquired cerebral degeneration not due to Wilson's disease].##We report on 4 cases of perennial hepatic encephalopathy and review similar published cases. The neurological picture consists of a cerebellar syndrome, both static and kinetic, dysarthria, choreo-athetoid abnormal movements and mental deterioration. Symptoms are permanent and usually worsen progressively. Some patients may present with a myelopathy, either isolated or combined with an encephalopathy. Relevant anatomical alterations, either encephalic or spinal, may be observed similarly in several varieties of liver disease, but in every case the role of portocaval shunts, whether spontaneous or surgically performed, appears essential. Altered results of laboratory studies, such as EEG or ammonemia, are described. Histological changes include a peculiar sort of hyperplasia of the protoplasmic astrocytes, along with a certain amount of neuronal loss. Surmised pathological mechanisms and applied therapy are briefly reviewed. For an appraisal of therapeutic results, perennial hepatic encephalopathies should be set apart from both the acute varieties and the usual chronic variety with its succession of recurrent exacerbations and remissions.
6410762##1983-5-1##Computed tomography of Wilson disease.##Computed tomography (CT) was performed on 25 patients with Wilson disease (hepatolenticular degeneration). The diagnosis was confirmed biochemically. CT was normal in seven patients, five of whom presented clinically with the hepatic form of the disease. In 10 patients, CT abnormalities were graded as mild: there were atrophic changes around the basal ganglia and in the cortex and cerebellum. In eight patients, besides areas of atrophy there were low absorption areas subcortically in the frontal lobi and in the cerebellar hemispheres, as well as brainstem atrophy. Hypodense lesions in the lentiform nucleus and the area of the dentate nucleus were also noted, although mathematical analysis in terms of decrease of Hounsfield units failed to demonstrate significant differences from normal values.
6646324##1983-5-1##[Ceruloplasmin and copper in the serum of patients with amyotrophic lateral sclerosis (ALS)].##The serum level of ceruloplasmin and copper were determined in 14 patients with ALS, 9 with Wilson's disease and 10 with other brain diseases. The enzyme level in 8 patients with ALS (57%) was decreased, similarly as in 8 with Wilson's disease (89%), and 2 (20%) in the control group. The mean ceruloplasmin level in the group of patients with Wilson's disease was 50% that in ALS patients. The copper level was decreased in only 1 ALS patient and 1 in the control group, while in patients with Wilson's disease it was low in 8 cases. These changes may be an effect as well as a cause of motor neuron disease.
6839983##1983-4-22##[Acute liver failure in abdominal Wilson's disease in early adulthood].##The acute abdominal form of Wilsons's disease was observed in three female patients aged 17, 18 and 30 years. Clinically uncharacteristic general symptoms and jaundice were dominant. Chemical pathology showed high bilirubin values with predominance of direct bilirubin, signs of hepatic and renal insufficiency and haemolytic anaemia. There were no neurologic symptoms and the Kayser-Fleischer ring was absent. Coeruloplasmin in blood was normal, copper concentration in blood and urine was clearly increased. Diagnosis of Wilsons's disease could only be established at post mortem by quantitative copper estimation in liver tissue. The patients succumbed 1--4 weeks after onset of symptoms through hepatic failure.
6406995##1983-4-12##[2 storage diseases: Fabry disease and Wilson disease].##
6222087##1983-4-1##Penicillamine: review and cutaneous manifestations.##D-Penicillamine, a heavy metal chelator used in the treatment of Wilson's disease and other conditions, may be associated with both noncutaneous and cutaneous side effects. Some of the cutaneous lesions are due to a toxic-metabolic effect on connective tissue; some may be explained on the basis of autoimmunity; some are acute sensitivity reactions, and some are secondary to unknown mechanisms. The types of cutaneous manifestations may, in some instances, be correlated with the disease being treated and the dosage and duration of penicillamine therapy.
6842414##1983-4-1##The effect of chelation therapy on the amino aciduria and peptiduria of Wilson's disease.##1. There is an excess urinary output of free amino acids and of urinary peptides in most cases of untreated Wilson's disease. Studies of 11 patients have shown that both these abnormalities are greatly improved by two years of standard chelation therapy. 2. The reduction in excretion of both free amino acids and peptides is purely quantitative, there being no significant change in the percentage composition of amino acids, either free or combined, in relation to their total urinary output. 3. Arguments are advanced that the peptiduria of the disease is usually due to a proximal renal tubular reabsorption defect, but in rare cases it may be due to excess bone breakdown or even to a combination of bone and renal tubular disease in the same patient.
6855139##1983-3-1##[Tyrosinosis with hepatolenticular degeneration (Wilson's disease)].##A 23-year old man had suffered since the age of one year from recurring pain and reddening of one or both eyes. Additionally, striated compaction in the corneal epithelium and at the level of Bowman's membrane was observed while he was still a child. A corneal lattice dystrophy was therefore suspected, even though there was hereditary reason for it. The disease was subsequently identified clinically and serologically as Richner-Hanhart syndrome, accompanied in this patient by hepatolenticular degeneration (Wilson's disease) with a Kayser-Fleischer corneal ring.
6634446##1983-3-1##[True hepatic Wilson's disease].##Fourteen cases of Wilson's disease, 9 of which in pure hepatic form are presented. Earliest clinical sign of liver disease was hepatosplenomegaly with altered indexes of hepatic function. The disease was found in 4 couples of brothers and sisters of families reported. For all cases diagnosis was based on the values of ceruloplasmin, serum copper, basal urine copper and urine copper after D-penicillamine. Furthermore in 8 cases very increased copper concentration in the liver was demonstrated. D-penicillamine therapy produced hepatic improvement in 8 cases, 6 of which affected by only hepatic form and the treatment was fairly tolerated. In 1 case this therapy caused nephrotic syndrome it was replaced with Trien-2HCL. Wilson's disease in its pure hepatic form must be considered in the differential diagnosis of liver diseases in pediatric age, especially when markers of viral hepatitis are absent. The identification of pure hepatic form provides early diagnosis of Wilson's disease, basic requirement for an effective therapy.
6634443##1983-3-1##[Differential diagnostic problems in acute and chronic hepatitis and hepato-cholangiographies of various etiologies in childhood].##The necessity is emphasized to perform always a careful anamnesis and a clinical inspection of patients before achieving laboratory examinations (avoiding to demand to a &quot;check up&quot; the diagnosis). This is particularly important in those diseases, like viral hepatitis, which become even more frequent, so that such diagnosis may be supposed basing on unreliable laboratory findings. The possibility is mentioned that different hepato-colangiopathies (Wilson's disease, intolerance to fructose, hepatic congenital fibrosis, hepatic ductal hypoplasia, granulomatous hepatitis, bacterial, micotic and protozoarian cholangitis, liver sufference in onchologic diseases) may simulate viral hepatitis.
6856918##1983-2-28##[Acute hemolytic anemia as a manifestation of Wilson's disease].##
6870474##1983-2-1##[The thirteen christmas' desserts. Unexpected disclosure of Wilson's disease].##
6826837##1983-2-1##Asymptomatic carrier state in Wilson disease.##
6826826##1983-2-1##Nuclear magnetic resonance (NMR) imaging in Wilson disease.##Nuclear magnetic resonance (NMR) scans of the head and liver were obtained in 13 patients with Wilson disease, and the results were compared with computed tomography (CT). Twelve age and sex matched normal controls were also scanned with NMR. The subjects were scanned using repeated free induction decay (RFID), inversion-recovery (IR), and spin-echo (SE) sequences. The IR scans of the brain provided excellent anatomical localisation while SE scans highlighted pathological areas. Within the brain, NMR demonstrated abnormalities in two patients with normal CT scans. More extensive involvement was shown with NMR in three additional cases. In the liver, NMR and CT showed similar abnormalities of morphology. T1 values were within the normal range in all cases, including three patients with high liver copper levels at the time of NMR examination.
6858775##1983-1-1##Some therapeutic observations in Wilson's disease.##
6830156##1983-1-1##CT manifestation of cerebral white matter lesion in Wilson disease.##
6846733##1983-1-1##Serial changes of cranial computerized tomographic findings in Wilson disease during D-penicillamine therapy.##Serial changes of cranial CT findings were studied in three siblings with Wilson disease during the course of D-penicillamine therapy. The older two cases with neurological presentation revealed low density areas in the region of the basal ganglia on the CT scans performed before treatment. Mild cortical atrophy and mild enlargement of the lateral and the third ventricles were also observed. The chelating therapy resulted in a considerable improvement of neurological symptoms and disappearance of Kayser-Fleischer rings. The low density areas of the basal ganglia disappeared. However, cortical atrophy and an enlargement of the ventricles were still present. In an asymptomatic girl, the cranial CT scans remained normal after chelating therapy. The cranial CT scan is considered to be of great use both in diagnosis and observation of the clinical course in Wilson disease, and it is also of prognostic value.
6847842##1983-1-1##Diagnosis of Wilson's disease presenting as fulminant hepatic failure.##The clinical course, results of standard laboratory tests, parameters of copper metabolism, and hepatic morphology in 9 cases (3 of our own and 6 from the literature) of Wilson's disease presenting as fulminant hepatic failure were compared with the findings in 5 cases of idiopathic fulminant hepatic failure. Patients with Wilson's disease were usually younger, and 7 of the 9 patients had Kayser-Fleischer rings. Patients with idiopathic fulminant hepatic failure had elevated 24-h urinary copper, decreased ceruloplasmin, and low or normal serum copper. Fulminant hepatic failure with Wilson's disease differed from idiopathic fulminant hepatic failure by the following biochemical findings: (a) higher copper levels in serum, urine and liver; (b) less pronounced elevations of transaminase levels; (c) higher concentrations of total bilirubin; and (d) lower hemoglobin values. Serum copper was the most useful biochemical test in diagnosing Wilson's disease before death. At autopsy, only hepatic copper concentrations clearly separated the two groups. Serial serum copper levels (antemortem) and quantitative analysis of hepatic copper (after recovery or postmortem) in patients with fulminant hepatic failure should help to exclude Wilson's disease.
6413775##1983-1-1##Hudson memorial lecture: Wilson's disease: genetics and biochemistry--their relevance to therapy.##
6889406##1983-1-1##The treatment of sickle cell anemia and Wilson's disease with zinc.##
6361779##1983-1-1##Biological roles of ionic zinc.##We tentatively conclude from our work that intracellular calcium acts as a second messenger to affect membrane function through activation of calmodulin. This activation, if too great, leads to pathological erythrocyte adherence and aggregation phenomena. We have shown that calmodulin inhibitors can prevent some of these calcium-induced abnormalities. Since some of this work involves a very specific anticalmodulin antibody, it appears very likely that calmodulin is involved in producing membrane effects. Zinc appears to act upon the membrane in part, at least, through the inhibition of calmodulin action. Our work leads us to believe that zinc regulates copper absorption from the gastrointestinal tract in a somewhat complex manner. That is, direct zinc-copper antagonism within the lumen of the gastrointestinal tract is not adequate to explain the effects of zinc on inhibiting copper absorption in man. It appears from our work that tissues must become loaded with zinc before an effect on copper absorption is observed. This produces a lag effect during which zinc administration does not produce a negative copper balance. However, after this lag effect, zinc has produced a negative to neutral copper balance in 5 of 5 Wilson's disease patients studied. At this time, therefore, we believe that zinc therapy can be offered as an alternative to penicillamine therapy in previously decoppered patients or patients who are not yet symptomatic. However, we recommend that this therapy only be used at this time in accordance with the one zinc therapy regimen we have tested.
6658398##1983-1-1##Penicillamine-induced dermatomyositis. A case history.##A 69-year-old woman with classical rheumatoid arthritis developed a severe dermato-myopathy during treatment with penicillamine. Remission occurred on withdrawal of the drug. Penicillamine (dimethylcysteine) is a pharmacological agent used for its chelating properties in the treatment of Wilson's disease and heavy metal poisoning, and in cysteinuria because of soluble disulphide formation. Within the last 17 years penicillamine has been increasingly applied in the treatment of rheumatoid arthritis, the mechanism of action still being unknown. A great number of side effects have been reported, including less common auto-immune disorders such as drug-induced systemic lupus erythematosus, myasthenia gravis and polymyositis. These and other possible side effects have been well reviewed by others (1, 2). To our knowledge only a few earlier cases of dermatomyositis as a complication to penicillamine treatment of rheumatoid arthritis have been reported (3, 4, 5). We describe here another case.
6687321##1983-1-1##Wilson's disease in one identical twin and treatment by triethylene tetramine 2HCl in another case.##
6216862##1982-12-1##Multiple side effects of penicillamine therapy in one patient with rheumatoid arthritis.##Skin rashes, proteinuria, systemic lupus erythematosus, polymyositis and myasthenia gravis have all been recorded as complications of penicillamine therapy in patients with rheumatoid arthritis. A patient who had developed all 5 is now described. The skin lesion resembled elastosis perforans serpiginosa, which has been reported as a rare side effect in patients with Wilson's disease but not in patients with rheumatoid arthritis treated with penicillamine.
7172963##1982-12-1##D-penicillamine in Wilson's disease presenting as acute liver failure with hemolysis.##Wilson's disease in a young woman presenting with an acute course is described. The clinical manifestations were fulminant hepatic failure associated with marked intravascular hemolysis. Immediate D-penicillamine and high-dose steroid therapy did not influence the course of the disease. Necropsy revealed an increased hepatic copper content and cirrhosis with extensive necrosis of the liver.
7182431##1982-12-1##[Determination of copper in liver puncture samples in the diagnosis of Wilson's disease].##Wilson's disease, a hereditary disorder of copper metabolism, is characterized by excessive storage of this metal in several organs. Storage of copper in liver tissue is of great importance in diagnosis and therapy. By means of the combination of two methods - low-temperature ashing and flameless atomic absorption - the copper determination can be made even in smallest liver samples (needle-biopsy samples). It is therefore possible to perform a histological examination, as well as a quantitative copper determination on one puncture sample.
6188021##1982-12-1##Immunocytochemical identity of hepatocellular hyalin in alcoholic and non-alcoholic liver diseases.##Intracellular, eosinophilic, hyaline inclusions (alcoholic hyalin, Mallory bodies) are found in livers of patients with a number of hepatic disorders, although they are most common in alcoholic liver disease. Tissues from patients with primary biliary cirrhosis, jejunoileal bypass, hepatocellular carcinoma, Wilson's disease, and Indian childhood cirrhosis were all positive for hyalin by hematoxylin and eosin staining. Immunocytochemical labeling, using guinea-pig antiserum specific for alcoholic hyalin, was utilized to determine the extent of crossreactivity between hepatocellular hyalin in these various conditions. This antiserum bound to hyalin in fixed paraffin-embedded sections of all liver tissues studied as detected by indirect immunoperoxidase labeling. Binding to normal human liver, however, was restricted to light staining at the surface of hepatocytes. Preimmune guinea-pig serum did not bind to either normal liver or to the test tissues. Our results suggest that hyalin found found in a diverse group of liver conditions represents an immunologically related structure and that its formation may involve a common mechanism.
7177224##1982-11-20##[Hemolytic anemia associated with severe liver insufficiency as an initial symptom of Wilson's disease].##
7125987##1982-10-1##Effective treatment of Wilson's disease with oral zinc.##
7180077##1982-10-1##[Pathobiochemistry of Wilson's disease].##
6815376##1982-9-15##Long-term management of inherited renal tubular disorders.##In inherited renal tubular disorders with isolated defects of tubular transport medical treatment is usually either not indicated or is simple and effective. In some inherited metabolic disorders with complex defects of renal tubular transport a specific therapy is known. For example, in galactosemia and hereditary fructose intolerance crude products may be restricted or in cases of Wilson's disease copper stores may be reduced. In idiopathic Fanconi syndrome, cystinosis, oculocerebrorenal syndrome and glycogenosis Fanconi-Bickel, a symptomatic replacement treatment based on supplementation of water, electrolytes and vitamin D has improved the non-uremic survival of these patients considerably within the last 20 years. For long-term management of inherited renal tubular disorders, treatment of tubular dysfunction, chronic renal failure, and involved extrarenal organs must be supported by genetic counseling and assistance for social integration.
7114265##1982-9-11##A comparison of copper-loading disease in Bedlington terriers and Wilson's disease in humans.##Eleven Bedlington terriers were found to have a mean hepatic copper concentration of 6,321 micrograms/g dry wt (normal, 200 micrograms/g dry wt) and renal copper concentration that was three or four times normal. Brain copper levels were normal in younger dogs, were elevated in two older dogs, and were 100 times normal in one dog that died of the disease. Increased concentrations of copper in the liver, kidney, and brain also characterize Wilson's disease. Erythrocyte survival was normal in three affected dogs, but serum glutamic-pyruvic transaminase levels were usually elevated. Unlike the hypoceruloplasminemia of patients with Wilson's disease, plasma ceruloplasmin activity was not only normal but was also slightly elevated in the terriers. Despite their normal or excessive ceruloplasmin, the Bedlington terriers could convert ionic 64Cu to radioceruloplasmin but did so only very slowly. These dogs accumulated significantly more 64Cu in their livers than normal, much like patients with Wilson's disease do before symptoms develop.
6753725##1982-9-1##Prenatal and postnatal diagnosis of diseases of copper metabolism.##Menkes' kinky hair disease can be successfully diagnosed both prenatally and postnatally using cultured skin fibroblasts derived from the patient or amniotic fluid cells from the affected fetus. Determination of intracellular copper concentration under normal and copper loaded conditions, as well as examination of the kinetics of copper retention may be necessary for diagnosis. At present, cell culture techniques have been proven to be applicable for postnatal diagnosis of Wilson's disease. More investigation is necessary to determine whether or not the present method for prenatal diagnosis of this disease is possible.
6817993##1982-9-1##Roentgenologic study of 41 cases of Wilson's disease.##
7169171##1982-9-1##[Abnormal platelet function in Wilson's disease].##
6290431##1982-9-1##Histochemical studies of fibroblasts from patients with Menkes kinky hair disease and Wilson's disease.##Cultured fibroblasts from Menkes kinky hair disease patients showed markedly reduced succinate dehydrogenase and amine oxidase activities. Cytochrome oxidase activity, however, was greatly reduced in some cells and almost normal in others. Cultured fibroblasts from patients with Wilson's disease showed moderately reduced succinate dehydrogenase and cytochrome oxidase activities. Amine oxidase activity was only slightly reduced when compared to that of normal. These results indicated that the histochemical phenotype observed in fibroblasts from patients with Menkes kinky hair disease and Wilson's disease were distinctly different from each other and from normal fibroblasts.
6184593##1982-9-1##Immunocytochemical identification of caeruloplasmin in hepatocytes of patients with Wilson's disease.##Decreased serum caeruloplasmin levels in patients with Wilson's disease have been attributed to decreased caeruloplasmin synthesis in the hepatocyte. An immunoperoxidase procedure was used to identify caeruloplasmin in liver biopsies. The pattern of staining in biopsies from patients with Wilson's disease did not differ from the pattern seen in normal adult or neonatal liver. This indicates that immunoreactive caeruloplasmin is synthesized by the liver cell in Wilson's disease. Low serum levels of caeruloplasmin may reflect an abnormality of copper incorporation into the apoprotein or an abnormality of holocaeruloplasmin export.
6124819##1982-8-21##Penicillamine in Wilson's disease.##
6124753##1982-8-7##Pancreatic enlargement and Wilson's disease.##
7102519##1982-8-1##Fatal cardiac complications of Wilson's disease.##
6752690##1982-8-1##Screening asymptomatic family members for Wilson's disease.##
6755575##1982-8-1##[Wilson's disease. II].##
6124700##1982-7-31##Penicillamine in Wilson's disease.##
7088087##1982-7-29##Hepatic copper overload and features of Indian childhood cirrhosis in an American sibship.##We studied the clinical histories of four white American siblings who died at 41/2 to six years of age of an unknown form of cirrhosis, in an effort to identify the etiologic factors in this familial syndrome. The family history disclosed no Indian heritage or parental consanguinity. The children were born and raised in New Jersey. Each had been well until progressive lethargy, abdominal swelling, jaundice, and fever developed four to seven months before death. The liver histopathology in each case closely resembled that of Indian childhood cirrhosis and included severe panlobular liver-cell swelling with Mallory body formation, prominent pericellular fibrosis, &quot;micro-micronodular&quot; cirrhosis, and marked deposits of copper and copper-binding protein. Hepatic copper levels were as high as 2083 microgram per gram of tissue (normal, less than 50 microgram). A number of features distinguish this syndrome from Wilson's disease and familial cholestatic disorders of childhood. A genetically determined disturbance in copper metabolism appears to be the most likely cause.
6953259##1982-7-23##Acute lymphoblastic leukemia in a patient receiving penicillamine for Wilson's disease.##
7146516##1982-7-15##[Analysis of biochemical parameters in the diagnosis of Wilson's disease].##
7146515##1982-7-15##[Wilson's disease. Clinical study of 10 patients].##
7083739##1982-7-1##NMR imaging of the brain using spin-echo sequences.##Eight normal volunteers and 32 patients with a variety of neurological disease were studied with a nuclear magnetic resonance (NMR) scanner using repeated free induction decay (RFID), inversion-recovery (IR) and spin-echo (SE) sequences. The results were compared with X-ray computed tomography (CT). RFID sequences which produce images that reflect changes in proton density displayed very little grey-white matter contrast and relatively small changes in disease. IR sequences which produce images that are dependent on T1 showed a high level of grey-white matter contrast and demonstrated changes in a variety of pathological processes. Although SE scans, which have a strong T2 dependence, had shown no abnormality in previous studies of patients with neurological disease, sequences of this type with longer values of tau displayed abnormalities in cerebral infarction, haemorrhage, herpes encephalitis, multiple sclerosis, cerebral oedema, hydrocephalus, tumours and Wilson's disease. All of these conditions were associated with an increase in T2. Abnormalities were demonstrated in cases of multiple sclerosis and brainstem infarction with NMR scans where no abnormality was seen with CT. More extensive changes were seen with NMR in cases of hemisphere infarction, systemic lupus erythematosis, herpes encephalitis, hydrocephalus (periventricular oedema) and Sturge-Weber disease. The margin between malignant tumour and surrounding oedema was better defined with contrast enhanced CT in four of eight malignant tumours, equally well defined in one, and better defined with NMR in three cases. NMR spin-echo sequences provide a sensitive technique for detecting abnormalities in a variety of neurological disease.
7109772##1982-7-1##[Acute hemolytic anemia and liver insufficiency as the 1st manifestation of Wilson's disease].##
6753060##1982-7-1##[Wilson's disease. I].##
6123745##1982-6-26##Penicillamine in Wilson's disease.##
7169463##1982-6-1##Wilson's disease with associated diabetes mellitus presenting as renal tubular acidosis.##
7087389##1982-6-1##Wilson's disease. Electron microscopic, x-ray energy spectroscopic, and atomic absorption spectroscopic studies of corneal copper deposition and distribution.##The eyes from three patients with Wilson's disease and bilateral circumferential Kayser-Fleischer rings were obtained at autopsy. The cornea from one eye of each of the patients was divided into five anatomic regions--superior, inferior, medial, lateral, and central--and each area was examined by x-ray energy spectroscopy interfaced with transmission electron microscopy and by atomic absorption spectrophotometry. The cornea of the second eye was examined by light microscopy. Electron-dense granules, rich in copper and sulfur, were present in both the peripheral and the central region of the cornea but were more numerous at the periphery. The total copper concentration, determined by atomic absorption spectrophotometry, was high in both the peripheral and the central area of the cornea. The association of copper with sulfur suggests that a sulfur-containing moiety functions in binding copper. The distribution of the copper granules correlates with the clinical appearance of the Kayser-Fleischer ring, but no correlation exists between the total copper content and the Kayser-Fleischer ring. This suggests that sulfur-copper binding results in aggregation of copper granules and production of the first clinically detectable corneal lesion in Wilson's disease.
6215139##1982-6-1##[Electroencepalographic Study of 52 cases of wilson's disease].##
6122924##1982-5-15##Wilson's disease, an end to the search for new therapy?##
7105219##1982-5-1##[The significance of CT diagnosis in Wilson's disease].##
7108701##1982-5-1##Loss of accommodation and the near response in Wilson's disease.##
6121233##1982-4-3##Patterns of hepatocyte injury in man.##Three patterns of hepatocyte injury in man, direct, immunological, and cholestatic, are described. The characteristics of the direct pattern are predominantly mitochondrial damage, central (zone 3) necrosis, and, usually, fatty change. It can be subdivided into the alcohol type (also seen with obesity, in diabetes, as a reaction to perhexiline, in Wilson's disease, and in Indian childhood cirrhosis) and the Reye's syndrome type (also seen with tetracycline toxicity, fatty liver of pregnancy, and cytotoxic drugs). Reactive drug metabolites, metal poisoning, and anoxia are also associated with the direct pattern of hepatocyte injury. The immunological pattern is characterised by damage to cell membranes with piecemeal necrosis of periportal (zone 1) hepatocytes and mononuclear-cell infiltration. Examples include chronic active hepatitis, primary biliary cirrhosis, and drug reactions such as those to halothane. In the cholestatic pattern there is disturbance of the bile-secretory mechanism with retention of bile within the hepatocytes. Cholestatic liver injury may be intrahepatic, as in sex-hormone cholestasis, or extrahepatic, as in choledocholithiasis or carcinoma of the bile ducts. Identification of the type of hepatocyte injury is valuable in diagnosis, in assessing prognosis, and in selecting treatment.
7082716##1982-4-1##Zinc, the brain and behavior.##The total content of zinc in the adult human body averages almost 2 g. This is approximately half the total iron content and 10 to 15 times the total body copper. In the brain, zinc is with iron, the most concentrated metal. The highest levels of zinc are found in the hippocampus in synaptic vesicles, boutons, and mossy fibers. Zinc is also found in large concentrations in the choroid layer of the retina which is an extension of the brain. Zinc plays an important role in axonal and synaptic transmission and is necessary for nucleic acid metabolism and brain tubulin growth and phosphorylation. Lack of zinc has been implicated in impaired DNA, RNA, and protein synthesis during brain development. For these reasons, deficiency of zinc during pregnancy and lactation has been shown to be related to many congenital abnormalities of the nervous system in offspring. Furthermore, in children insufficient levels of zinc have been associated with lowered learning ability, apathy, lethargy, and mental retardation. Hyperactive children may be deficient in zinc and vitamin B-6 and have an excess of lead and copper. Alcoholism, schizophrenia, Wilson's disease, and Pick's disease are brain disorders dynamically related to zinc levels. Zinc has been employed with success to treat Wilson's disease, achrodermatitis enteropathica, and specific types of schizophrenia.
7123082##1982-4-1##[Clinical variability of Wilson's disease. Presentation of 4 cases].##
6121964##1982-3-20##Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride.##Twenty patients with Wilson's disease in whom severe penicillamine intolerance developed have been managed with the orally active chelating agent trientine dihydrochloride (trien). The stage of illness of the patients ranged from the presymptomatic through severe neurological or hepatic disease to the &quot;decoppered&quot; postsymptomatic cases. Trien has proved to be a safe and highly effective treatment both for reversing symptoms and for maintaining patients previously successfully decoppered with penicillamine. There has been evidence of depletion of the body stores of copper by trien coinciding with the clinical improvement. In most of the patients the toxic symptoms which forced a change of therapy were reversed on trien therapy; however, elastosis perforans did not seem to benefit, and two patients with penicillamine-induced systemic lupus erythematosus were not helped by the change. No other toxic signs or symptoms were observed. There was no evidence of teratogenicity either in animals or in the six patients who became pregnant while taking trien; all six infants have developed normally. Trien is a satisfactory alternative therapy for Wilson's disease; its usefulness, is however, severely limited by the lack of a product license.
6278604##1982-3-11##[Peritoneal dialysis for eliminating copper in patients with Wilson's disease (author's transl)].##We report a case of Wilson's disease, with a rapidly progressive course, in which peritoneal dialysis was performed. The physiopathology of acute features occurring during the course of the disease is reviewed. The different methods for eliminating copper, particularly peritoneal dialysis, are discussed. The authors recall the precautions which are necessary when initiating D-penicillamine therapy.
7064906##1982-3-1##The effect of oral copper loading and portasystemic shunting on the distribution of copper in the liver, brain, kidney, and cornea of the rat.##In Wilson's disease, redistribution of copper from the liver to extrahepatic tissue coincides with the development of liver disease and cirrhosis. We have considered the possibility that portasystemic shunting may be a factor determining the organ distribution of copper in patients with liver disease. Thirty-two Sprague-Dawley rats were randomized into a sham-operated group, and a group subjected to partial occlusion of the portal vein (PPVO). Half the rats in each group were fed on normal diet and the remainder had copper added to the drinking water. Rats subjected to PPVO developed large portasystemic shunts. Over a 3-month period, none of the groups showed an increase in serum copper concentrations, or copper oxidase levels. Liver and kidney copper concentrations were similarly increased in copper supplemented sham-operated and PPVO rats, but brain copper content in both groups was similar to the unsupplemented controls. In neither unsupplemented nor copper supplemented rats subjected to PPVO, was the organ distribution of copper different from sham-operated controls. This study suggests that portasystemic shunting does not alter the organ distribution, or tissue concentration of copper.
7064950##1982-3-1##Persistent transaminasemia and fatty liver. Their use in the diagnosis of presymptomatic Wilson's disease.##A 41/2-year-old asymptomatic girl with persistent elevated serum transaminase levels for eight months was found to have Wilson's disease. The diagnosis was suspected by the presence of fatty liver and nonspecific chronic hepatitis on liver biopsy and was proved by studies of copper metabolism, including determinations of serum ceruloplasmin and hepatic copper concentrations. Unexplained persistent transaminase elevation in children demand investigation by needle liver biopsy. Th presence of fatty liver and hepatitis should raise the possibility of Wilson's disease, which may then be confirmed by more specific tests. Advantages to early diagnosis include the institution of specific therapy and prevention of progressive liver disease.
7065120##1982-3-1##Inherited copper toxicosis in Bedlington terriers: Wilson's disease (hepatolenticular degeneration).##
7094098##1982-3-1##[Results of long-term therapy of Wilson's disease].##
7094095##1982-3-1##[Biochemical and clinical changes in heterozygotes for Wilson's disease].##
7068961##1982-3-1##D-Penicillamine--induced pemphigus syndrome.##D-Penicillamine is a chelating agent which is effective in the treatment of Wilson's disease, cystinuria, and lead poisoning. In recent years, it has also been used to treat patients with rheumatoid arthritis with good results. The adverse effects of D-penicillamine are many. These include loss of taste, nephrotic syndrome, lupus erythematosus--like syndrome, polymyositis, dermatomyositis, myasthenia gravis, and agranulocytosis. Beginning in 1969, D-penicillamine was reported to induce a pemphigus eruption. We present a patient with D-penicillamine--induced pemphigus erythematosus and review previously reported cases.
6275694##1982-2-1##Nuclear magnetic resonance imaging of the liver: initial experience.##Nuclear magnetic resonance (NMR) scans of the liver were obtained in 12 normal volunteers and 32 patients using a whole-body machine developed by Thorn-EMI Ltd., and the results were compared with x-ray computed tomography (CT). Two types of NMR scan, saturation-recovery and inversion-recovery, were performed in order to obtain values for the spin-lattice relaxation time, T1. Although the saturation-recovery scans show little soft-tissue detail, the inversion-recovery scans demonstrated the interlobar fissure, hepatic veins, portal veins, bile ducts, and gallbladder. In comparison with CT (Siemens Somatom 2), both types of NMR scan showed some blurring due to respiratory movement but much less linear artifact across the liver from the air-fluid interface in the stomach. Focal disease within the liver was demonstrated by both CT and NMR, although an area of focal atrophy and another of hepatic infarction were only recognized with NMR. In diffuse disease the pattern varied. In steatosis CT was virtually diagnostic, while NMR showed no specific features. In hemochromatosis, hepatitis, eight cases of cirrhosis, and one of Wilson disease, both techniques showed abnormalities of varying specificity. In two cases of cirrhosis and one of primary biliary cirrhosis, only the NMR scan was abnormal. Nuclear magnetic resonance images are now sufficiently anatomically detailed to permit serious comparisons with technically advanced computed tomography. The information revealed is fundamentally different and can be expected to have some diagnostic utility.
7059298##1982-2-1##Wilson's disease. Report of a case in a Nigerian.##
7058150##1982-1-30##[Copper pathology (author's transl)].##Copper is an essential dietary component, being the coenzyme of many enzymes with oxidase activity, e.g. ceruloplasmin, superoxide dismutase, monoamine oxidase, etc. The metabolism of copper is complex and imperfectly known. Active transport of copper through the intestinal epithelial cells involves metallothionein, a protein rich in sulfhydryl groups which also binds the copper in excess and probably prevents absorption in toxic amounts. In hepatocytes a metallothionein facilitates absorption by a similar mechanism and regulates copper distribution in the liver: incorporation in an apoceruloplasmin, storage and synthesis of copper-dependent enzymes. Metallothioneins and ceruloplasmin are essential to adequate copper homeostasis. Apart from genetic disorders, diseases involving copper usually result from hypercupraemia of varied origin. Wilson's disease and Menkes' disease, although clinically and pathogenetically different, are both marked by low ceruloplasmin and copper serum levels. The excessive liver retention of copper in Wilson's disease might be due to increased avidity of hepatic metallothioneins for copper and decreased biliary excretion through lysosomal dysfunction. Menkes' disease might be due to low avidity of intestinal and hepatic metallothioneins for copper. The basic biochemical defect responsible for these two hereditary conditions has not yet been fully elucidated.
6175159##1982-1-1##Advanced catecholaminergic disturbances in the brain in a case of Wilson's disease.##
7125490##1982-1-1##[Association of an uncombable hair syndrome and Wilson disease].##
7067951##1982-1-1##[Diagnostic value and meaning of radiocopper loading test abnormalities in Wilson's disease (author's transl)].##
7123703##1982-1-1##Treatment of a presymptomatic 14-year-old girl with Wilson's disease.##
7157667##1982-1-1##The cardiomyopathy of Wilson's disease. Myocardial alterations in nine cases.##Though myocardial alterations are well recognized in haemochromatosis, little attention has been paid to the cardiac changes in Wilson's disease. To define the extent of myocardial degeneration in newly diagnosed or chronically treated Wilson's disease, we reviewed the autopsy findings in 9 cases with this condition. We compared our observations with those in 3 control cases, selected for comparable age and with liver disease having no known association with cardiac degeneration. Our results revealed cardiac hypertrophy in 5 out of 9 cases of Wilson's disease. There was evidence of interstitial and replacement fibrosis, intramyocardial small vessel sclerosis and focal inflammatory cell inflammation to a variable degree in all cases. One case had AV nodal degeneration, and a 15 year old boy had severe atherosclerosis of the left main coronary artery. Two patients died suddenly, presumably secondary to an arrhythmia; one of these patients had the most marked myocardial alterations. We could not correlate these changes specifically with the tissue levels of copper, treatment with D-penicillamine, or the presence of cirrhosis. We conclude that there are definite morphological abnormalities in the hearts of patients with Wilson's disease consistent with a cardiomyopathy. Though the myocardial changes were non-specific, the fact that 2 patients died suddenly, suggests the need for a prospective study of cardiac function in these patients in the future.
7304799##1981-12-1##Dopamine beta-hydroxylase inhibition in a patient with Wilson's disease and manic symptoms.##The authors studied the effect of dopamine beta-hydroxylase inhibition on the manic symptoms of a 34-year-old man. They found that fusaric acid decreased the patient's manic symptoms and that his symptoms approximately reverted to their previous state when a placebo was reinstituted.
7348140##1981-12-1##[Dermatoglyphics and skin folds in Wilson's disease].##Dermatoglyphics and creases of 45 homozygous and 62 heterozygous carriers of the WILSON-gene found in 36 families of the GDR have been compared with a normal population (sufficient number, similar regional distribution). The results have been tested by statistical methods in order to check significance of the observed differences. In contrast to other publications interdigital ridge counts and creases of palmae, plantae and toes have been included into the evaluations. Some of our results differed from those published by other authors. The possible reasons are discussed.
7326565##1981-12-1##Wilson's disease. An analysis of the cranial computerized tomographic appearances found in 60 patients and the changes in response to treatment with chelating agents.##Sixty patients with Wilson's disease have been studied by means of computerized cranial tomography (CT). The findings are described and analysed with particular reference to their value, both diagnostic and prognostic, in the management of this disease. The commonest abnormalities were ventricular dilation, 73 per cent; cortical atrophy, 63 per cent; brain-stem atrophy, 55 per cent. Characteristic hypodense areas in the regions of the basal ganglia were present in 45 per cent and almost invariably these were accompanied by one or more of the other CT abnormalities. This combination of findings is considered specific for Wilson's disease in the appropriate clinical context. CT abnormalities were most common and most marked in patients with a neurological presentation, only 2 out of 40 having a normal scan. Similar changes were also demonstrated in three-quarters of the patients with an hepatic presentation and nearly half of those who were presymptomatic. Nineteen patients were scanned on more than one occasion to assess the influence of treatment with penicillamine or triethylene tetramine on the abnormalities recorded initially. Fourteen showed basal ganglia hypodensities on first scanning and in ten of these there was a moderate to marked improvement in this abnormality in response to therapy. Corresponding with this there was considerable clinical improvement. Despite the findings of quite severe CT abnormalities in patients with Wilson's disease. suggesting considerable loss of neurons, patients will still respond well to treatment. We conclude that although the CT. Examination of patients with Wilson's disease is of value both in diagnosis and management, it is of no great help in prognosis.
12263972##1981-12-1##Statement on intrauterine devices.##These policy statements and guidelines from the International Planned Parenthood Federation's (IPPF) International Medical Advisory Panel (IMAP) concern IUDs. The following contraindications to IUD use are recognized: 1) pelvic inflaminatory disease, 2) known or suspected pregnancy, 3) history of previous ectopic pregnancy, 4) gynecological bleeding disorders, 5) suspected malignancy of the genital tract, 6) congenital uterine abnormalities or fibroids distorting the cavity, and 7) anemia, blood coagulation, severe cervical stenosis, copper allergy, Wilson's disease, and others. Generalities regarding appropriate IUDs are: 1) non-medicated devices (e.g. Lippes Loop) are studied for women who may not return for regular check-ups, 2) smaller medicated devices usually cause less menstrual blood loss than the non-medicated devices, 3) smaller devices are better for a smaller uterus and larger devices for the larger uterus, and 4) when a smaller device is expelled it is advisable to try a larger one and vice versa. Dalkon Shields should not be used by the IPPF system and all women using them should have the device removed. Correct insertion of IUDs is important and should be done by properly trained personnel. The timing of insertion is best during the menstrual period. Withdrawal of the applicator while leaving the device in place is the recommended insertion technique. Sterilization of IUDs should follow instructions on bulk-packaged IUDs. Complications include perforation, bleeding and pain, infection, and ectopic pregnancy. IUD removal should be done during menstruation. Good clinical management and follow-up care are recommended.
7333829##1981-12-1##Computerized cranial tomography in Wilson disease: report of a case before and after penicillamine therapy.##A patient with Wilson Disease presenting neurologic signs was treated with d-Penicillamine. Computerized cranial tomography (CT) performed before therapy showed symmetrical areas of low density in the region of the basal ganglia, enlargement of ventricles and bilateral increased density of the medial nuclei of the thalamus. This abnormality of the thalamus had not been reported previously in Wilson disease. After two years therapy there was an evident clinical improvement and at the same time a reduction of CT abnormalities. The reports on CT scanning in Wilson disease are reviewed.
7338703##1981-12-1##An assessment of efficiency in potential screening for Wilson's disease.##The efficiency of screening for Wilson's disease by serum caeruloplasmin determination was assessed by analysing the epidemiologic data of 289 affected families in Japan. The estimated gene frequency was 5.2 x 10(-3). The sensitivity of the screening test was 93% at a proposed cut-off level of 120 mg/l and the specificity was 99.83%. In Japan 1 500 000 children are born every year of whom 50 would be expected to have Wilson's disease. The present analysis of potential screening for all children would grade three of them as false-negatives and identify 2621 as false-positives. An analysis for children only from consanguineous marriages produced a more efficient result, with a much higher predictive value of the positive and case-finding rate. Although the number of patients identified in this latter high-risk screening group was small, it is worth considering as a pilot study.
6459860##1981-12-1##[Wilson's disease - clinical analysis of 80 cases].##
7329147##1981-11-25##[Wilson's disease: seven cases with hepatic onset (author's transl)].##
7305707##1981-11-1##Late onset of Wilson's disease. Report of a family.##Five cases of Wilson's disease were diagnosed in a family of eight siblings. All of them had Kayser-Fleischer rings. The first neurologic symptoms appeared in one person at age 46 years; in another, psychotic symptoms appeared at age 38 years; and in one patient, jaundice was noted at age 40 years. Two other persons, aged 53 and 43 years, were still without hepatic, neurologic, or psychiatric symptoms of the disease at the time of writing. The family described is very atypical with regard to the age at onset of Wilson's disease.
7305706##1981-11-1##Computed tomography in Wilson's disease.##In a case of Wilson's disease with flapping tremor, computed tomography demonstrated bilateral low-density areas in the thalamocapsular regions. Computed tomographic findings in Wilson's disease are discussed.
7308845##1981-11-1##Hepatic copper in primary biliary cirrhosis: biliary excretion and response to penicillamine treatment.##Excessive hepatic copper accumulation occurs in long-lasting cholestatic liver disorders especially in primary biliary cirrhosis. As in Wilson's disease, penicillamine has recently been introduced for the treatment of primary biliary cirrhosis. In Wilson's disease there is decreased biliary excretion of copper. The present study shows that as compared with controls the biliary excretion of copper is not decreased in primary biliary cirrhosis; instead it may be increased in some patients. However, when compared with high hepatic copper concentration biliary copper excretion was low. In contrast with copper, biliary secretion of bile acids was decreased in eight of the 17 patients. Treatment with oral penicillamine (600 mg/day) for one year resulted in a significant decrease of hepatic copper concentration, but had no consistent effect on the biliary excretion of copper or on the amount of histologically stainable orcein-positive copper-binding protein. The results suggest that excessive hepatic copper accumulation in primary biliary cirrhosis may not be primarily caused by a decreased biliary excretion, or that a new equilibrium is achieved in advanced primary biliary cirrhosis. D-penicillamine appears to improve significantly the biliary excretion of bile acids.
7290956##1981-10-10##[A benign form of Wilson's disease].##
7316342##1981-10-1##D-penicillamine and the ocular myasthenic syndrome.##D-penicillamine is a potent drug used to treat rheumatoid arthritis, Wilson's disease and cystinuria. D-penicillamine has recently been found to cause myasthenia gravis in certain susceptible patients. We present a typical case of one patient who developed myasthenia while taking D-penicillamine. The withdrawal of D-penicillamine and the institution of short-term anticholinesterase therapy resulted in the resolution of this disease. The literature is reviewed and attention is focused on the point that all patients who developed myasthenia while undergoing D-penicillamine therapy had ocular symptoms.
6118185##1981-10-1##The inadvisability of neuroleptic medication in Wilson's disease.##The use of neuroleptic drugs in the management of a patient with Wilson's disease was examined from the clinical, pharmacological, and pathophysiological points of view. The weight of evidence suggests that the medication poses a threat to life in patients with this disease because of its masking effects, lack of therapeutic rationale, and adverse reactions. Difficulty in recognizing the biological basis of the behavior disorders and in differentiating between the dementia in the disease and schizophrenic psychosis is associated with the use of inadvisable medication. In order to facilitate early administration of specific treatment, a proper staging of the disease and the criteria for early diagnosis are proposed.
6797802##1981-10-1##Wilson's disease (hepatolenticular degeneration): clinical analysis of 80 cases.##
7309888##1981-10-1##Is copper hepatotoxic in primary biliary cirrhosis?##In primary biliary cirrhosis (PBC) liver copper retention occurs as a complication of cholestasis. By analogy with Wilson's disease, it has been suggested that copper retention is hepatotoxic in PBC, and this has been the rationale for the use of D-penicillamine in this disease. The hypothesis that copper is hepatotoxic in PBC has not been tested and in this study we have evaluated the role of liver copper retention in the pathogenesis of PBC. Sixty-four patients with PBC have been studied. Fifty-four had increased liver copper concentrations. Liver cell synthetic function was well preserved. All the patients had normal prothrombin times, and only two had subnormal serum albumin concentrations. There was no correlation between liver copper concentrations and the degree of liver cell damage assessed biochemically (aspartate transaminase), and histologically. Electron microscopy was performed on liver biopsies from five patients with markedly increased liver copper concentrations. The liver cell ultrastructure was compatible with cholestasis. Liver cells contained electron dense lysosomes, which were shown to contain copper and sulphur by x-ray probe microanalysis. The characteristic organelle changes associated with copper toxicity in Wilson's disease were not observed. The biochemical, histological, and histochemical differences between PBC complicated by liver copper retention, and Wilson's disease, indicates that there are differences in the handling of copper in these disease. In this study we could find no evidence to suggest that copper plays an important role in the pathogenesis of liver dysfunction in PBC.
7330868##1981-10-1##Cranial computerized tomography in a patient with Wilson's disease.##A 24-year-old female with Wilson's disease showed symmetrical low density zones on the cranial CT, which seemed to represent structural changes in the lentiform nuclei. Diagnostic and prognostic usefulness of CT in Wilson's disease was discussed.
7050883##1981-9-30##[Clinico-therapeutic study of a girl with Wilson's disease].##
7026114##1981-9-1##The use of birth control pills in women with medical disorders.##Since little absolute data exist in the form of large prospective studies in patients with specific illnesses who are on oral contraceptives, the clinician must rely on well-founded empiric decisions in prescribing the pill for these patients. The decision should be based on a firm understanding of the pathophysiology and laboratory effects of the oral contraceptives. This must be juxtaposed with an understanding of the efficacy and effects of the estrogen and progestational components of the birth control pill and their interactions with maintenance medications. In the final analysis, though, the clinician must rely on a trial and error method in treating these patients. It must be stressed, however, that these women require careful monitoring, both clinically and biochemically. It is comforting to note that in all diseases studied to date, the use of birth control pills has not precipitated a catastrophic change.</AbstractText>            </Abstract>            <AuthorList CompleteYN="Y">                <Author ValidYN="Y">                    <LastName>Decherney</LastName>                    <ForeName>A H</ForeName>                    <Initials>AH</Initials>                </Author>            </AuthorList>            <Language>eng</Language>            <PublicationTypeList>                <PublicationType>Journal Article</PublicationType>                <PublicationType>Review</PublicationType>            </PublicationTypeList>        </Article>        <MedlineJournalInfo>            <Country>UNITED STATES</Country>            <MedlineTA>Clin Obstet Gynecol</MedlineTA>            <NlmUniqueID>0070014</NlmUniqueID>            <ISSNLinking>0009-9201</ISSNLinking>        </MedlineJournalInfo>        <ChemicalList>            <Chemical>                <RegistryNumber>0</RegistryNumber>                <NameOfSubstance>Contraceptives, Oral</NameOfSubstance>            </Chemical>            <Chemical>                <RegistryNumber>0</RegistryNumber>                <NameOfSubstance>Contraceptives, Oral, Synthetic</NameOfSubstance>            </Chemical>        </ChemicalList>        <CitationSubset>IM</CitationSubset>        <CitationSubset>J</CitationSubset>        <MeshHeadingList>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Arthritis, Rheumatoid</DescriptorName>                <QualifierName MajorTopicYN="N">physiopathology</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Central Nervous System</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Contraceptives, Oral</DescriptorName>                <QualifierName MajorTopicYN="Y">adverse effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Contraceptives, Oral, Synthetic</DescriptorName>                <QualifierName MajorTopicYN="Y">adverse effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Depression</DescriptorName>                <QualifierName MajorTopicYN="N">physiopathology</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Digestive System</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Endocrine Glands</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Eye</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Female</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Hematopoietic System</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Humans</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Lupus Erythematosus, Systemic</DescriptorName>                <QualifierName MajorTopicYN="N">physiopathology</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Pregnancy</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Skin</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Urogenital System</DescriptorName>                <QualifierName MajorTopicYN="N">drug effects</QualifierName>            </MeshHeading>        </MeshHeadingList>        <NumberOfReferences>19</NumberOfReferences>        <OtherID Source="PIP">004543</OtherID>        <OtherID Source="POP">00089737</OtherID>        <OtherAbstract Type="PIP" Language="eng">            <AbstractText>There is little absolute data in the form of prospective studies in patients with specific illnesses who are on oral contraceptives (OCs). Consequently, the clinician must depend on well-founded empiric decisions in prescribing the pill for these patients. The basis for the decision should be a firm understanding of the pathophysiology and laboratory effects of OCs. This needs to be juxtaposed with an understanding of the efficacy and effects of the estrogen and progestational components of the birth control pill and their interactions with maintenance medications. Available evidence is reviewed for the following medical disorders: central nervous system disorders (depression, Wilson's disease, headaches, epilepsy, multiple sclerosis, and the eye); immunologic and connective tissue diseases; diseases of the endocrine system, the gastrointestinal system, the genitourinary system, the memopoietic system; and skin disorders. 7% of women on OCs have increased or newly reported depression. Whether these are primarily psychogenic or metabolically derived is yet to be definitively determined. Wilson's disease can be exacerbated by OCs because of increased plasma ceruloplasmin and increased absorption of copper from the gastrointestinal tract. Headaches can be either a vague or a specific symptom, such as migraines, but 1/3 of these patients will become worse on OCs. There is good evidence that the headaches are caused by falling estrogen levels. There is no good evidence that epilepsy, in general, becomes worse on OCs. OCs have relatively no effect on the longterm prognosis in multiple sclerosis. Increased corneal sensitivity has been observed with OC use, and this has usually presented an intolerance to the use of contact lenses. This is primarily the result of increased edema of the cornea and changing of its contour. By inference, OCs cause some basic universal changes in the immunologic system. OCs have been reported as a cause of a rare form of rheumatoid arthritis, but the Royal College reports a decrease in incidence of cell-mediated immunologic disease, specifically rheumatoid arthritis in its more familiar form. There is no evidence that OCs markedly influence thyroid disease, but they do markedly alter thyroid function testing. OCs do not produce a chronic addisonian state nor do they inhibit the ability of the adrenal-pituitary axis to respond to stress. OCs can be used in thyroid disease but with some caution in hypothyroid states. They should not be used in patients with Cushing's syndrome and are not recommended in patients with adenomas. In general, estrogen works as an irritant to the gastric mucosa, but there is no increase in peptic ulcer diseases associated with OC use, and the incidence of duodenal ulcer disease is decreased. The most striking liver disease seen with OCs is cholelithiasis. The incidence is increased 2-fold. OCs should not be prescribed for patients with chronic renal disease because of the vascular effects as well as the reported increased risk of urinary tract infection. The Royal College report has shown a decreased incidence of iron deficiency anemia in patients on OCs. Various skin changes have been reported in women using OCs. The most common of these is chloasma. In all the diseases studied thus far, the use of OCs has not precipitated a catastrophic change.
7043293##1981-9-1##[Severe motor disturbance syndrome in Wilson's disease successfully treated by a stereotaxic method].##
6793904##1981-8-1##Recurrent abdominal colic as the sole symptom of Wilson's Disease: case report.##
7196520##1981-8-1##CT in Wilson disease.##
6793799##1981-7-13##Plasma amine oxidases in Wilson's disease.##
6458426##1981-7-1##Penicillamine-induced dermal fragility in Wilson's disease (hepato-lenticular degeneration).##
6173791##1981-7-1##[Indicators of brain biogenic amine metabolism in various extrapyramidal disorders].##The authors describe the results of determinations of the main metabolites of dopamine (DA), serotonin (S) and noradrenaline (NA) in the cerebrospinal fluid (ventricular and lumbar) in patients with various extrapyramidal system diseases. A profound decrease was demonstrated in the concentration of homovanillic acid (HVA)--the end metabolite of DA in parkinsonism, reflecting damage to DA--containing pathways and reduced DA synthesis in basal ganglia. Treatment with L-DOPA raises considerably the HVA level in the cerebrospinal fluid evidencing increased DA metabolism in the brain during administration of its precursor L-DOPA. In torsion dystrophy a statistically significant difference was found in HVA concentrations in the ventricular fluid depending on the clinical manifestations of the disease. In the patients with local muscular rigidity HVA level was much lower than in patients with the hyperkinetic form of the disease. It is concluded that the character of changes in the cerebral dopaminergic systems differs phenotypically in the form of torsion dystonia. In hepatolenticular degeneration (Wilson's disease) the level of all studied metabolites was decreased, which could be an evidence of deficient cerebral metabolism of their precursors--amines. In cases of Huntington's chorea a low level of HVA was found in the ventricular fluid, reflecting decreased total amount of DA in the brain due to damage to the corresponding neurons. Absence of detectable changes in MHPG concentration (the main cerebral metabolite of NA) indicates that this amine plays a lower role than DA and S in the biochemical mechanisms of the pathogenesis of extrapyramidal motor disturbances. The obtained data are important for the understanding of the pathogenesis and for evolving therapeutic methods in extrapyramidal diseases.
7322363##1981-7-1##[Case of hepatic coma with neuropathological features of Wilson's disease].##
6945083##1981-6-1##The dental management of a partially edentulous patient suffering from hepatolenticular degeneration (Wilson's disease).##
6973662##1981-6-1##[Metabolic disorders and corneal changes (author's transl)].##The following inborn errors of metabolism may show corneal changes: A. Inborn errors of metabolism affecting the corneal epithelium: (1) familial dysautonomia, (2) tyrosinaemia type II, (3) Fabry's glycolipidosis. B. Inborn errors of metabolism affecting the corneal stroma: I. Localized amyloidosis (lattice dystrophy of the cornea), II. Defects in carbohydrate metabolism: (1) localized mucopolysaccharidosis (macular dystrophy of the cornea), (2) systemic mucopolysaccharides, (3) glycogen storage disease. III. Defects in lipid metabolism: (1) localized from (Schnyder's crystalline dystrophy), (2) systemic forms (hyperlipoproteinaemia, hypolipoproteinaemia, Lecithin-cholesterol acyl transferase deficiency, Wolman's disease, Gaucher's disease). IV. Combined defects in lipid and carbohydrate metabolism (mucolipidoses). V. Other inherited metabolic disorders: (1) aminoacidopathies (cystinosis, Wilson's disease, ochronosis, Chediak-Higashi syndrome), (2) hemochromatosis.
7265809##1981-6-1##D-penicillamine in pregnancy--to ban or not to ban?##The action of D-penicillamine on collagen can cause undesired side-effects in the treatment of cystinuria and Wilson's disease, it is on the other hand essential to the therapy of rheumatoid arthritis and scleroderma. Furthermore D-penicillamine can be potentially teratogenic, since it crosses the placental barrier. From the literature and our own observation of two pregnancies it is shown that among 87 pregnant women who received D-penicillamine 46 cases were treated during the whole period of pregnancy. Two infants from the latter group were found to have severe connective-tissue defects. We suggest that the dose of D-penicillamine in pregnant patients with cystinuria and Wilson's disease should be kept as low as possible. In the case of rheumatoid arthritis D-penicillamine should not be given during pregnancy.
6453806##1981-5-21##[Electromyographic study in extrapyramidal motor disorders].##Standardized patterns of examination were developed in order to differentiate the disorders of the extrapyramidal system by means of electromyography. Pathological muscle activity was registered by stationary electromyography during rest, maintained posture, directed movements and passive extremity-excursions. Telemetric electromyography using eight-channel-biotelemetry-equipment showed pathological patterns of innervation in movements which are connected with migration such as walking. Characteristic findings were acquired in parkinsonism, choreatic, torsion dystonic and athetotic syndromes, ballism, Wilson's disease and drug induced dyskinesia as well as other hyperkinetic syndromes. The electromyographic findings proved to be useful in objectifying and differentiating the insufficient clinical data.
7232175##1981-5-16##[Acute hemolysis and kidney failure disclosing Wilson's disease. Diagnosis and therapeutic indications].##
6166516##1981-5-1##Mallory bodies in alcoholic and non-alcoholic liver disease contain a common antigenic determinant.##An immunohistochemical technique is described for the detection of Mallory bodies (MBs) in paraffin sections of liver tissue. This is based on proteolytic digestion of sections before exposure to an antiserum which recognises a unique antigenic determinant in MBs. With the use of this procedure it has been shown in alcoholic liver disease, primary biliary cirrhosis. Indian childhood cirrhosis, Wilson's disease, diabetes mellitus, and hepatocellular cancer that the MBs found in these disorders contain this unique antigenic determinant. It is postulated, therefore, that the mechanism of formation of MBs is similar in liver diseases of diverse aetiology. In addition, it has been demonstrated that the immunohistochemical procedure is more sensitive than routine staining; MBs were detected in five out of 12 fatty livers by immunohistochemical and only in one by H and E staining. As MBs in fatty livers were not associated with polymorph filtration or fibrogenesis it is argued that MB formation is not an absolute prerequisite for the progression of acute to chronic liver disease.
7235197##1981-1-1##The &quot;lumpy-bumpy&quot; elastic fiber. A marker for long-term administration of penicillamine.##A 29-year-old woman with Wilson's disease developed dermolytic skin lesions 2 years after initiation of treatment with penicillamine. Eight years later, still on penicillamine therapy, striae appeared over both of her breasts. Biopsy of involved skin during the 10th year of treatment with penicillamine revealed characteristic lumpy-bumpy alterations of dermal elastic fibers which were not present in the first skin biopsy 8 years previously. Biopsy of a stria showed changes similar to those in the dermolytic skin lesions. Lumpy-bumpy elastic fibers are pathognomonic for penicillamine-induced elastosis. They are easily recognizable with examination by conventional microscopy. Their appearance may serve as a warning of potentially serious, widespread elastic tissue involvement. These abnormal elastic fibers are not only found in the skin, but also in the lungs.
6940079##1981-4-1##Pemphigus-like mucosal lesions: a side effect of penicillamine therapy.##A patient with Wilson's disease on long-term penicillamine therapy was seen for evaluation and management of chronic persistent debilitating stomatitis, which was subsequently determined to be cytologically and histologically consistent with pemphigus vulgaris. A brief review of the pertinent literature disclosed that the dermatologic lesions of pemphigus secondary to penicillamine are alleviated by discontinuation of penicillamine and institution of prednisone therapy. Our patient's primarily oral lesions did not resolve with this recommended alteration in therapy, since penicillamine could be discontinued only briefly in the interest of maintaining acceptable serum copper levels and because of the paucity of available alternative copper-chelating agents. Eventually the patient was placed on tetraethylene tetramine (TETA), an experimental copper-chelating agent, and betamethasone (Celestone). This has provided a satisfactory reduction in serum copper levels and resolution of the oral lesions.
6110889##1981-3-21##Apocaeruloplasmin in Wilson's disease.##
6110867##1981-3-21##Wilson's disease and copper-associated protein.##
7470846##1981-3-1##Distribution of cerebral lesions in acquired hepatocerebral degeneration.##The brain lesions of our patients with chronic portal-systemic venous shunts were much the same regardless of the presence or absence of primary liver disease. Alzheimer's type 2 abnormality of astrocytes and demarcated areas of spongy degeneration were found, mainly in the grey matter, with more severe involvement of the basal ganglia and the deeper layers of the frontal, parietal and occipital cortex. The spongy degeneration showed an especially close correlation with the arterial blood supply, being greatest in borderland areas that fall between the regions usually supplied by one or other of the major cerebral arteries. Previous investigations have not been primarily concerned with selective vulnerability so that comparisons are difficult, but on review, there is evidence that this pattern of involvement is a feature of both Wilson's disease and acquired hepatocerebral degeneration. The toxic effect of the portal blood is greatest in the grey matter, probably because of the greater metabolic activity there, and the distribution of lesions within this area of greater vulnerability appears to be further influenced by circulatory factors.
6110114##1981-2-28##Wilson's disease and controller gene mutation.##
7281683##1981-2-20##[Penicillamine-induced elastosis perforans serpiginosa and pulmonary cyst in Wilson's disease (author's transl)].##A large air cyst was removed from the right lung of a 29-year-old female patient with Wilson's disease and penicillamine-induced perforating elastosis, the cyst first appearing after 9 years of treatment with penicillamine. Since, on the one hand, the microscopic and ultrastructural changes in the elastic tissue of the lungs were identical to those observed in the skin, both in areas of clinically-demonstrable elastosis perforans serpiginosa and clinically unaffected skin and, on the other hand, no other pulmonary disease was demonstrable to account for the development of the cystic lesion, it is concluded that penicillamine is the causative factor by means of extensive alteration of the elastic tissue. The morphological changes in the elastic fibres are so characteristic that it is easy to distinguish penicillamine-induced elastosis perforans serpiginosa from the idiopathic variant.
6109943##1981-2-7##Is Wilson's disease caused by a controller gene mutation resulting in perpetuation of the fetal mode of copper metabolism into childhood?##Wilson's disease is an inborn error of copper metabolism, characterised by raised liver-copper concentrations and low serum levels of copper and caeruloplasmin. The autosomal recessive mode of inheritance strongly suggests that mutation of a single gene causes the impairment of both caeruloplasmin synthesis and biliary copper excretion. The normal infant is born with the biochemical features of Wilson's disease (very high liver-copper levels and low serum copper and caeruloplasmin). Induction of normal copper metabolism after birth results in a fall in liver-copper concentrations and rise in serum caeruloplasmin. The repression of normal copper metabolism in the fetus and its induction after birth is probably regulated by a controller gene. It is suggested that mutation of a controller rather than a structural gene underlies the pathogenesis of Wilson's disease and that the disease results from failure to switch from the positive copper balance of the fetus to the normal copper balance of the child.
7458521##1981-2-1##Fluctuating Kayser-Fleischer-like rings in a jaundiced patient.##An alcoholic patient had cirrhosis and pigmented corneal rings similar to Kayser-Fleischer rings. A slitlamp examination by two ophthalmologists, independently, showed bilateral and circumferential rings. Patients with altered copper metabolism in liver disease other than Wilson's disease have been described to have pigmented corneal rings seen only on slitlamp examination. The results of our patient's copper metabolism studies disclosed that the intensity of the rings correlated directly with the serum bilirubin concentrations. Thus, patients with severe cholestasis may be initially seen with Kayser-Fleischer-like rings that should be evaluated further with copper metabolism studies.
7009305##1981-2-1##[Diagnosis of Wilson's disease in 1981].##
7207132##1981-1-16##[Liver copper determination in long-term treatment of Wilson's disease with D-penicillamine].##
7315154##1981-1-1##[Hemolytic anemia and liver failure -- a manifestation of Wilson's disease (author's transl)].##Wilson's disease is a rare inherited disorder of copper metabolism causing severe damage to vital organs. Effective therapy with partial or complete remissions is possible when diagnosis is established early. The first manifestation usually occurs in childhood or early adult life with signs of liver failure and/or hemolytic anemia (stage II), as in the presented case, or with symptoms of extrapyramidal cerebral disease (stage IV). Wilson's disease should be ruled out in all patients below the age of 30 years presenting with liver disease, Coombs-negative, non spherocytic hemolytic anemia or neuropsychiatric disorders of unknown etiology.
7212664##1981-1-1##Brainstem auditory evoked responses in spinocerebellar degeneration and Wilson disease.##Brainstem auditory evoked responses (BAERs) were studied in 30 healthy subjects, 20 patients with spinocerebellar degeneration (SCD), and 6 patients with Wilson's disease. In addition to the standard 8 click per second stimulation rate, increased stimulation frequency was applied which identified wave V for its stability under different stimulation rates. No prolongation of wave latencies was noted in SCD patients, irrespective of clinical features, except in 1 patient who had a latency slightly above the normal range. Wilson disease with neurological symptoms produced prolongation of wave latencies in every case, whereas the patients without neurological involvement showed a normal BAER pattern.
7020706##1981-1-1##[Studies on determining the mutagenicity risk of triethylenetetramine (author's transl)].##Triethylenetetramine (TETA) is the only available effective drug for the treatment of patients with Wilson's disease and with simultaneous intolerance to D-penicillamine. In the Ames-test, however both TETA and the structurally similar tetramine BE 6184 are mutagenic. The naturally occurring spermine, a closely related tetramine differing only in one additional methylene group in every carbon chain, shows no mutagenicity. TETA does not exhibit any mutagenic potency in the micronucleus-test.
7274508##1981-1-1##[Penicillamine-induced dermolytic dermatosis in a patient with Wilson's disease (author's transl)].##A 29-year-old female patient developed a dermolytic dermatosis after 2 years' treatment with penicillamine for Wilson's disease. The skin lesions were localized on skin areas exposed to trauma. Light and electron microscopic investigations showed alterations of all compartments of connective tissue. Patients under long-term high-dose treatment with penicillamine should be closely monitored for cutaneous and systemic connective tissue disease.
7215719##1981-1-1##Urinary copper excretion and hepatic copper concentrations in liver disease.##Urinary copper excretion was found to be increased in patients with cholestasis, hepatitis and cirrhosis, but the penicillamine-induced increment was normal. Wilson's disease patients had increased copper excretion before and after penicillamine, especially in untreated cases. Hepatic copper concentrations correlated with urinary copper excretion in cholestasis and treated Wilson's disease, but not in hepatitis or cirrhosis. In treated Wilson's disease, measurement of urinary copper excretion should be valuable in estimating the degree of removal of copper from the body during therapy. Urinary copper clearances were raised in various liver conditions, maximally in untreated Wilson's disease. It is suggested that only part of the serum non-caeruloplasmin copper is available for excretion into urine.
7297445##1981-1-1##[Hepatolenticular degeneration, Wilson's disease].##
22058523##2011-11-8##Depression in wilson's disease.##This study comprise of 23 patients of Wilson's Disease, who were assessed individually by a psychiatrist and neurologist separately. Clinically discernable psychiatric symptoms were detected in 11 patients. Depressed affect was the commonest finding in the series. While four out of five young patients showed depressive symptomatology, none of the six patients showed any depression. All four patients who had severely depressed affect were also patients who had most severe extrapyramidal features.
7204691##1981-1-1##Porphyria cutanea tarda complicating Wilson's disease.##A young woman is described in whom symptomatic porphyria cutanea tarda (PCT) developed during copper chelation therapy for Wilson's disease. Termination of ethanol ingestion and oral contraceptive use resulted in cessation of blistering skin lesions and reduction in urinary porphyrin excretion. This is the first recorded coincidence of these two rare hepatic diseases. Therapeutic implications are discussed.</AbstractText>            </Abstract>            <AuthorList CompleteYN="Y">                <Author ValidYN="Y">                    <LastName>Chesney</LastName>                    <ForeName>T M</ForeName>                    <Initials>TM</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Wardlaw</LastName>                    <ForeName>L L</ForeName>                    <Initials>LL</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Kaplan</LastName>                    <ForeName>R J</ForeName>                    <Initials>RJ</Initials>                </Author>                <Author ValidYN="Y">                    <LastName>Chow</LastName>                    <ForeName>J F</ForeName>                    <Initials>JF</Initials>                </Author>            </AuthorList>            <Language>eng</Language>            <PublicationTypeList>                <PublicationType>Case Reports</PublicationType>                <PublicationType>Journal Article</PublicationType>            </PublicationTypeList>        </Article>        <MedlineJournalInfo>            <Country>UNITED STATES</Country>            <MedlineTA>J Am Acad Dermatol</MedlineTA>            <NlmUniqueID>7907132</NlmUniqueID>            <ISSNLinking>0190-9622</ISSNLinking>        </MedlineJournalInfo>        <ChemicalList>            <Chemical>                <RegistryNumber>GNN1DV99GX</RegistryNumber>                <NameOfSubstance>Penicillamine</NameOfSubstance>            </Chemical>        </ChemicalList>        <CitationSubset>IM</CitationSubset>        <CitationSubset>J</CitationSubset>        <MeshHeadingList>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Adult</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Female</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Hepatolenticular Degeneration</DescriptorName>                <QualifierName MajorTopicYN="Y">complications</QualifierName>                <QualifierName MajorTopicYN="N">drug therapy</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Humans</DescriptorName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Penicillamine</DescriptorName>                <QualifierName MajorTopicYN="N">therapeutic use</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Porphyrias</DescriptorName>                <QualifierName MajorTopicYN="Y">complications</QualifierName>            </MeshHeading>            <MeshHeading>                <DescriptorName MajorTopicYN="N">Skin Diseases</DescriptorName>                <QualifierName MajorTopicYN="Y">complications</QualifierName>            </MeshHeading>        </MeshHeadingList>        <OtherID Source="PIP">010613</OtherID>        <OtherID Source="POP">00112978</OtherID>        <OtherAbstract Type="PIP" Language="eng">            <AbstractText>A case report is presented of a young woman in whom symptomatic porphyria cutanea tarda (PCT) developed during copper chelation therapy for Wilson's disease. The 22 year old white woman was seen in the summer of 1978 because of development of blisters on the dorsa of the hands associated with focal atrophic hypopigmentation, generalized hyperpigmentation of the skin, and hpertrichosis of the lateral forehead and face. A sibling had died in childhood with Wilson's disease. When the patient developed hepatomegaly, ascites, and an acute hepatitis syndrome at the age of 11, penicillamine therapy was empirically started, with gradual symptomatic improvement. When evaluated at the age of 22, abnormal laboratory values included a total bilirubin of 1.2 mg%; alkaline phosphatase, 96 U; serum glutamic oxaloacetic transaminase (SGOT), 175 U; serum glutamic pyruvic transaminase (SGPT), 122 U; gamma glutamyl trans peptidase (GGTP), 64 U; and Bromsulphalein (BSP) retention, 21% at 45 minutes. Skin biopsy from the hand revealed a noninflammatory subepidermal bulla with prominently PAS positive vessel walls in the festooned dermal papillae at the base of the blister. A fragmented liver biopsy failed to reveal evidence of active hepatitis or cirrhosis, but considerable stainable iron was present in both hepatocytes and Kupffer cells. A rubeanic acid stain for copper was negative. The patient was diagnosed as having Wilson's disease, hepatic hemosiderosis, and PCT. Cessation of all ethanol consumption and discontinuation of the oral contraceptives which she had been taking for 6 years, was recommended. On examination 9 and 22 months after these modifications were instituted, the patient felt asymptomatic and was without evidence of any new blisters or scars of her skin. The hyperpigmentation and hypertrichosis persisted, but she rigidly adhered to a program of penicillamine, topical sunscreen application, and abnegation of alcohol. Liver function studies were normal, and urinary porphyrin levels returned toward normal values. The clinical onset of this patient's blistering disease was temporally associated with ethanol and exogenous estrogen medication.
6785522##1981-1-1##Plasma amino acids in a patient with Wilson's disease presenting with an acute haemolytic anaemia.##
7014876##1981-1-1##The metabolism and pharmacology of D-penicillamine in man.##D-penicillamine is rapidly absorbed from the intestine and appears in plasma as free penicillamine, cysteine-penicillamine disulfide, and penicillamine disulfide. Penicillamine binds firmly to serum and tissue proteins. The urinary excretion of S-methyl-D-penicillamine, cysteine-penicillamine disulfide, penicillamine disulfide, and a newly identified metabolite, homocysteine-penicillamine disulfide, has been quantitated for patients with rheumatoid arthritis, cystinuria, and Wilson's disease. Fifty percent of an oral dose is excreted in the feces, but the metabolites have not yet been fully characterized. The pharmacologic effects of D-penicillamine are associated with disulfide bond formation or cleavage, thiazolidine formation, and metal chelation.
7014875##1981-1-1##The discovery of the therapeutic use of D-penicillamine.##An account is given of the identification of penicillamine in human urine by chromatographic and analytical techniques. At that time this observation appeared to be of esoteric interest only. Some years later, working at the Thorndike Memorial Laboratory at the Boston City Hospital, it occurred to me that the formula of this compound was ideally suited for use as a copper chelating agent for the treatment of Wilson's disease. The subsequent work leading to the acceptance of penicillamine as an important new therapy and also as to its mode of action is given with illustrations of some key experiments and with reference to the first patient ever treated with this drug.
6939890##1981-1-1##Wilson's disease.##The author reviews the pathophysiology of the disorder and gives an historical perspective on intervention.
6939878##1981-1-1##Penicillamine and the SLE syndrome.##Penicillamine-induced systemic lupus erythematosus (SLE) and penicillamine-immune complex nephritis are histologically and serologically distinct. One hundred and twenty patients with Wilson's disease treated with penicillamine have been analyzed. Eight developed the serologic changes of SLE; in 4, it was necessary to discontinue treatment. In addition, 6 patients developed immune complex nephritis, which necessitated discontinuing treatment. All but 1 have since been managed on triethylene tetramine 2HCl (Trien).
7192819##1981-1-1##Computed tomography in Wilson disease.##Computed tomography (CT) was performed on five patients with the &quot;cerebral form&quot; and one with the &quot;hepatic form&quot; of Wilson disease. The diagnosis was confirmed biochemically and by the presence of Kayser-Fleischer rings in all cases. In four patients, CT was done at the time of diagnosis; in two of these patients, the scan was repeated at intervals after initiation of treatment. CT was abnormal in all patients with the &quot;cerebral form.&quot; All CT abnormalities were of low density and were not changed by contrast infusion. The abnormalities involved the basal ganglia in all five patients; in two patients, areas of low density also involved the cerebellar nuclei and surrounding white matter. CT abnormalities, however, did not always correlate well with the clinical state and in two patients, CT findings worsened despite successful cupruresis. The one patient with the &quot;hepatic form&quot; had no CT abnormalities.
7301096##1981-1-1##Wilson's disease. Clinical correction with cranial computed tomography.##Cranial computed tomograms of 12 patients with proven Wilson's disease were correlated with clinical disturbances. CT abnormalities occurred only in the eight patients with neurological manifestations. The presence of atrophy and low density lesions of the basal ganglia shown on CT correlated well with clinical signs of extrapyramidal dysfunction. Cerebral atrophy and cerebellar cortical atrophy were only moderately related to the degree of intellectual dysfunction and ataxia, respectively; there were no specific clinical signs in cases with brainstem involvement. Abnormalities may be marked in scans taken within a year of neuropsychiatric symptoms, but the most severely abnormal CT scans occurred in patients with a relatively longer duration of untreated disease. Computed tomography provides the opportunity to follow the response of the abnormalities of the brain to cupruresis and can give some assistance in management.
7209197##1980-11-15##[Problems in genetics: Wilson's disease: clinical and familial diagnosis (apropos of case)].##
7208018##1980-11-9##[Wilson's disease (family study)].##
7450563##1980-11-1##Observations on copper associated protein in childhood liver disease.##Hepatic copper concentrations were compared with staining grades of copper associated protein (CAP) and histochemical copper in liver sections from 44 patients (one fetus, one pre-term infant, four term infants, eight normal children, 16 children with various liver diseases, and 14 patients with intrahepatic cholestasis of childhood (IHCC)). A similar comparative study of hepatic copper concentration with CAP and histochemical copper was performed in 21 patients with Wilson's disease. CAP occurred in the fetus, pre-term infant, and term infants without liver disease. This suggests that CAP is a normal constituent of the hepatocyte and is not a consequence of liver disease or biliary obstruction. CAP was not seen when hepatic copper concentration was normal; it was absent in eight children with no evidence of liver disease, eight children with non-cirrhotic liver disease, and seven of eight children with cirrhosis. When hepatic copper concentration exceeded 4.0 mumol/g dry liver weight grade 2 or grade 3 staining for CAP and histochemical copper was found in the fetus, pre-term infant, infants, and IHCC. CAP was found in IHCC only in the presence of raised hepatic copper levels, supporting evidence of a relationship between copper and CAP. In 17 of 21 patients with Wilson's disease hepatic copper concentrations exceeded 4 mumol/g. Positive staining for CAP was seen in seven of these patients being usually grade 1. CAP is a normal associated protein, present when hepatic copper concentrations are increased in normal liver cells. It is usually absent in hepatocytes from Wilson's disease despite similar hepatic copper levels. CAP may represent material which protects the hepatocyte from the toxic effects of copper.
7423173##1980-9-20##[Chronic hepatitis].##The term &quot;chronic hepatitis&quot; includes diseases of different etiology, i.e. viral (hepatitis B virus, non-A/non-B hepatitis virus[es]), drug-induced (e.g. oxyphenisatin, alpha-methyldopa), metabolic (Wilson's disease, alpha 1-antitrypsin deficiency) and so-called &quot;autoimmune&quot; hepatitis. In the clinical course, hepatitis running for up to 3 months is considered acute; when lasting for 3-6 months it is termed prolonged, and chronic hepatitis means a duration of more than 6 months by definition. In chronic hepatitis there is international agreement on basing nomenclature on morphologic findings and on distinguishing chronic persistent hepatitis (with a predominantly lymphocytic inflammation restricted to portal tracts) from chronic aggressive (or active) hepatitis. The latter is typified by piecemeal necrosis in the periportal areas (activity a); additional piecemeal necrosis along fibrous septa or bridging hepatic necorsis is the key feature for activity b. In hepatitis B virus infection, the symptomfree carrier of the virus with no inflammation in biopsy, or merely nonspecific reactive hepatitis, must be included under the heading of chronic hepatitis. Cirrhosis, however, although resulting from necrosis, inflammation and fiber formation, refers exclusively to the disturbance of lobular architecture and its microcirculatory consequences. The term &quot;cirrhosis&quot; is thus not included in the definition of chrome hepatitis and should be evaluated separately as an entity in its own right.
6105588##1980-9-6##Biliary excretion of copper in Wilson's disease.##
7451924##1980-9-1##Disordered esophageal motility in Wilson's disease.##We describe the manometric findings in a patient with hepatolenticular degeneration (Wilson's disease). After 21 years of penicillamine therapy, one of the principal neurological problems remaining in a 49-year-old white man with Wilson's disease is food-induced dysphagia. Barium contrast studies showed gross incoordination of the upper esophagus; the manometric study revealed dysmotility of the mid and distal esophagus.
7462905##1980-9-1##G6PD-deficiency: a potential high-risk group to copper and chlorite ingestion.##Although humans may accept fairly large amounts of orally ingested copper (0.25 to 1.0 gm) without visible harmful effects, patients with Wilson's disease, and persons with G6PD deficiency may represent persons at unusual risk to hemolytic anemia from ingestion of Cu(II). This study reports that in vitro exposure of G6PD deficient red blood cells to copper produced marked elevations of methemoglobin and decreases in GSH when compared with normal red cells. Chlorite, a by-product of chlorine dioxide disinfection of water, produced decreases in GSH and G6PD activity, while increasing methemoglobin levels markedly over red cells with normal G6PD activity. The combined action of chlorite and copper was additive in producing increased levels of hemoglobin and decreases in levels of GSH and G6PD deficient cells. The combined ingestion of copper and chlorite may represent an increased risk to persons with G6PD deficiency.
7453682##1980-8-31##[Wilson's disease. Diagnostic problems in forms with exclusively hepatic initial symptoms].##
7398171##1980-8-1##Liver imaging in a patient with Wilson's disease.##
7395941##1980-7-15##Chorea associated with oral contraceptive therapy.##Fernando and Chir 1st reported an association between chorea and oral contraceptives (OCs) in 1966. Differential diagnosis of chorea, in addition to Sydenham chorea, include Wilson disease; encephalitis; Huntington chorea; drug intoxication; benign familial chorea; pregnancy; systemic lupus erythematosus; Henoch-Schonlein purpura; polycythemia vera; hypocalcemia; hyperthyroidism; carbon monoxide poisoning; cerebral infarction, and; intracranial tumor. Chorea can also occur as an untoward side-effect of OC therapy, as shown by the case report of a 20-year old white woman. Chorea associated with OC therapy occur unilateraly but has also been bilateral in 37% of reported cases. 8 of 24 reported cases (33%) had a prior history of rheumatic fever - mean age of patient was 22 years (range, 16 to 40 years). The time between initiation of OC therapy and appearance of choreiform movements can vary from 6 days to 9 months, with a mean of 3 months. Time between discontinuation of OC therapy and cessation of symptoms vary from 3 days to 3 months, with a mean of 5 weeks. Speculations by various authors on the pathogenesis of chorea are described.
7395955##1980-7-1##Accommodation defect in Wilson's disease.##A 22-year-old man with Wilson's disease had blurred vision caused by a defect of accommodation that we believed to be supranuclear in origin.
7445606##1980-7-1##[Immunologic studies with the lymphocyte transformation test on the side effects of D-penicillamine therapy in Wilson's disease].##18 patients with Wilson's disease with and without proteinuria and 19 test persons without Wilson's disease were examined for a disturbance of the transformation on account of phythemagglutinin, streptolysin-O and several D-penicillamine preparations by means of the lymphocyte transformation test. Also during the therapy with D-penicillamine was no cause for a disturbed transformation of lymphocytes on the mitogen phythemagglutinin. A cell-conditioned immune reaction to D-penicillamine which could be established by means of the lymphocyte transformation test under the conditions chosen seems to be present in patients with Wilson's disease neither in lacking or insignificant nor in pronounced proteinuria. The increased transformation rates to streptolysin-O in Wilson's disease need confirmation in a larger number of patients. Like the increased spontaneous transformation rates they might refer to an immune-stimulating effect of the D-penicillamine.
7454259##1980-6-22##[Wilson's disease: clinical aspects and pathology].##
7386600##1980-6-1##The significance of variations in the distribution of copper in liver disease.##Biopsy and autopsy specimens of liver from patients with Wilson's disease in various stages, chronic cholestatic conditions (including primary biliary cirrhosis, extrahepatic biliary obstruction, sclerosing cholangitis, and biliary atresia), chronic active hepatitis, and Indian childhood cirrhosis, as well as normal neonates, were examined by means of histochemical techniques for copper and copper-associated protein. The intracellular localization of copper and the lobular distribution of the metal and its associated protein differed in these conditions. Periportal hepatocytes containing granules (lysosomes) that were reactive for copper and for copper-associated protein were characteristic of cholestasis and neonatal liver. However, in cholestasis extralysosomal copper was often present in the hepatocellular cytoplasm. In contrast, in Wilson's disease, despite very high concentrations of copper in the early stages, the metal was diffuse in the cytoplasm, and the histochemical reactions for granular copper and its associated protein were usually negative. Therefore, a failure to stain for copper does not exclude the diagnosis of Wilson's disease. In the late stages of Wilson's disease staining varied in different nodules. In Indian childhood cirrhosis copper was present throughout the parenchyma, with periportal predominance. Differences in the distribution of copper and the cellular changes associated with its deposition suggest that different pathogenetic mechanisms and possibly different intracellular targets are susceptible to the toxic effects of the metal. For diagnosis, staining for copper and for copper-associated protein may assist in the differentiation of primary biliary cirrhosis from chronic active hepatitis.
7004979##1980-6-1##[Wilson's disease: physiopathology, clinical aspects and therapy].##
6445305##1980-6-1##Triethylene tetramine dihydrochloride toxicity in primary biliary cirrhosis.##Triethylene tetramine dihydrochloride (trien) is a copper chelating agent used as the alternative drug of choice in the treatment of Wilson's disease. Because of its apparent safety, we have used the drug in 4 patients with primary biliary cirrhosis in whom penicillamine had to be withdrawn because of serious side effects. Trien is an effective cupruretic drug in primary biliary cirrhosis, but its use is limited by the occurrence of side effects that occurred in all 4 patients. Three patients developed gastrointestinal side effects, and one of these patients developed a skin rash. The 4th patient developed acute rhabdomyolysis within 48 hr of receiving the first dose of the drug. One patient tolerated therapy for 20 wk, and, although her liver copper concentration did not show a marked fall, aspartate transaminase levels fell, and her IgM concentration fell to normal. Trien is an unsuitable copper chelating drug in primary biliary cirrhosis, although it remains the alternative drug of choice in Wilson's disease.
6900726##1980-5-1##[Nursing of a child with Wilson's disease involving the cranial nerves].##
7375979##1980-5-1##Clinical studies of a large family with Wilson's disease.##We have identified 11 individuals with Wilson's disease, members of five sibships within a larger family which was traced through seven generations. Of 206 other family members evaluated for Wilson's disease, none had abnormally low serum ceruloplasmin or copper levels and none had Wilson's disease. There were two documented instances of consanguinity, associated with two of the five affected sibships and four of the 11 affected individuals. The patterns of occurrence of Wilson's disease within the family is consistent with the hypothesis that the disorder is transmitted as an autosomal recessive characteristic. It is likely that the apparently high frequency of disease within the family can be explained solely by the founder effect.
6449457##1980-5-1##[Wilson's disease].##
7374236##1980-4-25##[Cyclic adenosine monophosphate in the cerebrospinal fluid of patients with liver disease (author's transl)].##The concentration of adenosine 3':5'-cyclic monophosphate in the spinal fluid of ten patients with liver dysfunction was analyzed. Ages of the patients ranged from 31 to 75 years. The state of consciousness varied between normality and stupor. After a liver biopsy the diagnoses were as follows: cirrhosis in six cases, porphyria cutanea tarda in one case, hepatic metastases in two cases and Wilson's disease in one case. Mean values in these patients (22.91 +/- 4.18 pM/ml) have been significantly greater (p less than 0.0005) than those in ten control individuals (15.55n control individuals (15.44 +/- 3.66 pM/ml). Values corresponding to two patients in coma were still higher (52.62 and 36.50 pM/ml respectively). A previous lumbar puncture carried out in one of these patients when he was conscious showed a figure of 23 pM/ml. These results suggest a progressive rise of cyclic adenosine monophosphate in the spinal fluid in relation to clinical impairment, and may indicate a similar behaviour for this nucleotide to that of tryptophan, as reported by other authors. These findings point toward the role of the alteration of neurotransmitters in the pathogenesis of hepatic coma.
7367859##1980-4-18##Genetic expression of Wilson's disease in cell culture: a diagnostic marker.##Wilson's disease fibroblasts have an elevated intracellular copper concentration as compared to cultured control cells. A decreased ratio of copper to protein was observed in cytoplasmic protein (or proteins) having a molecular weight greater than or equal to 30,000 in Wilson's disease cells. The results of this culture study indicate its potential importance in the early unequivocal diagnosis of this disorder.
7374817##1980-4-12##[Current overview of hepatolenticular degeneration (Wilson's disease)].##
7363808##1980-4-4##[Wilson' disease: rapid diagnosis and differentiation of heterozygous and homozygous carriers with 64CuCl2 (author's transl)].##In the modified radiocopper test, a constant amount of copper and not of radioactivity is injected, a difference being made between males and females. The rate of incorporation of 64Cu into caeruloplasmin and urinary excretion of nuclides is measured. It is a method with low radiation exposure, providing a definite diagnosis after 30 hours. This was demonstrated in 27 homozygous patients, 30 parents and 33 siblings, and 25 controls: a clear-cut diagnosis was made in all untreated homozygous patients. In five of eight patients treated with D-penicillamine for several years, the values were in the range of heterozygotes, so that the test makes treatment control possible. The recognition of heterozygous carriers is interfered with by contraceptives and infections. The results in control subjects were all widely outside the range for patients with Wilson's disease.
6967005##1980-4-1##Esophageal tamponade in the treatment of bleeding varices. A decadel progress report.##Previous reports from this hospital in 1958 and 1967 have revealed that esophageal tamponade is a relatively dangerous type of treatment. Other investigators have been able to avoid many of the hazards of this technique. We have again assessed our results in 50 episodes of esophageal tamponade in bleeding esophageal varices in 39 patinets. Thirty-seven had alcoholic cirrhosis, one Wilson's disease, and one portal vein thrombosis. The diagnosis of variceal hemorrhage was established by endoscopy or angiography in virtually all. The great majority (86%) had had unsuccessful infusions of vasopressin previously. The Sengstaken-Blakemore tube (SBT) was used in 41 and the Linton tube (LT) in nine. Hemorrhage was controlled for at least 24 consecutive hours in 20 episodes (40%). Ninety percent of the patients died. Rupture of the esophagus following inflation of the gastric balloon in the esophagus caused three deaths (8%). Major nonfatal complications such as aspiration pneumonia occurred on five other occasions. Although the complications of esophageal tamponade were greatly reduced from our previous series, the efficacy of esophageal tamponade also decreased. There were no significant differences in the efficacy or complications of the SBT and LT. The high mortality and complication rates are still discouraging. We believe that the role of esophageal tamponade in the treatment of hemorrhage from varices is a secondary one.
7450350##1980-4-1##[Epidemiologic study of Wilson's disease].##
7353765##1980-4-1##Wilson's disease: diagnostic difficulties in the patient with chronic hepatitis and hypoceruloplasminemia.##Wilson's disease presents as a classical hereditary syndrome of clinical and biochemical abnormalities. Life-long treatment with copper-chelating agents may dramatically alter the subsequent course and outcome. Hence, considerable attention has been drawn to early recognition and treatment. Since the presentation of Wilson's disease may simulate chronic active hepatitis of unknown etiology, it has been emphasized that the diagnosis of the genetic disorder should be suspected and excluded in this clinical setting. In this report we describe the difficulties encountered in the evaluation of a patient with non-Wilsonian chronic active hepatitis and low serum ceruloplasmin levels. This case illustrates that the distinction between the Wilson's disease homozygote and the hypoceruloplasminemic patient with idiopathic chronic active hepatitis may be difficult to establish and requires a critical evaluation of data to avoid diagnostic pitfalls.
7359013##1980-4-1##Copper chelating agents. A comparison of cupruretic responses to various tetramines and D-penicillamine.##Toxic or hypersensitivity reactions occur frequently with D-penicillamine therapy. Therefore there is a need for effective, well-tolerated alternative chelating agents to control the copper accumulation which occurs in Wilson's disease and some other chronic liver diseases. A group of tetramines (linear and macrocyclic) was surveyed for cupruretic activity and compared to D-penicillamine. 2,3,2-Tetramine was the most effective agent when given either by gavage or intravenously. It was more effective than 2,2,2-tetramine (trien) or D-penicillamine and, in addition, induced a more prolonged cupruresis. Despite their higher formation constants for copper, the macrocyclic tetramines did not induce a significant cupruresis. In this study, the 2,3,2-tetramine was the most effective agent for inducing a cupruresis in both normal and copper-loaded rats. If well tolerated by humans, it could become a useful agent for management of disorders characterized by copper accumulation.
7218179##1980-4-1##Wilson's disease (a case report).##
7367085##1980-4-1##Familial cholestatic cirrhosis associated with Kayser-Fleischer rings.##A brother and sister who suffered from pruritus since infancy developed hepatic cirrhosis early in life. Although this clinical picture has never been seen in Wilson's disease, Kayser-Fleischer rings in the boy made further studies necessary. Oral radiocopper loading tests administered to both children and to their parents served to exclude Wilson's disease conclusively. Determinations of the concentrations and patterns of bile acids in the serum indicated that the abnormalities observed in these children are not related to errors in bile acid synthesis. Although a defect in bile acid transport is present, it appears to have occurred as a consequence of the liver disease.
7367952##1980-4-1##Long-term penicillamine therapy for Wilson's disease.##
6450519##1980-3-1##Laboratory and histological similarities between Wilson's disease and rats with copper toxicity.##Rats were injected intraperitoneally with copper-lactate daily for over 160 days (total dose of 30 mg copper in each animal). At 120 to 160 days of copper administration, animals developed symptoms similar to those of Wilson's disease, i.e., kidney functional disturbances, proteinuria, aminoaciduria, decreased blood ceruloplasmin oxidase activity and increased urinary copper excretion. Cirrhosis was found in some animals. Tubular necrosis of the kidneys, liver fibrosis and tigrolysis of thalamic nerve cells were also found. Copper depositions were observed in liver parenchymal cells, renal tubular epithels, thalamus glia cells and on the Descemet's membrane of the cornea. The similarities between induced copper- intoxication in rats and Wilson's disease are discussed.
6935303##1980-3-1##[Pathohistological report of periodontosis in an autopsy case of Wilson's disease (author's transl)].##
7434982##1980-3-1##[immunohistologic findings of kidney biopsies in Wilson's disease].##12 patients with Wilson's disease were examined by means of renal biopsy. In 9 of these patients a slight (4 patients) or a strong proteinuria (5 patients) appeared during the therapy with D-penicillamine. A biopsy was performed in 3 patients before the beginning of the therapy with D-penicillamine. The patients with severe proteinuria showed the largest immunohistological changes (partly distinct immune complex nephritis with epimembranous IgG- and complement-(C3-) depositions -- electronoptically membranous glomerulonephritis. In rebiopsy after a stoppage of the medicament of 1 year only a slight tendency to improvement was to be recognized.
6447415##1980-2-15##[Wilson's disease in the German Democratic Republic. III. Diagnosis and therapy].##Taking into consideration the manifold symptomatology of Wilson's disease on the one hand and the necessity of an early--possibly already at the asymptomatic stage before the 6th year of life--diagnostic ascertainment on the other hand, the diagnostic approach performed in the GDR is described. Furthermore, the directives of treatment and the successes of treatment are discussed as well as the various side-effects of the D-penicillamine therapy described, in which case the severe nephrotic syndromes are particularly considered.
7377841##1980-2-1##Wilson's disease, chronic copper poisoning, or Indian childhood cirrhosis?##
7420971##1980-2-1##[Regression of a Kayser-Fleischer ring in a case of Wilson's disease during penicillamine therapy (author's transl)].##The disappearance of a Kayser-Fleischer ring induced by the administration of penicillamine (D-penicillamine) for 17 years is described. The ring disappeared only in the lateral and medial portions leaving superior and inferior crescents. Possible mechanisms of this partial regression of the ring ae discussed.
7395295##1980-2-1##[Wilson's disease in the German Democratic Republic. II. Pathogenesis and clinical aspects].##From the point of view of the Leipzig Centre for Wilson's disease in the GDR the authors adopt a definite attitude to the questions of pathogenesis and clinic. Since for the performance of the life-saving long-term therapy the disease must be diagnosed early, in detail are described the preclinical (asymptomatic) and clinical stage--including its various forms of manifestation--and their differential diagnosis and it is dealt with the changed radio-copper-kinetics.
6243942##1980-1-29##Evidence that carnosine and anserine may participate in Wilson's disease.##
7352414##1980-1-1##Histology of the liver in Wilson's disease: a study of 34 cases.##Biopsy or autopsy samples of liver from 34 patients with clinical evidence of Wilson's disease were studied histologically. Seven had early changes ranging from slight pleomorphism of hepatocytes to fatty metamorphosis, vacuolated nuclei, and focal necrosis. Seven other specimens from cases classified as chronic active hepatitis were characterized by periportal degeneration and necrosis, in addition to many of the changes of the first group. Periportal copper accumulation was found in three of these specimens and was considered helpful in the distinction from other forms of chronic active hepatitis. Specimens from four of the precirrhotic cases showed periportal atypical lipofuscin granules. The 20 cirrhotic specimens were macronodular or mixed micronodular-macronodular and showed a wide variety of patterns and cytologic changes. Eight contained Mallory bodies. Copper was demonstrated in 13 of 15 specimens with adequate copper stains. Some of the findings described here may suggest or confirm a diagnosis of Wilson's disease, but none is considered specific. A proper approach to the diagnosis should correlate the clinical, laboratory, and morphologic findings.
7234865##1980-1-1##Hemolytic anemia in Wilson disease: clinical findings and biochemical mechanisms.##Two patients with Wilson disease who presented with severe hemolytic anemia are described. One was noted to have unusually high serum copper levels (369 micrograms/100 ml). A review of similar such patients in the literature suggests that, rather than having a low serum copper, patients with hemolysis accompanying Wilson disease have very high serum copper levels. For this reason, in vitro studies of the toxic effects of copper on erythrocytes were undertaken. It was found that, although copper does not have a major direct inhibitory effect on glycolytic enzymes such as hexokinase, the metal does inhibit hexokinase as a consequence of its interaction with oxyhemoglobin. However, such inhibition does not appear to be a major factor in copper-induced hemolysis. On the other hand, the addition of the lipid antioxidant butylated hydroxyanisole (BHA) suppresses hemolysis in copper-treated cells. These experiments suggest that the primary toxic effect of copper is mediated through its oxidant actions on membrane phospholipids rather than through its potential inhibitory effects on intracellular enzymes.
6907088##1980-1-1##Copper and hepatic function.##When hepatic excretion of copper into bile is impaired, the amount of copper in the liver increases. This happens in extrahepatic cholestasis, primary biliary cirrhosis and in two inherited diseases of copper disease. By six months of age the homozygously affected Bedlington terrier has already begun to accumulate copper in its liver. The trend continues, peaking at the age of five to eight years, when hepatic copper may exceed 10 000 microgram/g dry weight (normal 90--400 microgram/g in livers from mongrels). Despite these concentrations, which are several times higher than those found in any human disease, there is remarkable little evidence of hepatic inflammation or fibrosis in younger Bedlington terriers. The copper is condensed in lysosomes and is identified by X-ray emission spectroscopy. Hepatic cirrhosis eventually develops and death is often associated with ascites and jaundice. Despite characteristic histological differences between the livers in Wilson's disease and in the Bedlington disease, there is a striking general resemblance between the two conditions.
7438976##1980-1-1##Treatment of Wilson's disease with triethylene tetramine dihydrochloride. A case report.##Wilson's disease is an autosomal recessive disorder characterized by progressive cirrhosis or neurological signs. Early detection and prompt treatment can reverse the relentless course of the disease. Treatment with D-penicillamine substantially improves the outlook for such patients unless side effects preclude its use. We report the use of triethylene tetramine dihydrochloride (Trien), a new non-sulfhydryl-chelating agent, in a girl who was unable to tolerate D-penicillamine in spite of steroid coverage. The drug has been well tolerated without side effects for approximately 2 1/2 years. Our patient's favorable clinical response would suggest that Trien is a safe alternative agent for the treatment of Wilson's disease when D-penicillamine is not tolerated.
7372201##1980-1-1##Hemostasis in the copper-laden Bedlington terrier: a possible model of Wilson's disease.##A hemostatic survey was done on 14 Bedlington terriers, 13 of which have the recently discovered copper toxicosis. Their hepatic copper ranged from 109 to 9,888 microgram/g dry weight and their ages from 8 months to 8 years. Despite histologic evidence of hepatitis in younger dogs and cirrhosis in older ones, plasmatic coagulation factors were not depressed. In fact, the hemophilic factors VIII, IX and XI were above normal, more closely related to the age of the dog than to the hepatic copper. Furthermore, their platelet were unusually sensitive to adenosine diphosphate exposure. Offsprings of matings between Bedlington terriers and Beagles seem to be normal.
6787337##1980-1-1##Abnormal copper metabolism in cultured fibroblasts from patients with Wilson's disease.##Skin fibroblasts derived from patients with Wilson's disease have, under certain conditions, elevated concentrations of copper. However, the levels of intracellular copper varied from one experiment to another and the reason for this inconsistency has not yet been determined. 64Cu retention after 24 hours and its release in &quot;chase&quot; experiments was not abnormal, thus distinguishing these fibroblasts from Menkes' syndrome fibroblasts. The data provides evidence that the mutant gene responsible for Wilson's disease is expressed in fibroblasts under certain conditions.
7442347##1980-1-1##Transient external ophthalmoplegia in Wilson's disease.##
7256888##1980-1-1##Hemolytic anemia as a presenting manifestation of Wilson's disease.##
7467117##1980-1-1##Secondary athrocytotic cardiomyopathy--heart damage due to Wilson's disease.##Post-mortem atomic absorption spectrophotometry of the myocardium of a 14-year-old boy revealed a hundred-fold increase in copper. Further electrolyte analysis of the myocardium showed changes corresponding to metabolic heart muscle damage. Ultrastructural examination showed all the feature of a cardiomyopathy at the cellular level. Laser-Microprobe-Mass-Analysis demonstrated an inhomogeneous distribution of copper. An essential factor in the mechanism of death is heart damage.
549306##1979-12-15##[Wilson's disease in the German Democratic Republic. I. Genetics and epidemiology].##The experiences of the central institution for Wilson's disease are reported. On the basis of 126 patients who come from 90 clans with 92 families the authors adopt a definite attitude to the problem of genetics, epidemiology and genetic family consultation. The unexceptional validity of the autosomal-recessive hereditary transmission may be confirmed. An incidence of 2.9/100,000 is assumed, from which a gene frequency of 0.53% and a frequency of heterozygotes of 1.05% can be estimated. The questions of the genetic background of polyphenia are discussed.
533305##1979-12-1##Polyarthritis associated with Wilson's disease.##
531977##1979-11-26##[Wilson's disease. A misdiagnosed case with purely neurological manifestations].##
117347##1979-11-16##[Wilson's disease or liver cirrhosis of a different etiology].##
539789##1979-11-1##Serum antioxidant activity in normal and abnormal subjects.##Serum oxidant activity (AOA) was correlated with the serum caeruloplasmin and serum copper concentration and with the total and available serum iron-binding capacity in 313 normal and abnormal subjects. In all groups except in patients with Wilson's disease (hepatolenticular degeneration) there was a highly significant direct correlation between serum AOA and serum caeruloplasmin concentration. A statistically significant direct correlation between serum AOA and the available iron-binding capacity of serum was found only in normal subjects and in children with thalassemia major and iron overload. There was no correlation between serum AOA and the serum tocopherol concentration in any of the groups studied.
499590##1979-11-1##A progressive rise in serum copper levels in women taking oral contraceptives: a potential hazard?##123 healthy Jewish women (18-22 years) were divided into OC (oral contraceptives) users (n=75), and controls (n=48). All women were on a similar diet. The OC users were divided into 3 groups (1, 2 and 3) based on the OC preparations they were taking. Venous blood samples were collected; serum copper levels were measured using atomic absorption spectrophotometry (Parker et al.'s method). Serum copper levels did not correlate with time of menstrual cycle for each group, and for all groups considered together. Mean serum copper level in the control group, 120 ug/100 ml +/- 15 SD (standard deviation), was significantly lower than the serum copper level of all contraceptive groups considered together. Of the 3 groups, group 3 (those taking Neogynon) showed a steady and progressive rise in serum copper level. The mechanism of action of the rise of serum copper and ceruplasmin levels following OC intake is not clear. Hypercupremia may be due to excessive absorption of copper by the intestines, to a shift of copper from tissue to blood compartment, or to both. Chronic copper intoxication could result from hypercupremia associated with chronic OC use. Studies of Wilson's disease show that severe damage could result from excessive copper deposition in various tissues. Further research should be done to determine the potential hazards of chronic copper intoxication, particularly in patients taking Neogynon.
512660##1979-11-1##The formation and nature of the mixed valence copper-D-penicillamine-chloride cluster in aqueous solution and its relevance to the treatment of Wilson's disease.##Complex formation between D-penicillamine (Pen) and copper(II) ions has been studied under simulated physiological conditions in both the presence and absence of the blood plasma constituents albumin, alanine, histidine, and zinc(II). Chromatographic and uv/vis and electron spin resonance (esr) spectroscopic methods were used. The major species formed, at neutral pH and 0.15 mol dm-3 NaCl, is the violet species which is shown to have the same stoichiometry as the recently reported solid-state complex, i.e., [Cu8I Cu6II (Pen)12 Cl] 5-. The rate of formation of this species (MVC) is shown to be dependent on the Cu concentration, Cu:Pen ratio, relative Cl- ion concentration, pH, and temperature. Formation is inhibited by the presence of O2 and biological chelates. At the concentration levels found in blood plasma it is unlikely that the MVC ion has any significance in the therapeutic action of penicillamine in the treatment of Wilson's disease. Reexamination of the aqueous Cu-albumin-pen system reinforces earlier findings that pen is unable to mobilize Cu that is bound to albumin. Significant binding of pen to the protein is observed is not related to any protein-bound copper ions. Evidence that ternary complexes of the type amino acid-Cu-Pen can form in blood plasma is presented. These are unlikely, however, to be physiologically significant and the copper depletion induced by Pen in Wilson's disease cases must be elsewhere than in the blood plasma compartment.
514318##1979-11-1##Ultrastructure of nerve biopsy in Wilson disease.##
317129##1979-10-31##[Unusual and different clinical aspects of Wilson's disease in 2 sisters].##
384982##1979-10-1##Disappearance of Kayser-Fleischer rings after liver transplantation.##Kayser-Fleischer rings were observed in a 14-year-old boy with progressive liver disease. Laboratory data supported a diagnosis of hepatolenticular degeneration (Wilson's disease). Therapy with chelating agents was initiated, but discontinued because of side reactions. Successful liver homotransplantation was performed. The Kayser-Fleischer rings gradually faded and had completely disappeared by six years postoperatively.
522594##1979-9-1##[Wilson's liver disease in children and adolescents (author's transl)].##Hepatic symptoms are usually the first in Wilson's disease of children and adolescents, while neurologic symptoms and the corneal ring are still missing. Liver lesions due to copper accumulation may develop throughout years without clinical symptoms or biochemical abnormalities. Hemolytic jaundice or gastrointestinal bleeding are the presenting symptoms in some cases. In spite of being a rare syndrom Wilson's disease ought to be considered after hepatitis B or autoimmune liver disease have been excluded as causes of juvenile cirrhosis of the liver. If life-long treatment with D-penicillamin is started in an early stage of Wilson's disease, prognosis is rather good.
503243##1979-9-1##[D-Penacillamine. From constituent of penicillins to significant drug].##D-Penicillamine is used against a variety of diseases. For many years it has been successful in treating Wilson's disease, cystinuria and heavy-metal poisonings. It also proved to be effective against rheumatoid arthritis, scleroderma, chronic active hepatitis, pulmonary fibrosis and multiple sclerosis. However, the use of D-penicillamine is still limited owing to the frequent occurrence of considerable, though generally reversible, side effects. This article deals with the history of D-penicillamine as well as the methods of its synthesis, its pharmacokinetics, effects and side effects. In addition, the significance of the stereo isomeric L-penicillamine is discussed.
538130##1979-9-1##[Diphenylhydantoin stimulation test in Wilson's disease].##Coeruloplasmin and diphenylhydantoin levels were studied both in patients who were stabilised for the first time on diphenylhyantoin (300 mg daily) up to reaching a stable serum concentration (N = 6) and during steady-state concentration (N = 25). No significant DPH-dependent influence on the coeruloplasmin level in the serum was found. In our opinion, DPH is no suitable for the stimulation of coeruloplasmin and thus for the diagnosis of Wilson's disease, particularly in the preclinical stage, because absence of coeruloplasmin increase in the serum being found also in healthy persons.
538129##1979-9-1##[Some problems of Wilson's disease].##The Leipzig Center for Wilson's Disease in the GDR is charged with the registration and diagnosis of all homozygous Wilson gene carriers, the clarification of all suspected cases, including the heterozygote test, and the co-ordination of long-term treatment. At present, there are 78 recorded Wilson gene carriers living. On the basis of our own comprehensive observations and investigations over prolonged periods of time, questions concerning pathogenesis, genetics, diagnosis and therapeutic measures, including their side-effects, are dealt with.
161403##1979-9-1##[Serious side effects with D-penicillamine therapy for Wilson's disease].##Immunocomplex nephritis as one of the serious side-effects is dealt with on the basis of 41 patients with Wilson's Disease who have been treated for many years and were stabilised on D-penicillinamine. In one quarter of the patients, proteinuria was found 1 to 5 years after the beginning of the therapy. Until now, an immunocomplex nephritis with diffuse granular, mainly epimembranous IgG and C3 deposits on the glomerular basement membran was found in four patients. No circulating antibodies against cell nuclei were found. The finding of immunocomplex nephritis calls for the discontinuation of the therapy for an at present unknown period of time.
494648##1979-8-31##[Proliferative diabetic retinopathy for over twenty years without glomerulosclerosis (author's transl)].##Proliferative retinopathy and glomerulosclerosis (Kimmelstiel-Wilson disease), crucial prognostic features in determining morbidity and mortality of diabetics nowadays, appear to be closely related: joint inadence, parallel progression and similar histological findings. A report is given on four cases suffering from proliferative retinopathy for 20 to 26 years, yet without any signs of glomerulosclerosis. The patient are all advanced in age (68 and more) and in relatively good general condition, but have, tragically, been blind for many years. Hence proliferative retinopathy, though part of diabetic angiography, is proved to originate independently from glomerulosclerosis although apparently so closely related to this syndrome. Nothing can be said in explanation of this fact, neither on a metabolic nor an organic basis.
89484##1979-8-25##Undiagnosed Wilson's disease as cause of unexplained miscarriage.##
463930##1979-8-1##Renal stones in Wilson's disease.##Fifty-four patients with Wilson's disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson's disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson's disease was made. Of the several possible factors that may predispose patients with Wilson's disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson's disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine.
500870##1979-8-1##&quot;Lumpy-bumpy&quot; elastic fibers in the skin and lungs of a patient with a penicillamine-induced elastosis perforans serpiginosa.##Penicillamine-induced cutaneous elastosis perforans serpiginosa associated with a large air-cyst in the right lung is described in a 29-year-old female patient with Wilson disease. Identical light and electron-microscopic changes were present in both dermal and pulmonary elastic tissue, suggesting a disseminated drug-induced cutaneo-visceral elastosis. Lung cysts have not been previously reported in association with long term penicillamine treatment. The electron-microscopic morphology of the elastic fibers was found to be &quot;specific&quot; enough to allow separation of penicillamine-induced elastosis perforans serpiginosa from other forms of this disease.
18962514##1978-12-19##Simple and sensitive determination of hepatic copper by use of an extractive catalytic method.##For determination of copper in liver tissue and in liver biopsy samples an extractive catalytic determination is proposed. After digestion of the liver samples with nitric acid, copper is extracted as the salicylate-pyridine complex into chloroform and determined catalytically directly in the organic extract by addition of ethanolic solutions of sulphanilic acid, pyridine and hydrogen peroxide. Copper can be determined in the range from 10 to 350 ppm (dry weight basis) with a relative standard deviation of 5-15%. The method enables copper to be determined in liver biopsy samples of about 5 mg dry weight by use of a simple spectrophotometer, and can be used in diagnosis of Wilson's disease.
447011##1979-7-1##The role of radiocopper in the diagnosis of Wilson's disease.##In patients with normal serum concentrations of ceruloplasmin, measurement of the incorporation of radiocopper into this protein can aid in the clinically important differentiation of patients with hepatic illnesses that mimic Wilson's disease from patients with this disorder.
542546##1979-7-1##[The epidemiology of Wilson's disease in the German Democratic Republic and current problems from the viewpoint of population genetics].##Between 1949 and Nov. 30, 1977 a total of 123 cases of Wilson's disease have been registered in the GDR. Using the available statistics the incidence rate of the disease is assumed to be about 2.9/100,000, the gene frequency approx. 0.53 per cent and the heterozygote incidence 1.05 per cent, supposing that the Hardy-Weinberg law applies to a large extent. Conclusions are drawn from the available material with a view to detection of the disease infuture and to genetic family counselling.
396544##1979-7-1##A study of the caeruloplasmin concentrations found in 75 patients with Wilson's disease, their kinships and various control groups.##
87676##1979-6-9##Cytoplasmic copper and its toxic effects. Studies in Indian childhood cirrhosis.##Morphological, histochemical, and chemical study of three necropsy specimens of liver in the terminal stage of Indian Childhood Cirrhosis revealed a strikingly high copper content. it is proposed that excess accumulation of copper in the cytoplasm of hepatocytes disturbs the microtubular system, causing hydropic swelling and the formation of Mallory's hyalin. Copper and copper-binding protein showed topographical association with Mallory's hyalin. Diffuse cytoplasmic staining and the lysosomal copper distribution also suggested that copper had a cytotoxic effect. The pattern of copper distribution in Indian Childhood Cirrhosis differs from that in Wilson's disease and in prolonged cholestasis with excessive hepatic copper deposition, indicating a different mechanism of the copper accumulation.
457381##1979-6-1##Ultrastructural pathology with normal light microscopy of liver in Wilson's disease. A case report.##Light microscopy findings in early Wilson's disease (hepatolenticular degeneration) may be normal even when special cytochemical stains are used. We present a case of Wilson's disease in which light microscopy was negative, while electron microscopy showed the characteristic changes in the hepatocytes. Since low serum ceruloplasmin levels and high urinary copper excretion are not by themselves definite proof of Wilson's disease, and since copper content of the liver is not universally measured, electron microscopy examination of liver tissue appears to be a worthwhile additional tool for the early diagnosis of Wilson's disease.
572009##1979-6-1##Computerized cranial tomography in Wilson disease.##Hepatolenticular degeneration (Wilson disease) is suspected by the clinical picture and confirmed by characteristic laboratory demonstration of impaired copper metabolism. Three patients with Wilson disease involving the basal ganglia were shown to have abnormalities on computerized tomography (CT) scan, whereas four other patients without signs of cerebral involvement had normal brain scans. Wilson disease may be added to the long list of diseases to which the EMI scan may make a useful diagnostic contribution.
377266##1979-6-1##Chronic hepatitis.##Chronic hepatitis may be viral or &quot;lupoid&quot; or may be related to drug use, alcoholism, or Wilson's disease. This article outlines the routine and special laboratory investigations that are indicated when the presence of chronic hepatitis is suspected from symptoms referable to the liver or from biochemical or physical abnormalities in an asymptomatic patient. The importance of needle liver biopsy in diagnosis and in follow-up is emphasized. Special attention is given to the selection of patients for prednisolone therapy.
112411##1979-5-18##[Encephalopathy and liver diseases (author's transl)].##As the central organ of metabolism the liver is of the highest importance for the nervous system and for the brain in particular, which only becomes apparent under pathological conditions. It is of importance to neurologists that for them the differential diagnosis of subclinical or chronic intermittent decompensating types of hepatic encephalopathy is predominant. We are actually concerned here with encephalomyeloneuropathies which become manifest by failure on the part of the spinal marrow and the peripheral nervous system. Among the various hepatocerebral diseases the rare Wilson's disease and sporadic Wilsonismus should be mentioned from the differential diagnostic point of view, and especially the differential diagnosis of the porphyrias should be given attention, since they may first appear spontaneously and suddenly under metabolic stress, e. g. anesthesia.
448388##1979-5-1##Reading difficulty as a presenting symptom in Wilson's disease.##A case of Wilson's disease is reported in which the major symptom before treatment was a reading disability. This was caused by ocular dysmetria, and the abnormal eye movements were recorded by electronystagmography and optokinetic drum testing.
450766##1979-4-2##[Erythrocyte metabolism in Wilson's disease].##
433865##1979-4-1##Hemolysis, coagulation defects, and fulminant hepatic failure as a presentation of Wilson's disease.##
436329##1979-4-1##Hereditary hypoceruloplasminemia.##Serum ceruloplasmin values of less than 21.0 mg/100 ml in males or less than 23.0 mg/100 ml in females were observed in 14 out of 156 otherwise healthy members of a pedigree. The hypoceruloplasminemia segregated in a fashion suggesting that the affected individuals are heterozygous for a mutant gene that results in hypoceruloplasminemia. This mutant gene could be a Wilson's disease gene, but excessive copper loading was absent. It is suggested that hereditary hypoceruloplasminemia may be a benign entity distinct from Wilson's disease.
438004##1979-4-1##Copper metabolism: report of a case of Wilson's disease.##
430291##1979-4-1##Laboratory measures of copper metabolism in the differentiation of chronic active hepatitis and Wilson disease in children.##The accuracy of the serum ceruloplasmin level in distinguishing chronic active hepatitis from Wilson disease was compared to the 24-hour urinary copper excretion and hepatic copper content in 20 untreated patients with chronic active hepatitis and 25 with Wilson disease. Serum ceruloplasmin levels were decreased in five patients (25%) with chronic active hepatitis and were normal in seven patients (28%) with Wilson disease at the time of diagnosis. The 24-hour urinary copper excretion failed to provide accurate discrimination between the two groups, being elevated in all patients with Wilson disease and in five of eight patients with chronic active hepatitis studied. All patients with Wilson disease had hepatic copper levels greater than 400 microgram/gm dry weight, whereas patients with chronic active hepatitis had levels less than 300 microgram/gm dry weight. The discriminatory value of hepatic copper concentration makes this the most reliable test for differentiating chronic active hepatitis and Wilson disease in children and adolescents. The serum ceruloplasmin level may not be significantly accurate for definitive diagnosis in this age group.
423610##1979-4-1##Wilson's disease.##
224495##1979-3-8##[Wilson's disease. A clinical and pathological study on 6 cases (author's transl)].##In connection with 6 cases of Wilson's disease, the authors recall the main features of this hereditary metabolic disorder at late onset (usually the second decade), treatable with a chelating agent, when diagnosed at an early stage. Wilson's disease is first of all a liver disease and the authors emphasize the fact that cirrhosis is usually present when neurologic symptoms, revealing the disease in 5 cases, appear, even if there is no clinical or biological evidence for liver disease. In one instance hemolytic anemia and chronic active hepatitis were observed at clinical onset. Copper metabolism usually gives the key for diagnosis but its interpretation may be difficult, a normal serum ceruleoplasmin level being found in two patients and evaluated at 6% in the literature. This fact brings up the puzzling question of the pathogesis of the disease. Wilson's disease is not a simple ceruleoplasmin synthesis defect, but a lysosomal disease responsible for the lack of copper biliary excretion. This is pointed out by histochemical studies using a special rubeanic acid preparation (revealing copper deposit on the biliary side of the hepatic cell), and by electron microscopy showing lysosomal dystrophy.
433370##1979-3-1##[Spontaneous and DL-penicillamine-induced renal copper excretion in liver diseases (author's transl)].##The levels of cupriuresis before and after DL-Penicillamine have been investigated in 168 cases. The mean copper excretion before Penicillamine in chronic activ liver disease, chronic persistant hepatitis, cirrhosis and in transitional cases of aggressiv chronic hepatitis and primary biliary cirrhosis ranged from 29 gamma to 48 gamma/24 hr.; however, in some cases the daily copper excretion exceeds 100 gamma, as well in subjects with liver disease as in normals too. After ingesting 900 mg DL-Penicillamine the mean values of cupriuresis ranged from 500 gamma to 600 gamma/24 hr. Abnormal results were found in about 15% of those subjects with liver diseases; in only two of 20 cases with hypercupruria after Penicillamine Wilson's Disease was established.
254233##1979-2-22##Nursing care study. Wilson's disease: excess copper invades the body.##
427957##1979-2-1##[Dermatoglyphics in Wilson's disease].##
424037##1979-2-1##[The effect of penicillamine on the mental disorders associated with wilson's disease (author's transl)].##
432022##1979-2-1##[Diagnostic and therapeutic problems in Wilson's disease].##
555233##1979-1-1##[Evolution of nocturnal sleep in a case of Wilson's disease].##
555232##1979-1-1##[Checking of urinary copper in patients with Wilson's disease during treatment with D-penicillamine].##
426461##1979-1-1##Computed tomography in Wilson disease: report of 2 cases.##
371766##1979-1-1##Copper inhibits pressor responses to noradrenaline but not potassium. Interactions with prostaglandins E1, E2, and I2 and penicillamine.##Low concentrations of copper inhibited responses to norepinephrine and angiotensin (IC50 3 X 10(-6) M) but not to potassium in rat mesenteric vascular preparations perfused either with buffer or indomethacin and prostaglandin (PGE2). The dose-response curve was not shifted by indomethacin, imidazole, or PGE2 but was moved to the right by 2.8 X 10(-11) M PGE1 and to the left by 2.8 X 10(-7) M PGE1. These effects of copper are similar to the effects of PGI2 in the preparation. Copper moved the PGI2 dose-response curve against noradrenaline in parallel to the left, suggesting that the two were interacting at some point. Penicillamine, which may stimulate PGE1 synthesis, had PGE1-like interactions with the copper effect, suggesting that its value in Wilson's disease may be partly due to antagonism of the biological action of copper as well as to its copper-chelating properties.
550935##1979-1-1##Aspects of cuprogenic disorder in Wilson's Disease in India.##A brief account is given of some aspects of Wilson's disease in India, studied during the periods 1959 to 1967 and 1970 to 1978, with emphasis on disordered parameters of copper metabolism. Among the latter, serum copper oxidase (representing caeruloplasmin) was found to be the most constant laboratory evidence of Wilson's disease. It wad drastically lowered in all patients in both periods (25 and 44 patients respectively), when compared to its level in the parents and siblings of the patients, in other neurological patients and in normal subjects serving as controls. The other constantly involved parameter was direct-reacting serum copper which was highly significantly elevated in the patients compared to the other groups. Most of the patients presented with a predominantly neurological form of the disease, smaller groups presenting with predominantly osseomuscular or hepatic forms. The mean age of patients in both periods was approximately 13 years.
488556##1979-1-1##Lysosomal changes and enterocytic copper deposits in Wilson's disease.##In 4 siblings, of whom 2 had symptoms of Wilson's disease, electron microscopy showed that the number and size of lysosomes in the enterocytes were increased compared with controls. Electron-dense aggregates, observed near the lysosomes in the 2 symptomatic patients and 1 other sibling, were shown, by means of a microanalytical method, to contain copper. These findings could suggest a possible role of the small intestine in Wilson's disease.
477692##1979-1-1##Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration).##Clinical amelioration, clearance of Kayser-Fleischer rings and rising of ceruloplasmin concentration are described in a patient with the classical findings of Wilson's disease. These changes occurred during a 14-year period in which he used oral zinc sulphate (three times daily 200 mg) as the only medication to influence copper metabolism. Before starting this long-term zinc sulphate therapy he had used D-penicillamine (three times daily 300 mg) for only 6 weeks. The antagonistic action of zinc sulphate on copper resorption with amelioration of the clinical condition has been described before in this patient in 1961 by Schouwink. The patient had used at that time oral zinc sulphate for approximately 1.5 years. No changes in Kayser-Fleischer rings and ceruloplasmin levels were mentioned. Our findings suggest that oral zinc sulphate may not only prevent storage of copper in the tissues but may also contribute to the mobilization and excretion of deposits of copper.
535837##1979-1-1##Wilson's disease; increased aluminum in liver.##Interaction of trace metal metabolism was studied in a patient with Wilson's dease. Atomic absorption analysis showed markedly increased urinary excretion of copper and aluminum and an increased aluminum content was found in the biopsied liver by neutron activation analysis. These findings suggest a complicated pathogenetic mechanism involving other metals besides copper in the Wilson's disease.
536182##1979-1-1##Nephrotic syndrome induced by D-penicillamine therapy.##The paper presents a female patient in whom the penicillamine therapy for aggressive hepatitis triggered off the development of nephrotic syndrome. Histological findings revealed membranous glomerulonephritis. After the withdrawal of penicillamine therapy, the laboratory results returned to normal. The authors concluded that penicillamine should only be administered in conditions in which other means of therapy prove inefficient (i.e. Wilson's disease, cystinuria associated with calculi).
548642##1979-1-1##Wilson's disease--in a 2 year old child.##
759736##1979-1-1##Clinical spectrum of Wilson's disease (hepatolenticular degeneration).##Fifty-eight patients with Wilson's disease are reviewed, of whom 25 symptomatic patients experienced liver disease first and 28, brain disease. Ten of these patients presented with liver disease alone, 19 with brain disease alone, and 24 with evidence of both liver and brain disease. The remaining five were discovered as asymptomatic siblings of known patients. Three of the patients with hepatic presentation and one with neurologic presentation later experienced the other type of symptomatology, bringing the total number of patients with mixed disease to 28. Of the 44 patients with brain disease, 12 presented primarily with extrapyramidal findings, 6 with cerebellar findings, and 17 with both; pseudobulbar findings were noted in 9 patients, all of whom had other symptoms of severe nervous system disease. In addition to these presentations, in an appreciable number of patients the first symptoms were of a mental or emotional disorder. Disease of other organ systems, such as the joints and kidneys, also occurred but infrequently. Where adequate family information was available, 13 of 65 siblings (20%) were known to have had or were suspected of having had Wilson's disease. This is consistent with the autosomal-recessive pattern of inheritance.
531055##1979-1-1##The management of Wilson's disease with trienthylene tetramine 2HC1 (Trien 2HC1).##
428157##1979-1-1##[A case of Wilson's disease with series of various involuntary movements (author's transl)].##
452626##1979-1-1##Hepatic copper accumulation in primary biliary cirrhosis.##Hepatic copper accumulation is a regular feature of primary biliary cirrhosis (PBC). The levels are directly related to the clinical stage of the disease. Since the copper values in PBC are comparable to Wilson's disease, there is the potential for copper toxicity, although this is speculative since the two diseases differ in the binding, distribution, and intracellular localization of the copper. The involvement of copper toxicity in the progression of PBC is supported by the observation that the highest values occur in association with the hepatic failure that occurs in the advanced stage.Corticosteroid therapy appears to decrease hepatic copper levels in PBC. Although this therapy does not invariably lower the hepatic Cu content in patients with PBC, it does so in many individuals. Therapeutic trials with d-penicillamine are in progress. When results are available they will guide us in the management of individual patients with PBC. In the meantime, dietary copper should be restricted as is done in management of Wilson's disease.
82772##1978-12-9##Oral zinc in Wilson's disease.##
16114147##1978-12-1##[Wilson's disease. Anatomo-clinical study of six cases].##
718354##1978-12-1##Kayser-Fleischer-like ring in a cryptogenic cirrhosis.##A patient with cryptogenic cirrhosis was found to have corneal pigmentation rings indistinguishable from Kayser-Fleischer rings on slit-lamp examination. Although she had hepatic encephalopathy that included confusion, tremor, and slurred speech, diagnosis of Wilson's disease was ruled out because urinary cooper excretion and hepatic copper concentrations were below the range found in symptomatic Wilson's disease. The exact nature of these rings could not be determined, and they were considered as Kayser-Fleischer-like rings.
737791##1978-12-1##[Treatment of Wilson's disease using triethylenetetramine dihydrochloride (TETA)].##
738900##1978-12-1##Hereditary fructose intolerance in early childhood: a major diagnostic challenge. Survey of 20 symptomatic cases.##Twenty infants and young children with hereditary fructose intolerance (HFI) were admitted to hospital. None was diagnosed at admission. Referals were for vomiting of unknown aetiology (16X), pyloric stenosis or hiatus hernia (5X), toxic condition (3X), and hepatomegaly of unknown origin (5X). Feeding difficulties (20X), vomiting (18X), and failure to thrive (16X) were leading symptoms. The most frequent clinical findings were hepatomegaly (18X), pallor (14X), haemorrhages (13X). Ascites, oliguria, tachypnoea, fever, splenomegaly and rickets were less frequent. Laboratory findings were indicative of disturbed hepatic and renal tubular function and also of disturbed intermediary metabolism (hypokaliaemia, hypophosphataemia). However, hypoglycaemia was found in only 4 out of 15 patients tested. Differential diagnosis after hospital admission centered on metabolic disorders such as glycogenoses, galactosaemia, tyrosinosis, or Wilson's disease. Hepatitis, toxic hepatosis, liver tumour, intrauterine infection and sepsis were also considered. Eleven children had first ingested fructose within the first 6 weeks of life. The diagnosis was usually established only many weeks or months after first fructose intake and appearance of symptoms. This documents how difficult the diagnosis of this disease can be both in practice and in hospital. The course was severe in 11 children and lethal in 4. In only 5 patients was the course mild. The 16 survivors are doing well under fructose-exclusion diet. Irreversible visual impairment after intraocular haemorrhage occurred once. In each case HFI could have been suspected immediately, had a detailed nutritional history been taken. Practising paediatricians should know the composition of commonly used infant formulae. They should never prescribe sugared condensed milk for intractable vomiting prior to excluding HFI. Solution for intravenous infusion containing fructose and sorbitol are life-threatening for undiagnosed HFI patients.
215741##1978-12-1##The pharmacology of 2,3-dimercaptosuccinic acid and its potential use in arsenic poisoning.##Arsenic (As2O3)-poisoned rats were treated with either 2,3-dimercaptosuccinic acid (DMS) or dimercaptopropanol (BAL) at doses of 30 mg/kg/day. A control group received no treatment. The total quantity of arsenic excreted was not significantly different in response to 4 days of treatment with either DMS or BAL. In addition, there was no difference between the two drug treatment groups in the residual arsenic content of brain, liver, kidney and spleen after treatment. Both drugs reduced the arsenic content of each tissue to approximately 40% of that of untreated controls. Previous studies have shown that DMS is orally effective for the treatment of lead poisoning. The LD50 of DMS was determined to be in excess of 3 g/kg in rats and mice, approximately 30 times the LD50 of BAL. No gross, histopathological or biochemical evidence of toxicity was observed in mice, rats or dogs which received DMS 5 days per week for 6 months. DMS did not affect the excretion of zinc, iron, calcium or magnesium. Urinary copper excretion was significantly elevated in response to 30 mg/kg of DMS, suggesting that the drug might also be useful for the treatment of Wilson's disease.
154154##1978-11-30##[Active chronic hepatitis as the only manifestation of Wilson's disease].##
719416##1978-11-18##Don't forget Wilson's disease.##
700330##1978-11-1##Liver copper levels in intrahepatic cholestasis of childhood.##Liver copper concentration was studied in four groups of age-matched patients and in 9 patients with Wilson's disease of comparable age. Neutron activation analysis of hepatic copper concentration revealed markedly elevated hepatic copper levels, comparable with those in Wilson's disease, in 13 of 15 patients (P less than 0.001) with intrahepatic cholestasis of childhood. In 1 patient, autopsy confirmed very high liver copper values, whereas other tissues, including brain and kidney, gave normal results. Total plasma copper values were elevated in 11 of 13 patients with intrahepatic cholestasis of childhood (P less than 0.001); 24-hr urinary copper excretion was normal in 7 of 12 patients and slightly elevated in 5 (P less than 0.001). Kayser-Fleischer rings were sought in 10 patients and were absent. Hepatic copper concentration was not accurately predicted by plasma copper or 24-hr urinary copper. However, increased urinary copper excretion was associated with hepatic copper concentration greater than 250 microgram per g. It is concluded that copper metabolism is abnormal in intrahepatic cholestastis of childhood and can be distinguished from Wilson's disease. If hepatic copper concentration is greater than 250 microgram per g, copper chelation therapy should be considered.
731276##1978-11-1##An unusual neurological disorder of copper metabolism clinically resembling Wilson's disease but biochemically a distinct entity.##A patient with progressive neurological disease resembling Wilson's disease but in whom Kayser-Fleischer rings were absent, was given 67Cu and 64Cu, orally and intravenously, to measure the rate of absorption of copper using a convolution integral. The data show an abnormal distribution of body copper resulting in low copper concentrations in plasma, urine and liver but with an accumulation in the lower bowel probably due to a defect in mucosal transport. The importance of differentiating this condition from Wilson's disease is stressed.
741263##1978-10-7##[Wilson's disease in a black patient. Case report and brief literature review].##A Black patient with Wilson's disease is described. Clinical symptomatology and laboratory findings are reported and diagnosis, pathology, clinical picture and treatment of the disease are discussed.
709490##1978-10-1##Operant management of the behavioural sequelae of Wilson's disease: a case report.##An approach to the management of the behavioural manifestations of Wilson's Disease by operant technique is outlined. There was considerable improvement in the patient's ability to perform autonomously on this program. When the contingencies were changed the patient's behaviour deteriorated markedly, thereby suggesting that improvement in behaviour was not due to medication alone.
713425##1978-10-1##[Involvement of the exocrine pancreas in Wilson's disease? (author's transl)].##A normal exocrine pancreatic function was demonstrated by the secretin-pancreozymin-test in five patients with Wilson's disease either without (n = 2) or with cirrhosis of the liver but without portal hypertension (n = 3). In another patient with cirrhosis of the liver without portal hypertension the pancreas was normal at post mortem examination. In two patients with cirrhosis of the liver and portal hypertension bicarbonate (n = 1) and amylase secretion (n = 2) were diminished. The regression of portal hypertension under therapy with penicillamine in one of the latter cases was paralleled by the return to normal of exocrine pancreatic function. It is concluded that exocrine pancreatic insufficiency in Wilson's disease is dependent on the development and the progression of chirrhosis of the liver and not due to a primary manifestation of the disease itself.
736410##1978-9-1##Ophthalmoscopic changes in a patient with Wilson's disease during long-term penicillamine therapy.##The development of retinal pigment epithelial defects in a young patient with Wilson's disease after long-term penicillamine therapy is described. It is hypothesized that decreased copper availability secondary to penicillamine therapy may result in defective elastin within the lamina of Bruch with resultant defects in the overlying retinal pigment epithelium.
687188##1978-9-1##Wilson's disease and monoamines.##
672596##1978-8-11##[Wilson's disease with juvenile liver cirrhosis and death in acute dystrophic attack].##
581259##1978-8-9##[Acute fatal copper intoxication. Casuistic and considerations on differential diagnosis (author's transl)].##If the diagnosis of copper-intoxication cannot be made by determination of copper in the collected specimen of the intestine, there may be problems in the differential diagnosis. In Wilson's disease and other cases of symptomatical hypercupriaemia copper content of brain tissues is elevated, while it is normal in acute copper intoxication.
80410##1978-8-1##Histological demonstration of copper and copper-associated protein in chronic liver diseases.##Liver copper concentrations in percutaneous biopsy specimens were measured by neutron activation analysis and compared with histological staining for copper by rubeanic acid and rhodanine, and with copper-associated protein stained by orcein. Liver copper concentrations were elevated in 31 of 35 biopsies from patients with primary biliary cirrhosis (PBC), and discrimination between normal and elevated liver copper was correct in 32 of the 35 biopsies by staining with rubeanic acid, and 31 of the 35 by staining with rhodanine. Orcein staining of copper-associated protein was positive in 33 of the 35 biopsies. All 17 biopsy specimens from patients with Wilson's disease had high liver copper concentrations, but only nine had positive staining for copper, and six were orcein positive. Similarly, histological stains gave little indication of the liver copper concentrations in tissue from 16 patients with chronic active hepatitis. Staining of liver sections can be useful in detecting elevation of liver copper in PBC, but not in Wilson's disease, where the absolute concentration must be measured. Excess copper appears to accumulate in the liver in different chemical forms in PBC and Wilson's disease.
682676##1978-8-1##Hematologic (cytopenic) manifestations of Wilson's disease (hepatolenticular degeneration).##The records of 54 consecutive patients with Wilson's disease seen at the Mayo Clinic from 1952 through early 1977 were reviewed to determine the frequency fo hematologic abnormalaties in their evaluation. Leukopenia and thrombocytopenia sometimes have been ascribed to treatment with D-penicillamine and its toxicity; however, we have found cytopenia to be a frequent finding in the presenting laboratory data of patients with Wilson's disease. Twenty-eight patients (52%) had thrombocytopenia and 16 of these patients (30% of the total) also had leukopenia. Severe, acute, intermittent hemolytic episodes were the initial and only presenting complaint of one patient. Six of the patients with significant cytopenias had splenectomy, and in all cases the peripheral blood counts returned to normal values. Long-term treatment with D-penicillamine improved the hepatic and neurologic dysfunction in most patients; however, the cytopenias remained unchanged except in three patients (treated 2, 5, and 10 years).
721242##1978-7-1##Wilson's disease with special reference to ocular manifestations (a case report).##
672914##1978-7-1##[Wilson's disease--pathogenesis, diagnosis and course].##
672913##1978-7-1##[Wilson's disease--pathogenesis, diagnosis and course].##
683783##1978-7-1##Diagnostic dilemmas of Wilson's disease: diagnosis and treatment.##Wilson's disease, an autosomal recessive disorder of copper metabolism, may defy diagnosis in children. The classical triad of Kayser-Fleischer rings, neurologic dysfunction, and hypoceruloplasminemia may be absent. Patients may be seen initially with acute or chronic hepatitis, hemolytic anemia, or neurologic dysfunction. Guidelines are presented for diagnosis of Wilson's disease based on a review of 25 pediatric and adolescent patients. A high index of suspicion in necessary so that therapy with penicillamine may be begun before irreversible liver or neurologic damage occurs. The prognosis is excellent when diagnosis and treatment are established early.
715173##1978-7-1##The urinary excretion of radiocopper in presymptomatic and symptomatic Wilson's disease, heterozygotes and controls: its significance in diagnosis and management.##Radiocopper (64Cu, 67CU), given intravenously, has been used to study the pattern of excretion of copper in patients with presymptomatic, symptomatic and treated Wilson's disease, together with heterozygotes for the Wilson's disease gene and a control group of patients with a variety of neurological lesions mimicking Wilson's disease. Urine was collected for three periods after injection, 0 to 8 hours, 8 to 24 hours, at which time a test dose of penicillamine was given, and from 24 to 30 hours. Stable (endogenous) copper was also estimated on these samples and specific activity was determined. This was multiplied by a correction factor to allow for variations in dose and body weight. The findings for stable copper in urine were largely predictable. Controls and heterozygotes had the least copper excretion, the amounts rising in the presymptomatic to a peak in the symptomatic patients. Institution of therapy was associated with a fall in copper excretion pro rata with time. The most important radiochemical findings were as follows. Heterozygotes excreted less of the injected copper than controls both under basal conditions and after penicillamine. Presymptomatic patients excreted less radiocopper than heterozygotes after penicillamine although the excretion during the basal 24 hour period was very much greater. Patients with symptomatic Wilson's disease had by far the highest excretion of radiocopper in all three time periods which fell after treatment, pro rata with time, as had been found for stable copper. These results were subjected to computer analysis. There was no overlap between the various groups with the exception of a single control subject who had combined pyramidal and extrapyramidal system degeneration of obscure aetiology. This patient was classified by the computer study as 'heterozygote'. These findings lend further support to the hypothesis that the loss of a single gene for copper balance can be detected with a high degree of accuracy and also that presymptomatic patients can be selected from a sibship for prophylactic treatment without the risk of subjecting healthy heterozygotes to unnecessary and potentially hazardous long-term therapy.
78100##1978-6-24##Orcein-positive liver deposits in Indian childhood cirrhosis.##A striking, previously unreported pattern of orcein-positive deposits attributed to excess copper-binding protein was found in liver-biopsy specimens from twelve cases of Indian childhood cirrhosis. A comparable picture was found only in biopsy specimens from patients with Wilson's disease. Deposits seen in about 20% of the two hundred and seventy-nine cases in various control groups, which were associated with prolonged cholestasis, were slight in comparison. This finding could have important therapeutic and pathogenic implications.
349384##1978-6-15##Diagnosis of treatable Wilson's disease.##
696236##1978-6-1##Osteoarthropathy of hepatolenticular degeneration.##Ninety-six joints of 25 patients with hepatolenticular degeneration have been studied by means of scintigraphs with technetium (99mTc), a method which can disclose early synovial inflammation and postinflammatory articular degeneration. Signs of synovitis were found in 22 joints of 10 patients (40%) and degenerative changes were present in 15 joints of eight patients (32%). Eleven patients complained of joint pains; in four of them they were the presenting symptom. The radiological study showed osteoporosis in 22 patients (88%); flexion deformity was found in two cases, anomalous osteophytes in two, and signs of growth arrest, features of rheumatoid arthritis and aseptic necrosis in one case each. The pathogenesis of osteoarticular changes in Wilson's disease is discussed.
661832##1978-6-1##[Early diagnosis of Wilson's disease in childhood (author's transl)].##Most of the time Wilson's disease becomes clinically evident in childhood by atypical abdominal symptoms. Therefore early diagnosis is very difficult. In four out of eight patients with Wilson's disease, diagnosed relatively early in the Children's Hospital of Heidelberg University, we could demonstrate that each case of liver disease, which cannot be classified, may be suspicious of Wilson's disease. Even normal levels of ceruloplasmin in serum and copper in urine are not inconsistent with Wilson's disease. There is no screening method in infancy. Fatty liver in school children is very suspicious of Wilson's disease.
691374##1978-5-1##[Wilson's disease].##
666284##1978-4-1##Physostigmine in Wilson disease.##
205496##1978-4-1##[Lesions of the peripheral nerves in Wilson's disease. Electrodiagnostic findings (author's transl)].##Electrodiagnostical studies were carried out on three patients with Wilson's disease. The motor nerve conduction velocity was low but not markedly decreased. Some values of the sensory conduction velocity were decreased; the sensory action potentials showed low amplitudes and contained large amounts of late phases. Also, the electromyogram of one female patient showed denervation in the begin of treatment. There are no indications of polyneuropathy in Wilson's disease in the literature. There have been histological reports, however, which indicated lesions of the peripheral nerves in Wilson's disease as our own electrodiagnostical findings do.
631513##1978-4-1##Diagnosis of Wilson's disease.##
631501##1978-4-1##Incorporation of radiocopper into ceruloplasmin in normal subjects and in patients with primary biliary cirrhosis and Wilson's disease.##
75819##1978-4-1##Wilson's disease, presenting as chronic active hepatitis.##
730703##1978-4-1##Wilson's disease.##
730692##1978-4-1##Wilson's disease in South India.##
76110##1978-3-11##Screening for Wilson's disease.##
631639##1978-3-1##Lymphocytotoxicity test against rabbit hepatocytes in chronic liver diseases.##We have studied the cytotoxicity against rabbit liver cells of lymphocytes from the peripheral blood of 71 patients with various liver diseases. The group with chronic active hepatitis and three patients with acute alcoholic hepatitis showed significantly higher mean values of lymphocytotoxicity (P less than 0.001) compared with the other patients with chronic persistent hepatitis, post-necrotic fibrosis and cirrhosis. Wilson's disease, and prolonged viral hepatitis. The mean cytotoxicity of these last groups did not differ significantly from controls. In four out of six patients with chronic active hepatitis a significant decrease of lymphocytotoxicity was found after immunosuppressive therapy with oral prednisolone. A good correlation between the lymphocytotoxicity test and histological signs of activity suggests that a cell-mediated immune aggression is present in this disease.
673125##1978-3-1##[Hepatolenticular degeneration in 2 families living in the lower Beskidy Mountain range].##Two families affected with Wilson's disease living in submontane villages of Lower Beskid are presented. The previous observations are confirmed that most of the subjects affected with the disease in Poland origin from geographic isolates. This phenomen is due to increased number of homozygotes in genetically isolated groups.
273188##1978-3-1##D-penicillamine-induced mucocutaneous lesions with features of pemphigus.##Penicillamine (beta1 beta2 dimethylcysteine) is the drug of choice in the therapeutic management of Wilson's disease and cystinuria and has been used in the treatment of some heavy-metal intoxications. Recent studies have shown that it is efficacious in patients with rheumatoid arthritis. Side effects include sensitivity reactions, nephrotoxicity, bone-marrow suppression, hypogeusia, skin lesions, and the formation of autoantibodies. Two cases are described with the features of pemphigus which were attributed to penicillamine therapy.
621603##1978-2-1##Cholelithiasis and Wilson disease.##We have studied three children with Wilson disease who had clinical symptoms suggestive of cholecystitis as well as radiologic evidence of gallstones, subsequently proven at the time of laparotomy. The gallstones from the patients with Wilson disease had an appreciably higher content of cholesterol than gallstones from age-matched children with hemolytic disease. Since gallstones may be present for years before they produce clinical symptoms, young patients with Wilson disease should undergo routine investigation for the presence of stones; cholelithiasis should also be considered in the differential diagnosis of abdominal pain in such patients.
80911##1978-1-1##A neuronal nucleolar trigger mechanism traceable by a routine staining method.##In experimental Wilson's disease produced by the intracardiac injection of copper sulphate, it is seen that the glia-neuronal interactions play an important role in the pathogenesis of neural lesions. A &quot;trigger&quot; copper-RNA particle is transferred from the oligodendroglial nucleus to activate the neuronal nucleolus causing a flooding of the neurone with RNA. This trigger particle stains differently with Mason's trichrome, giving a bright red colour. This altered reaction gives an insight into the feedback process for the formation of ribosomal RNA in the neurones. The alteration appears to lead to a block in the repressor activity of the neuronal RNA formation.
86474##1978-1-1##Profiles of serum complement in patients with hepatobiliary diseases.##CH50 and the concentrations of C3, C4, C1 INH and factor B have been measured in sera from 34 control subjects and 178 patients with various hepatobiliary diseases, including primary biliary cirrhosis (PBC), chronic active hepatitis (CAH), cryptogenic cirrhosis (CC), alcoholic liver disease (ALD), Wilson's disease (WD), large duct biliary obstruction (LDBO) and viral hepatitis (VH). CH50 was decreased in CAH and CC. C3 was increased in PBC, LDBO and VH and decreased in CAH and CC. C4 was decreased in PBC, CAH, ALD and WD. C1 INH was increased in PBC, CAH, ALD, LDBO and VH. Factor B was increased in LDBO and VH and decreased in CC. In none of the patient groups was the mean C4 level increased or the mean C1 INH level decreased. All 5 indices of serum complement were lower in ascitic than nonascitic patients. Data on serum complement were similar in HBsAg positive and negative VH. Discriminant analysis facilitated separation of all the patient groups on the basis of complement data, except PBC and VA. Analysis of data using a within-group correlation matrix revealed a significant negative correlation between C4, the most discriminating variable of serum complement in CAH, and gamma-globulin concentration in CAH. The possible contribution of factors such as activation of complement, impaired hepatic synthesis of complement components, an acute phase response and cholestasis to altered serum complement profiles in different hepatobiliary diseases is discussed.
740190##1978-1-1##[CT scan in Wilson's disease (author's transl)].##We studied nine cases of Wilson's disease on CT scan. In all patients we found cerebral atrophy. In five patients without neurological symptoms we found no specific signs. In the four patients with neurological symptoms we found lenticular caudate nucleus or thalamic areas of hypodensity.
341333##1978-1-1##Eponym: the coups of Cu: Wilson's disease.##
752988##1978-1-1##[Wilson's disease: description of various cases].##
590312##1977-12-2##The influence of prolonged treatment with D-penicillamine on the immune response in Wilson's disease.##Humoral and cell-mediated immunity were studied in a group of patients with Wilson's disease not previously treated with D-penicillamine, and in a group of patients treated with the drug for more than two years. The previously untreated patients showed an exaggerated humoral immune response, i. e. increased levels of IgG and, IgM, higher titer of antibodies to Kunin's antigen, and depression of cell-mediated immunity, namely a decreased response to DNCB, decreased lymphocyte transformation after stimulation with Con A, PPD, Candida and streptokinase and a reduced response to streptokinase in the MIF test. After treatment the humoral response returned to normal, and in the case of IgA and antibodies to S. typhi O antigen, it even dropped below normal values. The cell-mediated immune response returned to normal with the exception of lymphocyte transformation by PHA and Candida albicans. In in vitro studies it was found that D-penicillamine had no influence on lymphocyte transformation when PHA and Con A were used as mitogens. With PPD as antigen, lymphocyte stimulation and migration inhibition were inhibited by concentrations of penicillamine ranging from 6 to 1000 microgram/ml.
600273##1977-12-1##[Morbus wilson--progressive fatal course of the hepatic form with apoplexy and abscess of the brain (author's transl)].##The onset with a hemolytic crisis, as often described in the literature, led to the diagnosis of Wilson's disease. Treatment was immediately started in the usual way with diet and d-penicillamin. But the disease had already caused serious liver damage and renal lesions, and the patient died fourteen weeks after diagnosis. Examination of further family members disclosed a cousine with impaired liver and kidney function, also suffering from the hepatic form of homozygous Wilson's disease.
600271##1977-12-1##[Morbus Wilson--pathogenesis, diagnosis, therapy, and course (author's transl)].##During childhood, Wilson's disease becomes manifest mostly in the hepatic form. In children every case of cirrhosis of the liver, hemolysis with high levels of conjugated bilirubin in the serum, and otherwise in explicable tremor make it imperative to exclude or confirm the existence of Wilson's disease. A false diagnosis often delays the start of therapy with d-penicillamine and low-copper diet. The prognosis, which was still fatal a few years ago, has improved considerably thanks to new therapeutic possibilities.
73055##1977-11-26##New screening method for Wilson's disease and Menkes' kinky-hair disease.##
930944##1977-11-1##Penicillamine-associated myasthenia gravis, antiacetylcholine receptor and antistriational antibodies.##Myasthenia gravis with thymic hyperplasia developed in a patient with Wilson's disease after eight years of penicillamine treatment. Four months prior to the onset of myasthenia, penicillin hypersensitivity was observed. Immunofluorescence on the excised thymus revealed immunoglobulin and complement deposition, but the myasthenia persisted after thymectomy and continuation of penicillamine therapy. Increased antiacetylcholine receptor antibody was demonstrable throughout. This patient subsequently became pregnant, enabling studies to be performed on the transplacental transfer of the immunoglobulin G (IgG) class antiacetylcholine receptor antibody. Eleven cases of rheumatoid arthritis with penicillamine-associated antistriational antibodies have also been observed; in three of these cases there was evidence of myasthenia gravis. These observations extend earlier reports of the association of penicillamine with myasthenia gravis and suggest that antistriational antibody, antiacetylcholine receptor antibody and thymic hyperplasia may be independent effects of penicillamine therapy.
931247##1977-11-1##[Arthropathies in Wilson's disease].##
273064##1977-11-1##Renal tubular acidosis in Wilson's disease: characteristics, mechanisms and implications.##
601776##1977-11-1##Pregnancy and delivery in penicillamine treated patients with Wilson's disease.##Pregnancy and delivery of two patients with Wilson's disease are reported. Case 1 was a 20-year-old housewife who had been taking D-penicillamine fore more than 10 years and had remained asymptomatic except an episode of dissociative reaction. She apparently survived longer than any of her three sisters who died of the same disease. She discontinued the use of D-penicillamine by herself when she was at the 22nd week of pregnancy. Case 2 was a 32-year-old housewife who developed an episode of mental disorder of short circuit reaction type with mild neurological symptoms and Kayser-Fleischer rings after the prolonged interval of medication since the first pregnancy and delivery. Three months after the complete recovery of neuropsychiatric symptoms she was at the 12th week of pregnancy and withheld penicillamine from herself. During the pregnancy they had not revealed any exacerbation in terms of clinical and laboratory findings. Each of them was delivered of a healthy baby. Although the pregnancy and delivery of both patients were successful, the authors recommended that they should not prolong the interval of medication to protect themselves against the onset or relapse of the illness.
243207##1977-10-27##New diagnostic method for Wilson's disease.##
913436##1977-10-12##Prognosis of Wilson's disease in childhood.##Wilson's disease in childhood has several characters distinct from those in adults. The progression of the disease tends to be rapid, hepatic manifestations are common, cerebral symptoms related to dystonia are predominant, and tremor is rare. Forty-nine children with Wilson's disease under the age of 15 were treated with D-penicillamine for 2 to 15 years. None of the presymptomatic patients subsequently developed any symptoms of the disease. The results of treatment in patients who had exhibited only hepatic symptoms were also excellent. However, neurological manifestations associated with a history of jaundice or ascites responded less well to chelation. These observations clearly indicate that early diagnosis and treatment are extremely important to ensure normal lives for children with Wilson's disease.
913055##1977-10-1##The effect of certain chelating compounds on the urinary excretion of copper by the rat: observations on their clinical significance.##1. A screening procedure is described to assess rapidly the clinical potential of chelating agents for the treatment of Wilson's disease. 2. Rats were used as the test animal; they were kept in metabolic cages and the urine was collected in copper-free containers. The compounds investigated were given by mouth as a standard dose of 100 mg. Copper was determined by atomic absorption spectrophotometry. 3. Basal urine copper excretion was 65-1 +/- SE 2-93 nmol/24 h (4-1 microgram +/- 0-185). After penicillamine this rose to 367-1 nmol and after trien to 305-9 nmol. 4. Certain compounds caused a reduction in the amount of copper excreted in the urine, probably by forming insoluble chelates with the metal, hence rendering it unavailable for excretion at the glomerulus.
892368##1977-10-1##Lipolysosomes in human liver: distribution in livers with fatty infiltration.##In this study we investigated whether lipolysosomes--lysosomes containing large lipid droplets--were present in livers of patients with various forms of hepatic injury. Organelles which displayed the same morphological characteristics and enzymatic activity as those originally described in the hamster and those found in the hepatocytes of patients with Wolman's or Wilson's disease were also found in hepatocytes of 13 of 14 randomly selected biopsy specimens from patients with minimal to severe fatty infiltration of the liver. The numbers and sizes of the lipolysosomes seemed to increase with the degree of fatty infiltration while their proportion in relation to the total number of lipid droplets remained below 5%. Based on these observations of a virtually constant association of lipolysosomes with excess lipid accumulation in liver cells we suggest that lysosomes probably play an important role in hepatic lipid metabolism and that various pathogenetic mechanisms may trigger their proliferation.
904351##1977-10-1##Early pleural decortication for thoracic empyema in immunosuppressed patients.##Patients with empyema and impaired immune response often remain in a toxic condition after tube thoracostomy because the infection is not localized and walled off satisfactorily. Consequently, the reported mortality rate is extremely high. Despite the expectation of a high mortality rate from thoracotomy and débridement in this category of critically ill patients, we were forced to perform pleural decortication in eight patients after lesser procedures had failed. They were immunodeficient because of (1) high-dose steroids (HDS) for sagittal sinus thrombosis, (2) HDS for systemic lupus erythematosus, (3) HDS for chronic myelogenous leukemia and myelofibrosis, (4) HDS for multiple myeloma, (5) hemolytic anemia with pulmonary infiltrates, (6) chemotherapy for Hodgkin's disease, (7) diabetes mellitus with Kimmelstiel-Wilson disease, and (8) diabetes mellitus with chronic glomerulonephritis. Six of the eight patients survived and were discharged with completely healed incisions 3 to 6 weeks after operation. This compares well with the survival rates reported by others. Although risky, the over-all survival rate may be better with thoracotomy and decortication than with prolonged tube drainage and open drainage in immunodeficient patients with empyema, and the period of morbidity is shortened considerably.
413153##1977-10-1##The pattern of the whole body distribution of radioactive copper (67Cu, 64Cu) in Wilson's Disease and various control groups.##
337458##1977-10-1##[Associated and secondary chondrocalcinosis].##The authors consider the problems posed by secondary and associated chondrocalcinosis (CCA) on the basis of a study carried out at many French Rheumatology centres (Centres de Rhumatologie Française) and in the light of data in the literature. CCA is associated with gout in 4 percent of cases, with hyperparathyroidism in 3.9 percent of cases, with haemochromatosis in 1.7 percent of cases and with hypothyroidism in 0.8 percent of cases. The existence of secondary CCA in gout, hyperparathyroidism, haemochromatosis, Wilson's disease, ochronosis, hypophosphatasia and perhaps hypothyroidism seems proven. These secondary cases of CCA represent 10.7 percent of the total 1226 : here CCA seems to form one element of a much broader syndrome, namely the metabolic arthropathies. The other associations, with the exception of those which are not considered in this paper (rheumatoid polyarthritis, diabetes mellitus, Paget's disease, osteochrondromatosis, acromegalia), are probably coincidental.
902043##1977-9-10##Fulminant Wilson's disease with haemolysis and renal failure: copper studies and assessment of dialysis regimens.##Two girls, aged 12 and 17 years, presented with hepatocellular dysfunction and severe haemolysis due to Wilson's disease (hepatolenticular degeneration). This was accompanied by acute renal failure. In the absence of renal function sufficient for the urinary excretion of penicillamine, studies were performed to assess the potential of peritoneal dialysis, ascites removal by ultrafiltration-reinfusion, and haemodialysis as alternative excretory pathways for copper. The greatest amount of copper, as judged by rising bath concentrations, seemed to be eliminated with haemodialysis. But this was accompanied by a progressive increase in serum copper concentrations with rapid clinical and biochemical deterioration leading to death within 48 hours. A small amount of copper was lost with ascites removal. Significant amounts of copper were removed during peritoneal dialysis (36 mumol/day (2287 microgram/day)), although a clinical response was not evident before haemodialysis was introduced. The administration of penicillamine orally, intravenously, or intraperitoneally produced no measurable increase in copper excretion into the peritoneal dialysate. Hence peritoneal dialysis alone appears to offer the greatest potential benefit with regard to both eliminating copper and altering the course of this fulminant form of Wilson's disease.
243400##1977-9-1##Hepatolenticular degeneration--Wilson's disease.##
888802##1977-8-1##Fulminant hepatitis. A presentation of Wilson's disease.##A boy, 10 years of age, was admitted to the hospital with rapid onset of hepatic failure and died within three weeks. Laboratory and pathological data were consistent with Wilson's disease. We discuss the importance of Wilson's disease in the differential diagnosis of acute liver failure.
331163##1977-8-1##Hepatolenticular degeneration (Wilson's disease) and pregnancy. A review and report of a case.##This article presents a case report of Wilson's disease in pregnancy and a review of this entity during gestation. Biochemical and pathological data are reviewed and current treatment is discussed. Pertinent questions of interest to the obstetrician are indicated with reference to Wilson's disease.
560768##1977-7-10##[Wilson's disease].##
861910##1977-7-9##Wilson's disease: a common liver disorder?##In two sibships 7 of 24 siblings were homozygous for Wilson's disease. In family A, the largest kindred of this recessively inherited disease thus far reported, the proband presented with chronic active hepatitis, one sibling died of cirrhosis, a second had clinical evidence of chronic liver disease and two others had biochemical and histologic changes in liver biopsy specimens. In family B the proband had cirrhosis and portal hypertension and one sibling had biochemical and histologic evidence of liver disease. All six living patients had low serum concentrations of ceruloplasmin and copper and a high 24-hour urinary excretion of copper, which was greatly increased by administration of D-penicillamine. None showed neurologic abnormalities and only one had Kayser-Fleischer rings (detectable only by slit-lamp examination). Each patient had an erythrocyte sedimentation rate (ESR) of 8 mm/h or less. After 3 and 2 years, respectively, of D-penicillamine therapy the conditions of the two probands had improved. Liver function became normal in three siblings, and no abnormalities developed in the remaining one. Thus, since Wilson's disease may present with chronic active hepatitis or cirrhosis with a normal ESR and without ocular or neurologic signs, it may be a more common cause of liver disease in young people than has been appreciated.
408620##1977-7-8##[Applied neurochemistry (author's transl)].##Metabolic disorders may also be accompanied by neurological symptoms. Diagnosis is ofter difficult because clinical opportunities are rare. But some things can be detected even by simple means. In particular, primary biochemical disturbances are discussed, insofar as they may have an unfavorable effect on the nervous system. Among these are hypoglycemia, hyperglycemia, cerebral nutritional disorders, phenylketonuria. Wilson's disease, folic acid deficiency and acute intermittent porphyria.
875462##1977-7-1##The ophthalmologic manifestations of Wilson's disease.##Fifty-three patients with Wilson's disease were studied with regard to ophthalmologic abnormalities. Of the 35 symptomatic patients initially seen and treated at the Mayo Clinic, 34 (97%) had Kayser-Fleischer rings and 6 (17%) had sunflower cataracts at the time of diagnosis. In patients followed for a year or more, penicillamine therapy resulted in improvement of the Kayser-Fleischer rings in 18 of 20 (90%) patients and total clearing of the sunflower cataracts in 4 of 5 patients. The specific pattern of copper deposition in Kayser-Fleischer rings and the improvement with treatment occurred along four reproducible stages. None of five asymptomatic siblings of patients with known Wilson's disease had Kayer-Fleischer rings at the time of initial study. In one (untreated) of the five, Kayser-Fleischer rings developed 20 months after the initial normal slit-lamp examination. The presence of Kayser-Fleischer rings, and the absence of other ophthalmologic signs (such as nystagmus, cranial nerve palsies, and other movement disorders), can be of great assistance in the diagnosis of Wilson's disease. Once the condition has been diagnosed, specific medical therapy with penicillamine and low-copper diet dramatically improves what would otherwise be an inevitably fatal course.
302903##1977-7-1##The mechanisms of hemolysis in Wilson's disease: study of a case and review of the literature.##
869375##1977-6-1##Wilson's disease: disseminated intravascular coagulation?##
558126##1977-6-1##Kayser-Fleischer-like rings in patients without Wilson's disease.##Three patients, one with cryptogenic cirrhosis, one with active chronic hepatitis and one with neonatal hepatitis, were found to have corneal pigmentation rings indistinguishable from early Kayser-Fleischer rings on slit lamp examination. They did not have the clinical features of Wilson's disease and their serum copper and ceruloplasmin concentrations were normal. Urinary copper excretion rates and hepatic concentrations were only slightly raised but were below the range found in symptomatic Wilson's disease. It is concluded that the Kayser-Fleischer ring would no longer be considered as pathognomonic of Wilson's disease.
877627##1977-6-1##Chronic active hepatitis and cirrhosis in Wilson's disease.##A 32-year-old woman was found to have chronic active hepatitis and cirrhosis after exploratory celiotomy resulted in hepatic decompensation. Subsequent investigation confirmed the diagnosis of Wilson's disease. This case demonstrates that Wilson's disease may manifest itself as chronic active hepatitis as late as the fourth decade of life without neurologic symptoms or findings. Wilson's disease should be actively considered in patients with chronic active hepatitis or cirrhosis, even in older age groups and despite the absence of central nervous system manifestations.
576947##1977-5-30##Ravages of copper in early Wilson's disease.##
576942##1977-5-30##Hemolytic anemia in Wilson's disease. A report of three cases with transient increase in hemoglobin A2.##Three patients with Wilson's disease and initial manifestations of intravascular hemolysis also had transient elevations of hemoglobin A2. It is important to recognize such manifestations in establishing an early diagnosis.
198888##1977-5-23##[Striatal syndrome and hypokalemia].##The authors present the case of a patient with a striated syndrome resembling Wilson's disease but without the disorder of cooper metabolism. The clinical picture was completely masked by a hypokalemia at 1 mEq/l following urinary loss of this cation, due to ascending interstitial nephritis. Correction of the potassium deficiency produced rapid reappearance of the initial neurological syndrome.
67445##1977-5-7##Wilson's disease and chronic active hepatitis.##
857731##1977-5-1##Elastosis perforans serpiginosa induced by penicillamine.##A patient with Wilson disease, under prolonged treatment with penicillamine, developed lesions of elastosis perforans serpiginosa (EPS). Examination of biopsy specimens by light microscopy revealed the characteristic changes of EPS. Examination by transmission electron microscopy revealed structural changes in the elastic fibers not previously described. The appearance of the lesions by scanning electron microscopy is described for the first time. It is suggested that penicillamine induced EPS may be morphologically distinct from the idiopathic form.
195257##1977-5-1##[Copper and nervous system. An experimental study (author's transl)].##Sodium azide is known to produce alterations in mammalian copper proteins, thus rendering them unable to bind exogenous metal, which remains in the &quot;labile pool&quot; condition. Continuous administration of sodium azide at LD50 for 30 days causes copper accumulation in several tissues and even in the nervous system, with characteristic changes in neurones and glial cells, very much resembling the alterations observed in Wilson's disease. Dietary copper administration, on the contrary, though raising the level of tissue-bound metal, does not produce cellular damage. These findings allow us to suppose that sodium azide may alterate the coppper chelating proteins in the tissues, especially in the nervous system, thus causing the storage of cell-toxic &quot;labile pool&quot; metal. The pathogenesis of Wilson's disease and the problem of &quot;pathoclisis&quot; in the nervous system are debated.
919044##1977-5-1##[2 cases of verruciform perforating elastoma after prolonged administration of D-penicillamine in Wilson's disease].##
859765##1977-4-11##[Cholesterol esterification catalysed by LCAT and erythrocyte lipid pattern in Wilson's disease].##
888700##1977-4-1##Juvenile Wilson disease: unusual features in three cases.##
857745##1977-4-1##Arthropathy of Wilson's disease. Study of clinical and radiological features in 32 patients.##The principal clinical features and radiological findings relating to the locomotor system have been studied in 32 consecutive hospital admissions of patients with Wilson's disease. 5 of these patients were recently diagnosed and had as yet received no treatment, while 27 were routine admissions for follow-up and biochemical supervision of their illness. No patient was specifically included or excluded from the series because of the presence or absence of locomotor symptoms. The most common radiological abnormality was a generalized increase of radiolucency, interpreted as skeletal demineralization (21 cases), followed by premature osteoarthrosis (8 cases). Changes in the spine were common and included osteochondritis, reduction of intervertebral joint spaces, osteoarthrosis, and a tendency to squaring of vertebral bodies. Other bony changes included fluffy irregularity of femoral trochanters, osteochondritis dissecans of the knees, osteophytic protrusions at bone ends, and bunches of tongue-like osteophytes at joint margins. The symptoms associated with these radiological abnormalities comprised back pain and stiffness with restricted movement, pain and stiffness of knees, hips, and wrists, and tenderness to pressure over margins of affected joints. Joint hypermobility was also observed in 9 patients. Episodes of acute polyarthritis with serological changes were seen in 5 cases; all these episodes appeared to be related directly to treatment with penicillamine.
271391##1977-4-1##Ocular manifestations of Wilson's disease in Iran.##Within the last 5 years, 25 proved cases of hepato-lenticular degeneration (Wilson's disease) have been seen at the Children's Hospital Medical Center affiliated to Tehran University. The disease manifested abnormal copper metabolism in the following respects: (1) Hypoceruloplasminaemia was present: (2) 24-hr urinary copper excretion was low; (3) Tissue concentration of copper was high; (4) Treatment with penicillamine led to increased copper excretion in the urine and usually to relief of symptoms. The ophthalmologist cannot always assist the paediatrician in diagnosis, but fourteen of the 25 patients showed a Kayser-Fleischer ring and these were all in the older age groups. The following conclusions were drawn: (1) The incidence of Wilson's disease in Iran is high; (2) Penicillamine treatment may be successful; (3) Any young person with kidney, liver, or neurological disease of uncertain aetiology should have a detailed ophthalmological examination.
65694##1977-3-12##Wilson's disease and chronic active hepatitis.##
842989##1977-3-1##Acute intravascular hemolysis and acute liver failure associated as a first manifestation of Wilson's disease.##In three patients, the first manifestation of Wilson's disease was a syndrome in which acute intravascular hemolysis and acute liver failure were associated. This syndrome developed in three periods; the first, lasting 3 to 14 days, was characterized by fatigue, fever, and jaundice; the second, lasting 1 or 2 days, by severe intravascular hemolysis; and the third, lasting 2 to 6 days, by hepatic encephalopathy. All of the patients died from liver failure 7 to 21 days after the onset of the syndrome. The association of acute intravascular hemolysis and acute live failure is a characteristic manifestation of Wilson's disease; it is rarely associated with other liver diseases. This association might result from hepatic cell necrosis due to accumulation of copper, the consequences being acute liver failure and destruction of erythrocytes by the large amounts of copper released from the necrotic hepatic cells to the plasma.
842986##1977-3-1##Pigmented corneal rings in non-Wilsonian liver disease.##Kayser-Fleischer rings are pigmented corneal rings at the limbus of the cornea in Descemet's membrane that have been deemed pathognomonic of Wilson's disease. However, we have observed four exceptions in patients with non-Wilsonian liver disease. Three patients had primary biliary cirrhosis and one patient had chronic aggressive hepatitis with cirrhosis. Pigmented corneal rings were seen only by slit-lamp examination. Hepatic, serum, and urinary copper and serum ceruloplasmin levels were significantly elevated in the patients with primary biliary cirrhosis. Radiocopper (64Cu or 67Cu) studies in patients with primary biliary cirrhosis showed plasma disappearance curves which allowed a clear distinction from Wilson's disease in that all three patients with primary biliary cirrhosis showed a secondary rise in radiocopper that presumably represented copper incorporation into ceruloplasmin. In one patient, in whom 64Cu in ceruloplasmin was studied specifically, incorporation was found to be normal.
193062##1977-3-1##[Cytochemical studies of peripheral white blood cells in Wilson's disease].##Using cytochemical methods the authors studied the activity of certain lysosomal enzymes and cytochrome oxidase in peripheral blood leucoytes in 22 patients with Wilson's disease. The control group comprised 50 healthy blood donors. It was found that the activity of acid phosphatase in the lymphocytes of patients was higher than in controls, the mean indices being respectively 90.50 +/- 8.95 and 60.38 +/- 3.95. The activity of beta-glucuronidase was found to be lower in the lymphocytes of patients, the mean value was 25.10 +/- 8.59 in patients and 64.91 +/- 5.78 in controls. The activity of cytochrome oxidase was lower in the granulocytes of patients with Wilson's disease than in controls, the mean values being 54.5 +/- 12.14 and 156 +/- 15.41 respectively. The activity of acid phosphatase in granulocytes as well as that of non-specific esterase in lymphocytes was similar in both groups. Decreased antigen degradation in Wilson's disease may be due not only to liver cirrhosis but also to disturbances in the metabolism of white blood cells, including, among others, decreased activity of cytochrome oxidase. The rise of the activity of acid phosphatase and reduced activity of beta-glucuronidase indicate chronic antigenic stimulation of lymphoid system.
65591##1977-2-26##Wilson's disease and chronic active hepatitis.##
597990##1977-2-1##[Eye manifestations of Wilson's disease].##
839581##1977-2-1##Torsion dystonia: a case report.##A 35-year-old black female with typical torsion dystonia is discussed. Tremors in the right upper extremity began with a febrile illness at age eight. Difficulty in using the extremity began two years later. Overt writhing movements and torticollis began at age 17. The disorder has been progressive, but not disabling. Neurological examination revealed only extrapyramidal motor system dysfunction. Serum dopamine Beta hydroxylase levels were normal, and an evaluation for Wilson's disease was negative. A sibling has minor writing difficulties.
190476##1977-2-1##The peroxisomes of human hepatocytes.##In an ultrastructural study of human liver biopsy specimens we found that peroxisomes are regularly present in normal human hepatocytes. Their relationships with the endoplasmic reticulum observed in other species and in other organs were also demonstrable in this material. Some normal peroxisomes were found to display marginal plates or peripheral crystalline inclusions which were present in pathologic specimens as well. In certain inherited metabolic disorders (Menkes' steely hair disease, analbuminemia) the volume of the individual peroxisomes appeared to be considerably reduced. But most pathologic processes affecting hepatocytes seem to produce any or several of the following: increased volume or numbers per cell, changes of shapes, alterations of the consistency of the matrix, appearance of dense numbers per cell, changes of shapes, alterations of the consistency of the matrix, appearance of dense inclusions, or clustering of peroxisomes in some portions of the cytoplasm. Some of these abnormalities are reversible based on observations in three patients with Wilson's disease treated with D-penicillamine. The mean +/- standard deviation of diameters of peroxisomes in four normal subjects was 0.618 +/- 0.143 mum. Significant reductions or increases in mean diameters of peroxisomes were noted in all but two of the 16 pathologic specimens. There were other morphologic abnormalities present in the remaining two specimens. We conclude that various pathologic processes involving the hepatocytic cytoplasm exert different effects on peroxisomes. Although no specific pattern of morphologic alteration emerged from this exploratory study, a possible involvement of peroxisomes ought to be considered whenever metabolic or pathologic processes affect the liver.
68781##1977-2-1##[Alcoholic hyaline-like bodies in nerve cells of the caudate nuclei in various diseases of children].##Intracytoplasmic hyaline bodies were noticed in nerve cells of the caudate nuclei of the infantile diseases: Leigh's encephalomyelopathy (12-year-old, male), Wilson's disease (14-year-old, male), Morquio's disease (12-year-old, male), pseudoulegyric type of hepatocerebral degeneration (19-year-old, male) and Schilder's disease (15-year-old, male). The hyeline bodies were noticed as linear, striate, dendritic or antler-like in form and stained pink or red with hematoxylin-eosin, orange or red with tmasson trichrome, and dark blue or purple with phosphotungstic acid hematoxylin. The characteristics of the neuronal inclusions have much resemblance to the &quot;alcoholic hyaline-like bodies&quot; which were described by K. Kojima in the caudate nuclei of alcoholics. The results may indicate that the presence of the hyaline bodies in the caudate nucleus is not pathognomonic for alcoholic intoxication, but may suggest the presence of a certain common metabolic disorder among the described diseases.
930749##1977-1-1##Failure of L-dopa to relieve activated rigidity in Parkinson's disease.##Rigidity in Parkinson patients can be easily quantitated by determining net work required to passively flex and extend the forearm through an arc of 100 degrees. Rigidity thus measured can be subdivided into two very distinct types, resting and activated. Resting rigidity, measured while the patient is relaxed, responds to all effective therapeutic agents and correlates closely to degree of clinical improvement. Activated rigidity, measured during voluntary activity, is not relieved by any presently available medical treatment. It remains unchanged at pre-therapy levels even in patients who may temporarily appear to have dramatic improvement in clinical symptomatology. Longitudinal measurements made in hundreds of parkinson patients over intervals ranging from 5 to 15 years show continuing high levels of activated rigidity through the entire period of study. In marked contrast to our wide experience with parkinson patients is a single, well documented case of Wilson's disease who appears to have recovered completely both by clinical examination and by all of our machine measurements. This patient had high levels of extrapyramidal deficit, repeatedly measured over a period of four months when penicillamine therapy was being investigated. He then suddenly reverted to normal and returned to full time employment. High values of resting rigidity activated rigidity, akinesia and resting tremor all reverted to normal and have remained normal for the past 6 years. The implication of this study is that L-dopa and related treatments only mask the symptomatology of Parkinson's disease and are not retarding the underlying pathological process. Penicillamine, on the other hand, probably does relieve the destructive process in Wilson's disease and may in early cases, permanently relieve the extrapyramidal dysfunction.
244388##1977-1-1##Peptiduria in the Fanconi syndrome.##Peptide excretion has been studied in 20 cases of Wilson's disease and in maleate-induced Fanconi syndrome in the rat, ligand-exchange column chromatography being used to separate peptides from free amino acids. There is a statistically significant increase in urinary peptides in both types of the Fanconi syndrome. In both man and the rat, a large fraction of the excreted peptides has been shown to contain hydroxyproline, and therefore to be derived from collagen degradation. In both groups there is a close correlation between the output of hydroxyproline and that of total peptide-bound amino acids. Arguments are advanced that the peptiduria is due to increased urinary clearance of plasma peptides rather than to a metabolic cause. Peptides excreted in patients with the Fanconi syndrome are shown to have a different proportionate amino acid composition to those in urine specimens from normal controls. The mean size of urinary peptides derived from collagen must be at least five or six amino acids per peptide chain. Maleate-induced Fanconi syndrome in the rat is thought to be a close analogue of the syndrome in man, and further results obtained in the animal model may well be directly applicable to human disease.
892260##1977-1-1##Biliary copper excretion in man and the rat.##The form in which copper is bound in bile was studied in bile from patients with Wilson's disease, control subjects and rats. Bile was labelled with 64Cu. Sephadex column chromatography using gels G-200--G-10 showed a major 64Cu and protein peak of about 5,000 daltons and a minor peak of about 8,000 daltons. A high-molecular-weight peak (above 800,000 daltons) which was present when the eluting solution consisted of water or saline was shown to be an artefact which could be abolished by the addition of bile salt to the eluting solution. Bile from control subjects, Wilson's disease patients and from the rats behaved in the same manner binding copper to low-molecular-weight proteins. The relationship of these findings to the pathogenesis of copper retention in Wilson's disease is discussed.
924311##1977-1-1##Voice and speech in Wilson's disease.##
21123##1977-1-1##[Clinical polymorphism and ceruloplasmin variants in hepatolenticular degeneration].##The relationship between differences in the clinical polymorphism of hepatolenticular degeneration (Wilson's disease) and characteristics of CP (ceruloplasmin) structural changes were investigated. The comparative study of Wilson's disease patients revealed two forms of clinical development of this disease which differ from each other by the expression of the visceral symptoms preceding the establishment of the typical neurological picture. The peptide map analysis of tryptic hydrolysates of the CP from individual patients has demonstrated the altered peptide patterns in five cases. Clinical and genetic heterogeneity of Wilson's disease is discussed.
614957##1977-1-1##[A case of Wilson's disease (hepatolenticular degeneration) with a distinct clinical development].##
838566##1977-1-1##Heterogeneity of Wilson's disease in Israel.##In a survey in Israel of 50 patients with Wilson's disease, it was found that this disease occurred in all ethnic groups. In the Arab patients there was a significantly early age of onset and the disease followed a more severe course than that in the Jewish patients. The overall sex ratio of patients was nearly 1:1, and genetic analysis of 20 families confirmed an autosomal recessive mode of inheritance. The very similar age of onset and type of disease within sibships and the varying ages of onset noted between the Arab and Jewish patients suggest that the disease is genetically heterogeneous.
838874##1977-1-1##Reduced oxidase activity in the caeruloplasmin of two families with Wilson's disease.##Caeruloplasmin has been determined immunologically and by coper oxidase activity in 25 normal subjects, 20 patients with Wilson's disease, and 80 patients with chronic liver disease. Repeated estimation in four patients with Wilson's disease and two heterozygous mothers from two families revealed a consistent reduction in the copper oxidase activity of caeruloplasmin (12-32 units copper oxidase activity/mg caeruloplasmin) relative to the values obtained in normal subjects, patients with chronic liver disease, and other Wilson's disease patients (mean 65-79 units/mg). It is suggested that the functional abnormality in caeruloplasmin observed in these two families is an inherited variant, which does not appear to be due to the presence of a serum inhibitor of copper oxidase.
917352##1977-1-1##Primary and secondary disturbances in trace element metabolism connected with genetic metabolic disorders.##Several primarily inherited disturbances of minerals and trace elements have been discovered within the last 20 years. Secondary disturbances of selenium and zinc induced by dietetic treatment of inborn errors of metabolism and by parenteral nutrition also came to our knowledge recently. Two main types of chronic or primary hypomagnesaemia are known which are caused either by impaired intestinal absorption or by false magnesium handling by the kidneys. In acrodermatitis enteropathica, an autosomal-recessive inherited disease leading to characteristic skin lesions, alopecia and dystrophy, low zinc concentrations of serum, urine and hair are measured. The intestinal absorption of zinc is reduced. In copper metabolism two inherited diseases are known with low serum and usually caerulosplasmin concentrations. In Menkes' steely hair syndrome (trichlpoliodystrophy) an intestinal net malabsorption of copper exists, whereas in Wilson's disease the copper contents of several organs are increased.
20919328##2010-10-5##Course of Chronic Active Hepatitis in Wilson's Disease [Abstract].##
122670##1977-1-1##Penicillamine-induced arthropathy in Wilson's disease.##
122652##1977-1-1##Preparation of and clinical experiences with trien for the treatment of Wilson's disease in absolute intolerance of D-penicillamine.##
122651##1977-1-1##Brief observations on the management of Wilson's disease.##
866569##1977-1-1##Pregnancy in Wilson's disease.##The effect of pregnancy has been studied in 10 mothers with Wilson's disease. Three were presymptomatic but had the typical biochemical lesion, two of these were receiving penicillamine treatment at the time of conception, the third had yet to be diagnosed. The remaining seven mothers had had symptoms of Wilson's disease and had been receiving treatment for periods ranging from two and a half to 19 years. These mothers had 15 pregnancies between them, 13 went to full term but two ended prematurely at 26 and 30 weeks. In only one did pregnancy have an unfavourable effect on the Wilson's disease; this mother had been on penicillamine for only two and a half years in a suboptimal dose because of drug induced thrombocytopoenia. In addition she had extensive oesophageal varices and pregnancy was complicated by toxaemia. The other nine patients remained well and two had three pregnancies each. On six occasions penicillamine was taken throughout pregnancy, but in seven it was discontinued from the sixth to the twelfth week. All 15 babies were normal but one died of extreme prematurity (26 weeks gestation). Pregnancy does not appear to be contraindicated in well treated Wilson's disease and penicillamine does not seem to pose an undue risk to the foetus.
191922##1976-12-9##[Severe hemolytic jaundice and Wilson's disease].##The onset of spontaneous hemolytic jaundice in a young subject should lead to the search for Wilson's disease when clinical examination reveals cirrhosis. This hemolysis may evolve in the form of severe jaundice to a stage where the cirrhosis remains usually latent or well tolerated. The intervention of a toxic, allergic of infective factor liable to produce a hepatic lesion which frees a dose of copper sufficient to trigger off hemolysis, is discussed. The mechanism of the latter, that of the coagulation disorders observed, liver cell failure and widespread intravascular coagulation, are analysed in this paper and compared with data in the literature. The dramatic character of the case indicates that it is necessary to treat as a routine with penicillamine all homozygous forms of Wilson's disease.
1036679##1976-12-1##Wilson disease. Comparative ultrastructure in a sibship of nine.##Comparative electron microscopy was done on liver tissue from a family of nine siblings to determine whether presymptomatic, affected patients with Wilson disease could be differentiated from heterozygous, normal carriers. Two of the nine had developed the neurologic manifestations of the disease; three others were considered to be homozygous but normal, two were heterozygous and normal, and two were classified as genotypically uncertain because of borderline biochemical abnormalities. Alterations of the mitochondria and endoplasmic reticulum suggestive of copper toxicity were present in both the heterozygous and the genotypically uncertain siblings, and a clear distinction could not be made on this basis. The severity of the abnormalities appeared to correlate with liver copper level, and organelle changes were found to precede lipid accumulation.
1050367##1976-12-1##Wilson's disease: a rare genetic disorder.##
1037129##1976-12-1##[Episodic mental disorders in Wilson's disease (author's transl].##
1012227##1976-11-3##[Wilson's disease. Summary of studies carried out in a family group with Wilson's disease. Significance of amino-acid balance in homo and heterozygotes for the detection of liver damage].##
61477##1976-10-9##D-penicillamine-induced IgA deficiency in Wilson's disease.##
958285##1976-10-7##Letter: Pregnancy in penicillamine-treated patients with Wilson's disease.##
971577##1976-10-1##Urinary excretion of peptides and of hydroxyproline in Wilson's disease.##1. A study has been made of peptide excretion in twenty cases of Wilson's disease, ligand-exchange column chromatography being used to separate peptides from free amino acids. Previous reports of excess of peptide output in the disease were confirmed and the excess was shown to be highly significant statistically. 2. A considerable fraction of the excess of peptide output was shown to consist of hydroxyproline-containing peptides derived from collagen degradation. 3. The method of rank correlation showed that the difference both in free amino acid and peptide-bound amino acid output in cases of Wilson's disease and in control subjects was mainly quantitative; the pattern of amino acid excretion was qualitatively similar in both groups. 4. Evidence is presented that the increase copper output in the urine in the disease is not secondary to peptiduria.
978218##1976-10-1##Immunological observations on patients with Wilson's disease.##In 19 patients with Wilson's disease we found an increased humoral immune response, i.e. a higher level of IgG and IgM, a higher titre of antibodies against Kunin's CA antigen and a depressed cell-mediated immunity i.e. a lower response to DNCB and E. coli in skin tests, lower lymphocyte transformation when stimulated by Con A, PPD, Candida albicans and streptokinase and a lower production of macrophage migration inhibition factor. The changes observed in the group of patients with liver cirrhosis caused by other facotrs than Wilson's disease were similar but less pronounced. We also found that leukocytes of patients with Wilson's disease have an impaired bactericidal activity and that copper ions have an inhibitory effect on some tests for cell-mediated immunity. It seems probable that immunological abnormalities in Wilson's disease are caused by liver cirrhosis but we cannot exclude an inhibitory effect of copper ions upon the immune response and an associated effect upon leukocyte metabolism.
985469##1976-9-7##Reactions of D-penicillamine with copper in Wilson's disease.##
970298##1976-9-1##Computer-based approach to chelation therapy: a theoretical study of some chelating agents for the selective removal of toxic metal ions from plasma.##COMICS is a computer programme for calculating equilibrium concentrations of metal complexes and reactive species in multi-metal-multi-ligand systems. Its usefulness for analysing metal ion equilibria in blood plasma has been improved by including albumin as a ligand. Using this model system the distribution and removal of copper(II) and zinc ions in histidinaemia, lead poisoning and Wilson's disease have been examined. The efficacy of TRIEN in removing excess copper(II) is shown. The use of specific tripeptides such as Gly-Gly-His methyl ester for the selective removal of copper(II) is suggested. A possible chemoprophylaxis of influenza based on complexation of zinc is discussed. Calculations confirm that thiosemicarbazones such as methisazone and 2-acetylpyridine thiosemicarbazone are effective competitors for heavy metal ions under physiological conditions.
136925##1976-9-1##Skin lesions induced by penicillamine. Occurrence in a patient with hepatolenticular degeneration (Wilson Disease).##A 41-year-old patient with hepatolenticular degeneration (Wilson disease), who had been treated for 15 years with penicillamine, developed small white papules at sites of venipuncture in the antecubital fossae and at surgical suture sites. Histologically, these papules showed focal areas of connective tissue degeneration in the dermis, but there was no evidence of inclusion cysts. The changes most likely resulted from the effect of penicillamine on new connective tissue formation at the sites of injury. The patient also developed crinkling of the skin of her face and neck while on the penicillamine regimen, and these changes were attributed, at least in part, to the effects of this drug on connective tissue.
952837##1976-9-1##The histological effects of copper and zinc on chick embryo skeletal tissues in organ culture.##1. The effects of copper and zinc on organ cultures of chick embryo cartilage and bone maintained in low-trace-metal, chemically defined media for up to 8 d were studied macroscopically, histologically and histochemically. Length and wet-weight measurement of explants were assessed statistically. 2. No effects were found with Cu concentrations of 0-5-1-5 mug/ml medium. Between concentrations of 5 and 40 mug Cu/ml medium, lengths and wet-weights of cartilage cultures decreased significantly (P less than 0-001) compared with controls. The decrease was directly proportional to increasing Cu concentration, and that of the length was greater with increasing period of culture (P less than 0-001). 3. With 5--20 mug Cu/ml medium cartilage and bone became yellow in colour, and chondrocytes were swollen, rounded and basophilic. They were detached from their lacunae and the quantity of matrix was reduced. Loss of alkaline phosphatase (EC 3.1.3.1) activity and disappearance of glycogen accompanied the degeneration. Osteogenesis ceased, cells failed to divide and mature, lost their enzymes and died. Cu did not accumulate in the bone matrix. 4. The direct toxic effects of Cu for cartilage and bone may underlie some of the skeletal changes in hepatolenticular degeneration (Wilson's disease). 5. As Zn concentrations were increased from 2-5 to 7-5 mug/ml medium, lengths and wet-weights of cartilaginous cultures were significantly increased (P less than 0-001). As Zn concentrations were further increased (from 10 to 40 mug/ml medium), lengths and wet-weights were significantly decreased (P less than 0-001). 6. Zn stimulated chondrocyte division and vacuolation of cytoplasm. With higher Zn concentrations toxic changes of granular basophilia, lacunar detachment and necrosis were seen. Differentiation and functioning of osteoblasts, osteoclasts and chondroclasts were stimulated by Zn. 7. Zn was found in bone matrix, osteoblasts, osteocytes and hypertrophied chondrocytes.
950097##1976-9-1##Effects of anticopper therapy on hepatocellular mitochondria in patients with Wilson's disease: an ultrastructural and stereological study.##Liver biopsy specimens from 7 patients with Wilson's disease (hepatolenticular degeneration), obtained before and after 3 to 5 years of D-penicillamine therapy, were studied by electron microscopy and stereology. The characteristic mitochondrial abnormalities encountered in the hepatocytes of untreated patients were less pronounced or disappeared after treatment in 5 of the 7 patients. Simultaneously, relative mitochondrial volume, surface density of the external mitochondrial membranes, and the number of these profiles per unit area increased, whereas abnormal elevations SGOT and SGPT returned to normal levels.
966633##1976-9-1##[Insufficiency of the exocrine pancreas in Wilson's disease (author's transl)].##The function of the exocrine pancreas was examined by the secretin-pancreozymin-test in 3 patients with Wilson's disease. In all cases we found a partial insufficiency. At the time of investigation the patients were 6(7)/12, 11(6)/12 and 21 years old. The youngest one was examined before therapy with D-Penicillamin. We suppose that storage of copper in lysosomes causes a cytotoxic damage of the exocrine part of the pancreas requiring substitution therapy in advanced cases.
970997##1976-8-1##Hypouricaemia and increased renal urate clearance associated with hyperparathyroidism.##A 64-year-old female was found to have hypouricaemia, with serum uric acid ranging from 0.06-0.12 mmol/l (1.1-2.0 mg/100 ml), associated with an increased urate clearance of 48.9 ml/min and hyperparathyroidism. Known causes of increased uric acid clearance were excluded. Pyrazinamide reduced urate clearance dramatically to 2.1 ml/min, suggesting that the tubular defect was either one of increased secretion or a failure of postsecretory reabsorption. No other tubular abnormality was apparent except diminished urine concentrating ability. Hypouricaemia has not been previously reported in association with hyperparathyroidism and a mechanism relating the two disorders could not be readily postulated. The tubular defect shown in this instance resembled that reported in association with Wilson's disease and Hodgkin's disease. This case and earlier reports of isolated tubular defects of uric acid handling enhance our understanding of uric acid excretion.
999439##1976-8-1##[Treatment of Wilson's disease in children. Five case reports].##Reporting 5 cases of Wilson' disease occuring in children and expressed by a major liver involvement, the practical aspects of therapy are discussed. In 4 cases, follow-up exceeded 3 years. 1. D-Penicillillamine, a chelating agent, is administered for the purpose of inverting the cupric balance. Cupruria has, therefore, no absolute value and must be interpreted according to multiple factors. 2. The effects of D-penicillamine on the liver, as assessed by clinical, biological and histological data, appears encouraging. Laparoscopic examinations, so as to appreciate the evolution of the cirrhosis are still lacking. 3. The decrease in spleen size and signs of hypersplenism probably illustrate the reversibility of the portal hypertension. In Wilson's disease, portal hypertension requires special measures which exclude surgical portal diversion.
1004094##1976-8-1##[Wilson's disease treated with penicillamine (author's transl)].##
780309##1976-7-1##[Wilson's disease (hepatocerebral degeneration)].##
986923##1976-7-1##[3 cases of Wilson's disease in adults, with special reference to copper metabolism screening with 64Cu].##
960872##1976-7-1##[Nephrotic syndrome after treatment with penicillamine in Wilson's disease].##In a 33-year-old man with Wilson's disease a nephrotic syndrome appeared as a severe complication under penicillamine therapy. Under strong observation and exact controls of protein in the urine, leucocytes, differential blood picture and thrombocytes after interruption of the medication and retrogression of the side-effects a retarding new stabilisation of penicillamine can take place. Other side-effects of penicillamine observed as well as control measures under a long-term treatment with penicillamine are briefly discussed.
1024802##1976-6-1##[ Report on a case of Wilson's disease : hemodynamic classification].##
828961##1976-6-1##[Correlation between serum values of copper, ceruloplasmin, SMAO, SDAO, in health- subjects, in pregnant women and in some pathological conditions (author's transl)].##Copper directly reactive with diethylditiocarbamate, ceruloplasmin, monoamine oxidase (SMAO) and diamine oxidase of the serum (SDAO) were studied in healthy subjects, in nine months pregnant women and in some pathological conditions. Increased values of copper were found in pregnancy. Ceruloplasminaemia was increased in hyperthyroidism, congestive hearth failure, Hodgkin's disease, and in pregnancy. Ceroluplasminaemia was strongly reduced in Wilson's disease. SMAO was increased during pregnancy. Statistical analysis showed no correlations between the variations of the data in different pathological conditions. In healthy subjects and in pregnant women, correlation was found between the values of ceruloplasmin obtained using both enzymatic and KCN methods. Statistical analysis of regression lines obtained in both groups of patients showed significative differences between slopes and elevations. It is possible that ceruloplasmin in pregnant women has different composition compared with healthy controls.
1277546##1976-5-3##Direct measurement of serum non-caeruloplasmin copper in liver disease.##The serum non-caeruloplasmin copper concentrations were measured in normal subjects and patients with various types of liver disease by a sensitive direct method involving complexing the copper and measurement by atomic absorption spectrophotometry. In normal subjects the mean concentration (+/- S.D.) was 10.1 +/- 1.6 mug/100 ml, males having a slightly higher value (10.7 +/- 1.3 mug/100 ml) than females (9.2 +/- 1.8 mug/100 ml). In patients with various non-hepatic diseases concentrations were raised (15.8 +/- 8.9 mug/100 ml), as also in hepatitis (14.7 +/- 4.3 mug/100 ml), cholestasis (16.1 +/- 6.4 mug/100 ml) and cirrhosis (16.3 +/- 8.7 mug/100 ml). Heterozygotes for Wilson's disease and patients treated for Wilson's disease had concentrations (12.9 +/- 5.9 and 9.8 +/- 3.7 mug/100 ml, respectively) which did not differ significantly from normal whereas untreated patients had very significantly raised concentrations (22.9 +/- 4.5 mug/100 ml). Direct measurement of serum non-caeruloplasmin copper is more accurate than indirect measurement and may help in assessing the effect of treatment but it is concluded that measurement of this fraction of serum copper will not enable Wilson's disease to be differentiated from other forms of liver disease.
1261757##1976-5-1##Abnormalities of chemical tests for copper metabolism in chronic active liver disease: differentiation from Wilson's disease.##Because identical clinical findings, alterations of hepatic function, and changes in hepatic morphology can occur in Wilson's disease (WD) and chronic active liver disease (CALD), chemical tests that reflect copper metabolism are important in the differential diagnosis of these conditions. The authors therefore measured 24-hr urinary copper excretion, hepatic copper concentration, and serum ceruloplasmin concentration in 54 patients with CALD. Twenty-four hour urinary copper excretion was increased in about 50% of patients, was significantly higher during active disease compared to remission, and was in the WD range in approximately 10% of patients. Hepatic copper concentration was also increased in the majority of patients, generally during active disease, and it sometimes overlapped with values reported in WD. By contrast, serum ceruloplasmin levels were elevated in nearly one-half the Cald patients and were never below normal. It is concluded that the chemical tests routinely used to assess copper metabolism in WD are frequently abnormal in CALD. Because the serum ceruloplasmin concentration never fell in the WD range and often was elevated, it is the most reliable routine chemical screening test to differentiate between CALD and WD.
986276##1976-5-1##[Electrophysiological changes of the brain in Wilson's disease under D-penicillamine treatment].##
1260817##1976-4-2##[Diagnosis of symptomatic forms of wilson's disease (author's transl)].##
1246264##1976-3-18##Letter: The pregnant woman with Wilson's disease.##
1259633##1976-3-1##Copper and ceruloplasmin contents in the blood serum of peripheral and pre-hepatic veins.##Cooper and ceruloplasmin contents were determined in samples of peripheral and pre-hepatic venous blood of 11 patients with Manson's schistosomiasis and one patient with hepatolenticular degeneration, all of çhich submitted either to porto-caval or spleno-renal shunt. Individual difference were not significant in any of the non-Wilsonian patients. The results are discussed in regard to the current knowledge on the pathogenesis of Wilson's disease.
1277094##1976-3-1##[Wilson's disease. A case history].##
8913##1976-3-1##[Konovalov-Wilson's disease].##
1248830##1976-2-29##[Dermatoglyphics of homo- and heterozygotes for Wilson's disease (hepatolenticular degeneration) (author's transl)].##Dermatoglyphics of 11 patients with Wilson's disease and 16 of their clinically asymptomatic relatives of first degree were investigated; 11 of the latter ones were heterozygous in agreement with the turn over rates of Cu-67, 12 under the assumption of autosomal recessive inheritance. On the finger tips the Mb. Wilson patients showed 52.7% whorls, their heterozygous relatives about 40%; compared with our controls (males 33.16%, females 28.82%, Aue-Hauser, 1970) that means a strong increase of this pattern type. On the palm the high frequency of hypothenar patterns in homo- and heterozygotes for Wilson's disease and of loops with accessory triradius in the 4th interdigitum of the patients with Wilson's disease was striking.
55651##1976-2-21##Non-invasive quantitation of corneal copper in hepatolenticular degeneration (Wilson's disease).##The corneal copper content was measured by X-ray excitation spectrometry in two controls and in seven patients with Wilson's disease. Patients who were treated irregularly or not treated at all showed a high corneal copper content. Those who were adequately treated had low levels, comparable to the controls. In one case the corneal copper content declined 45%, after a course of dimercaprol. The corneal copper measured showed no correlation with the slit-lamp appearance of the Kayser-Fleischer ring. It is suggested that non-invasive X-ray excitation spectrometry can provide a fast and reliable method for the early diagnosis of Wilson's disease and for the objective evaluation of the efficacy of the treatment of this disease.
1044220##1976-2-1##My battle against Wilson's disease.##
1247345##1976-2-1##Platelet function and coagulation in patients with Wilson disease.##Sixteen patients with Wilson disease (hepatolenticular degeneration) were studied from the hemostatic point of view, particularly with regard to platelet function. Five of the patients had a mild bleeding tendency that was characterized by easy bruising. Moderate thrombocytopenia was observed in three of the five bleeders and in two of the others. One bleeder was thrombocytotic and hyperfibrinogenemic. Bleeding times, platelet retention and prothrombin consumption were abnormal rarely. However, 15 of the 16 patients had some abnormality of platelet aggregation: one when adenosine diphosphate was added to platelet rich plasma, three when epinephrine was added, and the remainder when collagen was added. The collagen abnormalities were delayed or absent aggregation (five patients, four of whom were bleeders) and absence of a change of shape (12 of the 16 patients). Platelet aggregation was completely normal in only one patient.
819461##1976-2-1##Red cell aplasia following prolonged D-penicillamine therapy.##Red cell aplasia developed in a case of Wilson's disease following an increase in D-penicillamine dosage after 14 years' treatment. In vitro study of the effect of D-penicillamine on 59Fe incorporation by marrow cells did not suggest that the patient's erythropoiesis was particularly sensitive to D-penicillamine or determine the mechanism of drug toxicity. However, three weeks after the drug was withdrawn, evidence of marrow regeneration was apparent, and within 10 weeks the haemoglobin had returned to normal. The patient has subsequently remained asymptomatic on an alternative chelating agent, triethylenetetramine dihydrochloride.
1061160##1976-2-1##Menkes disease: a biochemical abnormality in cultured human fibroblasts.##Cultured skin fibroblasts from patients with Menkes disease, an X-linked disorder involving a defect in copper metabolism, were analyzed for copper concentration by means of atomic absorption spectrophotometry. These cultures consistently exhibited elevated copper concentrations (mean = 335.5 ng of copper per mg of protein) when compared to control fibroblast cultures (mean = 59.2 ng of copper per mg of protein). External factors that could influence the copper content of cultures were found not to affect the differences in copper concentration between control and Menkes cells. Furthermore, Menkes cells could be differentiated from cultured fibroblasts of controls, of presumed heterozygotes, and of Wilson's disease patients by copper concentration. These observations led to the conclusion that the increased copper content of cultured Menkes cells was characteristic of Menkes disease, resulting from the expression of the genetic abnormality. This provides a genetic marker, a defect in metal metabolism demonstrated in human fibroblasts, that should prove valuable in both the diagnosis of Menkes disease and in the study of the fundamental defect of this genetic disorder.
941680##1976-1-1##An autopsy case of the &quot;demyelinating type&quot; of Wilson's disease.##A 17 year-old male, who was mentally and bodily retarded from the age of 7 years. At the age of 16 years, several neurological signs appeared. Pathologically, there was widespread myelin loss and tissue sponginess in the white matter of the cerebrum and cerebellum, bilaterally and symmetrically. A great many Alzheimer type II glia and Opalski glia were widely distributed in the cerebral cortex and the basal ganglia. Despite severe destruction of the white matter, mesenchymal and gliofibre proliferation were not noticed. In the liver, Laennec's cirrhosis and a great many copper granules in the cytoplasm of the parenchymal cells were identified. From the above mentioned findings the present case, being a new type, could be called &quot;Demyelinating type of Wilson's disease&quot;.
782594##1976-1-1##The eye in Wilson disease.##
65341##1976-1-1##Neurological diseases as reflections of general metabolic disturbances (Wilson's disease, Refsum's disease and metachromatic leukodystrophy).##
1263584##1976-1-1##The effect of long-term treatment with d-penicillamine on the humoral immune response in patients with Wilson's disease.##
1023089##1976-1-1##Wilson's disease (hepatolenticular degeneration).##Wilson's disease, or hepatolenticular degeneration, is a rare inherited disorder of copper metabolism which usually affects young people. Excess copper accumulates in the tissues, primarily in the liver, brain, and cornea. This copper deposition results in a wide range of hepatic and neurological symptoms, and may produce psychiatric illness. Hepatic involvement often occurs in childhood, while neurological deficits generally are detected at a later age. The disease is inherited in an autosomal recessive fashion. Ocular findings are of particular importance because the corneal copper deposition, forming the Kayser-Fleischer ring,is the only pathognomonic sign of the disease. The structure of the ring and the presence of copper have been well established. An anterior capsular deposition of copper in the lens results in a characteristic sunflower cataract in some of these patients. Other ocular abnormalities have been described but are much less common. The pathogenesis of the disease and the basic genetic defect remain obscure. It is clear that there is excess copper in the tissues, but the mechanism of its deposition is unknown. It is in some way associated with a failure to synthesize the serum copper protein ceruloplasmin normally. Another theory suggests that an abnormal protein with a high affinity for copper may bind the metal in the tissues. The diagnosis may be suggested by the clinical manifestations and confirmed by the presence of a Kayser-Fleischer ring. In the absence of these findings biochemical determinations are necessary. The most important of these are the serum ceruloplasmin, the urinary copper, and the hepatic copper concentration on biopsy. Treatment consists in the administration of the copper chelating agent, penicillamine, and the avoidance of a high copper intake. This usually results in marked clinical improvement if irreversible tissue damage has not occurred. Maintenance therapy for life is necessary in order to continue the negative copper balance. The detection and prophylactic treatment of asymptomatic individuals with the disease is especially important. Seven cases of Wilson's disease have been presented in order to illustrate many of the features which have been discussed, with emphasis on the ocular findings.
1006022##1976-1-1##[Contribution of radioisotopes in the study of Wilson's disease].##
1029259##1976-1-1##[Early symptoms and early diagnosis in Wilson's disease].##
1203737##1975-12-20##Letter: Treatment of Wilson's disease.##
1186824##1975-12-18##Pregnancy in penicillamine-treated patients with Wilson's disease.##
53713##1975-12-13##Letter: Treatment of Wilson's disease.##
129963##1975-12-12##[The activity of aminotransferases in serum and cerebrospinal fluid in neurological diseases (author's transl)].##The activities of the aminotransferases, GOT and GPT, were determined in the serum and cerebrospinal fluid of patients with Parkinson's disease, Huntington's chorea, Wilson's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, phenylketonuria, and head injuries. 1. In patients with Huntington's chorea the activity of SGOT was lower than in controls (P = 0.02); in Friedreich's ataxia LGPT activity was decreased (P less than 0.001); in patients suffering from ALS SGOT (P = 0.005), SGPT (P less than 0.001) and LGOT (P less than 0.001) activities were increased. 2. Long-term treatment of Parkinson's disease and Wilson's disease with L-dopa resulted in an increase in SGOT, LGOT, and SGPT activity over approximately 2 months, with subsequent normalization of these enzyme activities in spite of continued therapy. Guanidine treatment led to an increase in aminotransferase activities in patients with ALS. Penicillamine caused a decrease in SGOT and SGPT activities in Wilson's disease. These results illustrate the necessity of taking therapeutic measures into account in the interpretation of data on aminotransferase activities.
1185415##1975-12-1##Juvenile Wilson disease: histologic and functional studies during penicillamine therapy.##Because the long-term effects of penicillamine on hepatic morphology in Wilson disease are virtually unknown, seven patients with this disorder were studied two to seven years after the onset of drug treatment. All were without symptoms at follow-up. By comparison to initial biopsies (four patients), posttreatment specimens showed either considerable reduction in portal fibrosis (two patients) or no significant change (two patients); portal inflammation and necrosis were greatly diminished or absent in three. In none was there complete restitution of normal architecture. Three patients lacked initial biopsies. In these, portal cirrhosis, inflammation and necrosis, and fatty vacuolization of the hepatocytes were present three, five, and seven years after onset of therapy. Lipofuscin pigment was abundant in follow-up biopsies. The data demonstrate that morphologic improvement is achieved in some patients with Wilson disease receiving penicilliamine, but that this is not predicted by biochemical factors. Sequential biopsies are necessary to evaluate completely the extent of healing.
1192154##1975-11-29##Letter: Treatment of Wilson's disease.##
1105368##1975-11-1##Wilson's disease. A treatable liver disease in children.##
1197060##1975-11-1##[Pigment cirrhosis of the liver. I. Wilson's disease--hepatolenticular degeneration].##
1199668##1975-10-1##The effect of long term treatment with penicillamine on the copper content in the liver in patients with Wilson's disease.##Determination of hepatic copper concentration is the most exact criterion in the diagnosis of Wilson's disease. In the course of penicillamine therapy the copper content in the liver decreases, but normal values are achieved only after five or more years of treatment. Normalisation of the hepatic cooper concentration lags distinctly behind the clinical state. Distinct improvement of clinical state is already reached after a half to one year of treatment. The correlation between hepatic copper concentration and the amount of copper's excreted in the urine is statistically significant before the starting of treatment and during administration of penicillamine as well. The urinary copper excretion is a good indirect and indicator of the copper concentration in the liver.
1239275##1975-10-1##On the defect of synthesis ceruloplasmin in the liver polyribosomes in Wilson's disease.##Comparative immunochemical analysis of ceruloplasmin-synthesizing polyribosomes in liver biopsies from control subjects and homozygous carriers of the Wilson's mutation was performed. According to I125-antibody binding data, the amount of ceruloplasmin-forming liver polysomes in patients with Wilson's disease was 10--20 times lower than that in non-Wilson patients. Correspondingly, the pulse labeling of ceruloplasmin polypeptides was decreased several-fold in the cell-free liver preparations from patients with Wilson's disease.
240530##1975-9-1##Studies on the nature of complexes formed by copper with human alimentary secretions and their influence on copper absorption in the rat.##1. Human gastrointestinal secretions formed soluble copper complexes when labelled in vitro with 64Cu. 2. Copper-binding substances of low molecular weight were demonstrated in the saliva, gastric juice and secretin-stimulated duodenal aspirate of nomal subjects by dialysis and gel-chromatography studies. 3. The nature of the copper complexes formed by secretions obtained from patients with Wilson's disease was similar to that oc complexes formed by secretions of normal subjects. 4. Bile contained a copper-binding fraction of high molecular weight which was more concentrated in gall-bladder than hepatic bile. Between pH 5 and pH 8, this component had a greater binding affinity EDTA at a concentration of 10 mmol/1. 5. Absorption of 64Cu from 64Cu-labelled saliva, gastric juice or L-histidine solution (100 mmol/1) administered intraduodenally into groups of rats was similar to that observed in a control series given [Cu]cupric acetate in sodium chloride solution. In contrast, the absorption of 64Cu from labelled hepatic and gall-bladder bile was significantly reduced. 6. The results suggest that dietary copper forms soluble complexes with the alimentary secretions and that these complexes influence absorption of the metal according to their molecular size. The net uptake of ingested copper from the gut lumen ms, low-molecular-weight ligands in the alimentary secretions and a macromolecular copper-binding complex of bile.
1205062##1975-9-1##[Dissociative action of copper on the polysomes in the rat liver and brain. A possible pathogenic mechanism of Wilson's disease].##
127478##1975-9-1##The serum immunoglobulin levels in Down's syndrome and other diseases associated with mental disorder.##The serum levels of IgA, IgM, IgG and IgD were determined in patients with Down's syndrome (69 cases), Oligophrenia (101 cases) and Morbus Wilson (18 cases). In sera from Down's syndrome patients a significant increase in the levels of IgA, IgG and IgD were found. IgM levels were identical to those of healthy controls. The immunoglobulin levels in both the oligophrenia and Wilson's disease patients were not different from those of controls.
51205##1975-8-30##Letter: Missed Wilson's disease.##
126208##1975-8-29##Studies on the polymorphism of C3, Tf and Bg in Down's syndrome and other diseases.##The distribution of phenotypes C3, Ff and Bg was investigated in sera of patients with Down's syndrome, oligophrenia, Wilson's disease and heart infarct. Quantitative determination of the concentration of C3 and C4 components of human complement was also carried out in these patients. The results are compared to healthy controls and are discussed with already reported data from other authors. Despite differences in the percentage distribution of various phenotypes in the patients' sera as compared to that of the controls, no statistically significant association could be established.
1176118##1975-8-25##Dermatoglyphic analysis as a diagnostic tool in Wilson disease?##Dermatoglyphic analysis was performed in a family with 3 children with Wilson disease. With our findings we could not confirm the results published in two earlier papers by other authors who noted a positive relation between Wilson disease and an increased number of whorls. The practical significance of the findings is discussed.
1165409##1975-8-1##Wilson's disease: investigation of an Iowa family.##
1177052##1975-8-1##Basal ganglia scans in the human.##Using a 64Cu complex, we obtained human basal ganglia scans in three normal volunteers and in one patient with Wilson's disease with an oral dose of 1 mCi. The method with this new radioactive compound was simple and safe and the results were very encouraging.
1219186##1975-8-1##[Quantitative determination and phenotyping of ceruloplasmin in morbus Wilson (author's transl)].##Sera of 17 patients with Wilson's disease and of 48 relatives were investigated as to a possible correlation between ceruloplasmin phenotypes and Wilson's disease. The control group included 727 healthy subjects. The results of the quantitative determination of ceruloplasmin confirmed the overlapping in the groups of so-called heterozygotes and controls known from the literature. The ceruloplasmin phenotypes in starch gel electrophoresis we observed were of the most common phenotype Cp BB in the patients as well as in the controls. Therefore, patients with Wilson's disease also show the normal Cp-phenotypes.
1152537##1975-8-1##Wilson's disease (hepatolenticular degeneration) of late adult onset: report of case.##Wilson's disease usually has its onset in childhood, adolescence, or early adulthood. The clinical picture of hepatic dysfunction without dysfunction of the central nervous system is more typical of the disease in the child or the adolescent than in the adult. We are presenting the case of a man whose age at onset of the disease was 55 years and who had the hepatic complications of Wilson's disease without clinical evidence of disease of the central nervous system. All patients with chronic hepatitis (chronic active liver disease) or cirrhosis of unknown etiology should be screened for the possibility of Wilson's disease. This screening should include slit-lamp biomicroscopy for Kayser-Fleischer rings, determination of serum ceruloplasmin concentration, and measurement of 24-hour urinary excretion of copper. If doubt exists concerning the diagnosis, either a radiocopper kinetic study, using 64Cu or 67Cu, or, if the patient's condition permits, a liver biopsy with measurement of hepatic copper concentration should be done. The rubeanic stain of hepatic tissue for copper is unreliable in making or excluding the diagnosis of Wilson's disease.
1228806##1975-8-1##[Results of electroencephalographic and familial studies in Wilson's disease].##The results of electroencephalographic and familial studies of 31 Wilson's disease patients coming from 26 kindreds are presented. Prior to treatment, 8 patients showed pathological conditions, while 9 and 11 patients showed borderline and normal conditions, respectively, it having not been possible to determine electroencephalographic conditions characteristic of Wilson's disease and find any relationships between the intensity of E.E.G. changes and the clinical picture and stage of development of the disease, respectively. Under penicillamine treatment, there was observed a tendency toward normalization of pathological conditions rather than deterioration of normal E.E.G. findings. So far as familial studies are concerned, the authors report the results obtained for 9 fathers, 19 mothers, and 24 siblings from a total of 21 kindreds; what is remarkable in this connection is the comparatively small percentage of normal E.E.G. findings for healthy siblings. It was only in one single kindred that it was possible to observe similarities between E.E.G. variations of individual family members.
49762##1975-7-26##Letter: Liver transplantation for Wilson's disease.##
1215885##1975-7-5##[Familial Wilson's disease: copper induced hemolysis, hypersplenism and hyperpigmentation as the main symptoms].##Wilson's disease was diagnosed in a 16-year-old adolescent who presented with signs of hypersplenism due to cirrhosis, with marked hyperpigmentation of both lower legs and neurological disturbances. In view of progressive thrombocytopenia and leukocytopenia, splenectomy was performed during therapy with penicillamine later in the course, and the result was good. The patient's 12-year-old sister was found to have a hepatic form of Wilson's disease with typical biochemical findings. During the initial hospitalization a severe, spontaneous copper-induced hemolysis was noted. Another sister probably has a presymptomatic form of the disease. The parents are healthy but heterozygote carriers with regard to biochemical findings. The importance is stressed of hypersplenism, hyperpigmentation of the legs and especially of acute hemolysis in infancy as pointers in the diagnosis of Wilson's disease. Further diagnostic and therapeutic aspects are discussed.
1163990##1975-7-11##Laboratory diagnosis of degenerative joint disease.##Degenerative joint disease (DJD) is characterized by pain on use. X-rays show cartilage narrowing and osteophytes. Synovial effusions are non-inflammatory, i.e. clear wiht good viscosity and less than 2000 WBC per mm. 3 Cartilage fragments may be seen in the joint fluid. Important systemic diseases that can cause degenerative joint disease include ochronosis, hemochromatosis, hyperparathyroidism, acromegaly, Ehlers-Danlos syndrome, diabetes and syphilis with their neuropathic joints, Wilson's disease and hypothyroidism. The late results of other diseases such as rheumatoid arthritis and aseptic necrosis may resemble DJD.
1150026##1975-7-1##Pigmented corneal rings in a patient with primary biliary cirrhosis.##A patient with primary biliary cirrhosis who had high hepatic, serum, and urine copper levels was found by slit-lamp biomicroscopy to have pigmented corneal rings similar to Kayser-Fleischer rings. Wilson's disease was excluded on the basis of the elevated serum ceruloplasmin and copper levels, the lack of neurological disease despite advanced liver disease, a negative family history, and the typical clinical features of primary biliary cirrhosis. Although the exact chemical nature of the corneal rings is unknown, the cornea may be another tissue associated with elevated tissue copper levels in primary biliary cirrhosis.
1142738##1975-7-1##Lipolysosomes in human hepatocytes. Ultrastructural and cytochemical studies of patients with Wilson's disease.##Lipid droplets surrounded by a peripheral membrane closely apposed to an electron-dense layer and containing acid phosphatase activity, similar to the lipolysosomes in hamsters described by Nehemiah and Novikoff (J. Cell Biol. 59: 246a, 1973; Exp. Mol. Pathol. 21:398, 1974), were found in the hepatocytes of patients with Wilson's disease. These organelles account for 1 to 2 per cent of the observed lipid droplets at the stage of the disease when excess fat is present. The occurrence of lipolysosomes in a condition not known to be associated with an acid lipase deficiency suggests that lipolysosomes may represent a nonspecific, alternate route for the mobilization of excess lipid from hepatocytes.
1152534##1975-7-1##Copper metabolism after biliary fistula, obstruction, or sham operation in rats.##Intravenously administered carrier-free 67Cu appeared rapidly in the bile of rats with a recently created biliary fistula; maximal excretion occurred within the first 2 hours. However, if the biliary fistula had been created 3 or 4 days before injection of the 67Cu, only one-fourth to one-half as much of the isotope appeared in the bile. There also was a small decrease in stable biliary copper. When rats with biliary fistula were compared with rats with permanent biliary obstruction, over a period of 6 weeks, both exhibited a marked increase in plasma copper and an equally pronounced increase in the rho-phenylenediamine oxidase activity of plasma but no increase in hepatic copper. Peaks in blood were reached within 2 weeks and then slowly diminished. Sham-operated rats had parallel, but much lower, copper and enzyme changes. Correlations between these rat studies and the copper retention of Wilson's disease and of primary biliary cirrhosis are suggested.
1101097##1975-7-1##[T-rosette test in Wilson's disease].##Twenty-three patients with Wilson's disease were studied. Using the rosette formation test it was found that the count of T-lymphocytes in the peripheral blood of these patients (29,77% +/- 12,58) was lower than in the control group (61,68% +/- 13,14). Using skin tests for demonstration of delayed hypersensitivity it was noted that in the group of patients the frequency of positive reaction with Candida albicans antigen was lower and these patients showed also less frequently positive reactions after DNCB immunization. The obtained results indicate that in Wilson's disease the functions of T-lymphocytes are distrubed. This may be the cause of previously observed hyperactivity of B-lymphocytes.
1220508##1975-6-1##Osteoarticular pains and changes in Wilson's disease: a radiological study in fourteen patients in nine Turkish families.##A series of 14 patients with Wilson's disease were evaluated in order to determine the characteristic bone changes found in this metabolic disorder. The following radiologic and clinical findings deserve to be summarized: (1) Osteoarticular pains as first manifestations of Wilson's disease were found in six patients. (2) In all but 2 of our patients, minor or moderate or even severe bone abnormalities characteristic for Wilson's disease were observed. (3) There were three groups of sibs. Among these sibs, the lesions were not only similar in type but were also acquired approximately at the same time, showing the influence of the different genes responsible for this metabolic disorder.
241690##1975-6-1##Molecular biology of copper. A circular dichroism study on copper complexes of thionein and penicillamine.##Chicken liver Cd, Zn-thionein (metallothionein) was isolated from Cd-pretreated chickens weighing 1 500 g. The native Cd, Zn-thionein contained 9 g-atoms of metals per 12 000 g of protein. Upon the addition of Cu(CH3CN)4ClO4, all Cd2 and Zn2 were successfully replaced. 15 g-atoms of Cu from the acetonitrile perchlorate complex were bound to the protein. Due to the absence of aromatic amino acid residues, thionein has unique ultraviolet and circular dichroism properties. The shoulder of the ultraviolet spectrum at 250 nm (A250 X A280(-1) = 23.9) was shifted to 275 nm (A250 X A280(-1) = 1.6). No significant absorption was detected in the visible region. Th conformational changes of the protein moiety were much more visible in the circular dichroism spectra. The titration with Cu(CH3CH)2 caused the appearence of three new Cotton effects: 257.5 nm (+), 350 nm (+) and 301 nm (-). The negative Cotton effect at 239 nm of the original metallothionein was completely levelled off. The binding strength of copper with thionein is extraordinarily high: it survives proton treatment up to pH 1.9. Displacement of the Cd2 by Cu employing Cd-thionein which was formed at pH 2.2 resulted in the same circular dichroism properties as observed for Cu-thionein. D-Penicillamine proved a suitable model for the metal-free thionein, since redox reactions and polymerization of the sterically hindered thiol residue are known to be slow. The correlation of the circular dichroism properties of either copper complex using thionein or D-penicillamine was surprisingly high. Circular dichroism measurements of Cu(I)-D-penicillamine revealed Cotton effects at 255 nm (+), 280 nm (+) and 355 nm (-). Upon examining the red-violet mixed Cu(-i)-cu(II)-D-penicillamine complex, Cotton bands in the visible region at 425 nm (-) and 495 nm (+) were seen. In many blue copper enzymes, the copper is assumed to be in the neighborhood of both cysteine and aromatic amino acid residues, which are known to play an important role in the electron transfer. This is not the case in the Cu-thionein, which would explain many different properties of this copper protein. It is very attractive to conclude that the sterically hindered SH-group of D-penicillamine reacts with excess copper in a specific way, similar to the Cu-thionein. This phenomenon could explain the considerable success of D-penicillamine in the treatment of Wilson's disease.
1107956##1975-6-1##Wilson's disease in Turkey, a review of 49 cases in 41 families.##
805973##1975-5-16##[Proceedings: Differentiation of homozygote and heterozygote, therapy and follow-up study in 4 families with Wilson's disease].##
1143693##1975-5-2##[On the therapeutic combination of S-adenosylmethionine with D-penicillamine in Wilson's disease].##After some general preliminary remarks concerning aetiopathogenetic hypoteses and therapeutic possibilities for Wilson's disease, the Authors report the data obtained from a long-term study carried out on a family of nine brothers. These subjects were all affected with Wilson's syndrome and kept under a D-penicillamine treatment. The addition of 4-5 oral adminstrations a day of 30 mg SAMe resulted in highly significant favourable modifications of all the laboratory data considered to test liver function. The progressive worsening of the same data observed after 60, 90 and 120 days from SAMe withdrawal, seems to prove the actual activity of this molecule on liver function. During SAMe therapy no clinical and laboratory side-effects (macular and papular eruption, pruritus, neutropenia, thrombocytopenia, etc.) were observed while they were detectable in some patients treated with D-penicillamine alone.
1094875##1975-5-1##D-penicillamine induced Goodpasture's syndrome in Wilson's disease.##Fatal pulmonary hemorrhages and rapidly progressive glomerulonephritis occurred in three patients with Wilson's disease (hepatolenticular degeneration) who had been treated with penicillamine for 2 to 31/2 years. Light microscopic studies of the kidneys showed severe glomerulonephritis with crescent formation, and the lungs showed intraalveolar hemorrhages. Although the clinical and pathologic abnormalities were those of Goodpasture's syndrome, immunofluorescence microscopic studies in the one case tested showed an interrupted, rather than linear, fluorescence pattern.
1131002##1975-5-11##A series of 20 successful Warren shunts.##Recent reports suggest that the distal splenorenal shunt does fulfill its physiological promises. The portal and the gastroesophagealsplenic areas are divided into separate &quot;venous watersheds.&quot; As a result, varices are decompressed but portal hypertension is preserved. It should, therefore, have its greatest advantage for patients with the most severe impairment of hepatic reserve. In this evaluation, the procedure was considered the operation of choice for all shunt candidates who had a patent splenic vein. A series of 20 patients, 12 with Laënnec cirrhosis, seven with postnecrotic cirrhosis, and one with Wilson disease, survived shunting and were discharged from the hospital. One patient died of hepatic coma eight weeks after operation. If lengthy follow-up studies confirm its capacity to prevent hemorrhage, the distal splenorenal shunt may be the safest elective shunt operation for patients with cirrhosis.
1092490##1975-5-1##The development of cirrhosis in Wilson's disease.##
1127989##1975-5-1##Biliary bile acid composition in Wilson's disease.##Biliary bile acid composition and pattern of bile acid conjugation with glycine or taurine were found to be within normal limits in six patients with documented Wilson's disease. Four patients had previous biopsy evidence of cirrhosis (three with active hepatitis), but most conventional liver function tests gave normal results at the time of the study. Serum levels of conjugates of cholic acid, measured by radioimmunoassay, were not increased. However, plasma disappearance if intravenously injected glycine conjugate of cholic acid was significantly delayed in all subjects, suggesting that this is a more sensitive test of hepatic excretory function and may be of value for assessing hepatic function in patients with this rare genetic disorder. No evidence of a primary disturbance in bile acid metabolism was found in these patients.
1097955##1975-5-1##[Penicillamine and other therapeutic methods in the treatment of Wilson's disease].##
1137458##1975-4-1##Proceedings: The musculoskeletal features of Wilson's disease: a clinical, radiological, and serological survey.##
1134180##1975-4-1##Superoxide dismutase activity (erythrocuprein) in Wilson's disease.##
169314##1975-3-10##[A case of Wilson's disease with hepatoma (author's transl)].##
47714##1975-3-1##Kayser-Fleischer ring and associated cataract in Wilson's disease.##A 22-year-old woman with hepatolenticular degeneration, or Wilson's disease, was note clinically to have Kayser-Fleischer rings and associated cataracts. Histopathologic, histochemical, and electron microscopic study of the cornea showed deposition of copper in the peripheral Descemet's membrane, with excessive accumulation in Hassall-Henel warts. Copper deposits were also noted in the anterior and posterior lens capsule without the presence of degenerative changes in the epithelial or cortical cells of the lens. We propose that cellular activity is required for the depostion of copper material into the thick basement membranes of the cornea and lens, in contrast to the concept of simple diffusion.
1117834##1975-3-1##Wilson's disease. Clinical and laboratory maniestations in 40 patients.##
1162221##1975-3-1##[Hysteria, schizoprenia, Wilson's disease].##
1226193##1975-2-4##[Recent findings in the therapy of Wilson's disease].##
1122921##1975-2-1##Liver inclusions in erythropoietic protoporphyria.##Needle-like inclusions have been found, by electron microscopy, in the livers of two unrelated patients with erythropoietic protoporphyria. Since they have not been noted in other hepatic conditions but do occur in the livers of protoporphyric mice it is suggested that they represent markers for protoporphyric liver disease. Paracrystalline inclusions that have been previously described in Wilson's disease and porphyria cutanea tarda were also present in the hepatocytes of one of these patients.
1158478##1975-2-1##Penicillamine in prevention of symptomatic Wilson's disease: 8 year follow up in two sibs.##
803541##1975-2-1##The estimation of red cell superoxide dismutase activity.##A method is described for the estimation of red cell superoxide dismutase (erythrocuprein) and a normal range of activity established. It is likely that this enzyme is essential to the red cell for the detoxification of superoxide radicals, and plays a protective role similar to that of the glutathione-glutathione peroxidase system. It is suggested that superoxide dismutase deficiency may be an unrecognized cause of Heinz body hemolytic anemia. The separation of superoxide dismutase from hemoglobin by polyacrylamide gel electrophoresis is also described. Normal superoxide dismutase activity was measured in one case of Wilson's disease.
1111691##1975-2-1##Acute hemolytic anemia as a presenting manifestation of Wilson disease.##
1124157##1975-2-1##Copper toxicity, rats and Wilson's disease.##
1118720##1975-2-1##[Pregnancy and parturition in Wilson's disease (author's transl)].##
1244090##1975-1-1##Tryptophan metabolism in nervous disease.##The paper describes effects of tryptophan loading on tryptophan metabolism in healthy persons as well as alterations of tryptophan metabolism observed in varians diseases associated with nervous symptoms, i.e. Wilson's disease, Hartnup disease, phenylketonuria and acute intermittent porphyria. The results are discussed.
1235088##1975-1-1##Low molecular weight proteinuria.##Low molecular weight (LMW) proteinurias vary widely in their microprotein composition. In general, there is little correlation between a given microprotein composition and a defined clinical disease (with the exception of the predominant beta-2-microglobulin in Wilson's disease). Free immunoglobulin light chains are a practically invariable component of, and may be the only detectable LMW protein in, 'tubular' proteinuria. The origins and significance of some frequently occurring urinary LMW proteins are discussed.
1227804##1975-1-1##[The portal circulation in liver parenchymal lesions, due to Wilson's disease and treated for a long time with D-penicillamine].##
808415##1975-1-1##The kinetics of copper uptake by the liver in Wilson's disease studied by a whole-body counter and a double labelling technique.##The hepatic uptake of 64Cu in the body was studied by whole-body counting in normal subjects, homozygotes, and heterozygotes of Wilson's disease. Special attention was paid to the copper kinetics during the first hour after injection of 64Cu. Two different measuring techniques were used simultaneously: one collimated NaI(Tl) crystal was in a fixed position over the liver, the counts being recorded by a single channel analyser connected to a multi-channel analyser in a multi-channel scaling mode; and a second collimated crystal makes scanning movements along the body axis, the counts being recorded by a multi-channel analyser in a multi-spectrum scaling mode. With this procedure it is possible to use a double nuclide labelling technique by means of which both the 64Cu values for an organ can be corrected for the 64Cu blood content in the region of interest, and information can be obtained on the actual dynamic 64Cu movement in the body.
1105063##1975-1-1##Experimental liver diseases.##The use of animal models in the experimental production of liver diseases similar to those of man is still in its infancy. There is a need to discover new models more closely related to counterpart syndromes in man in the fields of hepatorenal syndrome, neonatal jaundice, Wilson's disease, cholelithiasis, viral hepatitis, biliary atresia, and cirrhosis, to mention only a few. With the continued indiscriminate inbreeding of companion animals as well as the planned inbreeding of laboratory animals, there is little doubt that many more will soon be available. The current availability of mutant rats and sheep with bilirubin transport defects has allowed for a better understanding of how organic anions are transported by the liver. Many other currently available experimental animal models herein briefly reviewed have been only superficially studied. It is the intent of this chapter to provide for post-doctoral students an appreciation for the many animal model systems available for experimental hepatic research.
829635##1975-1-1##[Experiences with penicillamine in Wilson's disease].##Reports are being made on the principles of treatment of morbus Wilson with the help of seventeen patients and two persons in the pre-clinical stage (asymptomatic). Treatment should be begun as soon as possible in the asymptomatic stage. On the whole the pseudo-sclerosis symptoms react more favourably to treatment than many hypokinetic symptoms. A continuous course of treatment with penicillamine still effects a disappearance of the symptoms even after three to four years. Since evidence of a negative copper balance is widely used in determining the amount of the penicillamine dosage, the measurement of basal copper secretion and copper secretion with the use of penicillamine is discussed as a useful criterion.
1197691##1975-1-1##[Heterozygote test using 64 Cu in Wilson's disease].##
1226956##1975-1-1##[Homo- and heterozygotic differentiation in Wilson's disease].##
4468374##1974-12-1##A microangiographic and histologic study of the kidney in Kimmelstiel-Wilson disease.##
4619238##1974-12-1##[Utilization of copper in the organism and its role in the pathogenesis of Wilson's disease].##
4435281##1974-11-1##[Therapy and rehabilitation of Wilson's disease (author's transl)].##
4449905##1974-11-1##[Nature of course and rehabilitation in the clinical stage of Wilson's disease].##
4422873##1974-10-10##[Hemolytic anemia in Wilson's disease].##
4430389##1974-10-1##[Diagnostic and therapeutic experiences in Wilson's disease. I. Pathogenesis, biochemistry and clinical aspects of Wilson's disease].##
4470769##1974-10-1##[Wilson's disease and pregnancy].##
4213024##1974-10-1##Determination of apoceruloplasmin by radioimmunoassay in nutritional copper deficiency, Menkes' kinky hair syndrome, Wilson's disease, and umbilical cord blood.##
4475793##1974-10-1##[Metabolism of ceruloplasmin and copper in the blood in Wilson's disease].##
4475792##1974-10-1##[Evaluation of the need of ceruloplasmin and serum copper analyses in the diagnosis of Wilson's disease].##
4458736##1974-9-30##[Cytohistological aspects of the liver in Wilson's disease].##
4411529##1974-9-30##[Wilson's disease].##
4414471##1974-9-27##Letter: Wilson's disease and copper-binding proteins.##
4851957##1974-9-1##Excretion of copper in sweat of patients with Wilson's disease during sauna bathing.##
4852755##1974-9-1##Letter: Diagnosis of Wilson's disease.##
4215046##1974-9-1##[Serum immunoglobulin level in patients with Wilson's disease].##
4834970##1974-8-1##Ultrastructure of brain and nerve biopsy tissue in Wilson disease.##
4847708##1974-8-1##Hemolytic anemia of Wilson's disease.##
4451159##1974-7-1##[Experimental reproduction of Wilson's disease].##
4849421##1974-7-1##[Possibilities and limitation for diagnosis of Wilson's disease from liver biopsies (author's transl)].##
4215106##1974-6-15##[Wilson's disease (experience of long-term treatment with penicillamine---con penicilamina].##
4836038##1974-6-1##Dysarthria in Wilson's disease.##
4835813##1974-6-1##Psychologic investigation of Wilson's disease.##
4835812##1974-6-1##Effects of penicillamine therapy and low-copper diet on dysarthria in Wilson's disease (hepatolenticular degeneration).##
4835811##1974-6-1##Wilson's disease. Electroencephalographic and evoked potential studies.##
4835810##1974-6-1##Bicarbonate excretion in Wilson's disease (hepatolenticular degeneration).##
4835809##1974-6-1##Long-term body retention of radiocopper (67Cu) and the diagnosis of Wilson's disease.##
4835807##1974-6-1##Similarity of chronic copper toxicity in rats to copper deposition of Wilson's disease.##
4599351##1974-6-1##Introduction. Symposium on copper metabolism and Wilson's disease.##
4209105##1974-6-1##Body retention of injected 67Cu in patients with homozygous or heterozygous Wilson's disease and in normal subjects. Comparison of whole-body counting systems.##
4850472##1974-4-1##Akinetic mutism in Wilson disease.##
4849882##1974-2-1##[The &quot;pure&quot; hepatic forms of Wilson's disease in children. Apropos of 10 cases].##
4820637##1974-2-1##Defective biliary excretion of copper in Wilson's disease.##The biliary excretion of copper was measured in eight patients with Wilson's disease (three untreated, with hepatic dysfunction) and 10 control subjects (three with hepatic dysfunction). The duodenum was perfused with an amino-acid solution containing a non-absorbed marker, (51)CrCl(3), and juice was aspirated from the duodeno-jejunal junction. The mean concentration of copper in the duodenal aspirate in Wilson's disease was significantly lower than in the control group. The mean biliary copper excretion rate in Wilson's disease of 8.6 +/- 0.8 mug/20 min (SEM) was also significantly below that of the control group (16.4 +/- 0.8 mug/20 min). The presence of liver dysfunction made no significant difference to the excretion rates in either group of patients. These results suggest that the copper accumulation in Wilson's disease is due to the inability of the liver to excrete copper into bile in adequate amounts.
4819908##1974-2-1##Slow saccadic eye movements in Wilson's disease.##This is the first reported case of Wilson's disease where a global defect of saccadic eye movements has been documented by electro-oculography. The defect of rapid eye movements is discussed in relation to current anatomical, pathological, and experimental work relating to the descending frontobulbar saccadic eye movement system. It is suggested that the caudate nucleus pathology in Wilson's disease might be responsible for the defect of saccadic movement by interrupting a descending polysynaptic pathway.
4610550##1974-2-1##Kinnier Wilson's disease and Wilson's sign. S.A. Kinnier Wilson (1878-1937).##
4832602##1974-1-1##Evidence for a urate reabsorptive defect in patients with Wilson's disease.##
4464503##1974-1-1##Use of the 198Au liver scan in assessing the therapeutic effect of penicillamine in Wilson's disease.##
4418329##1974-1-1##[Biochemical and clinical aspects of Wilson's disease (author's transl)].##
4219083##1974-1-1##Study of copper metabolism in kinky hair disease (Menkes' disease) and in hepatolenticular degeneration (Wilson's disease) utilizing 67Cu and radioactivity counting in the total body and various tissues.##
4215182##1974-1-1##[2 cases of Wilson's disease diagnosed at the infra-clinical stage. Prolonged, early treatment using penicillamine. Result].##
4759424##1973-12-1##Letter: Doubt Wilson disease.##
4787044##1973-12-1##Hepatolenticular degeneration (Wilson's disease) and rickets in children.##
4801897##1973-12-1##Wilson's disease: modification by L-DOPA.##
4750215##1973-11-1##Elastosis perforans serpiginosa during penicillamine therapy for Wilson disease.##
4762580##1973-11-1##Renal urate excretion in patients with Wilson's disease.##
4358747##1973-11-1##[The organic psycho-syndrome in Wilson's disease (longterm follow-up with psychologic testing in 4 patients during d-penicillamin-therapy) (author's transl)].##
4726442##1973-9-21##Wilson's disease: identification of an abnormal copper-binding protein.##The metal-binding protein metallothionein was isolated from the livers of Wilson's disease patients and control subjects. The metals were removed from the native protein to produce the apoprotein, and copperthionein was prepared by equilibrium dialysis. Copperthionein from Wilson's disease patients had a copper-binding constant four times as great as that of the protein from control subjects. These results suggest that the alterations in copper homeostasis in Wilson's disease result from the synthesis of an abnormal metal-binding protein with an increased affinity for copper.
4125854##1973-9-14##[Presymptomatic Wilson's disease. Diagnosis, therapy and family examination].##
4751778##1973-9-1##Osteoarticular changes and synovial biopsy findings in Wilson's disease.##
4750027##1973-9-1##[Hepatocerebral degeneration (Wilson's disease). Demonstration of the clinical picture and demonstration of own case].##
4755718##1973-9-1##[Familial aspects of Wilson's disease].##
4751469##1973-7-1##[Hemorrhagic diathesis in Wilson's disease. Plasmatic or thrombocytic etiology?].##
4744615##1973-7-1##[Ceruloplasmin stimulation test in the treatment of epilepsy and diagnosis of Wilson's disease].##
4728043##1973-7-1##Copper chelation in patients with Wilson's disease. A comparison of penicillamine and triethylene tetramine dihydrochloride.##
4199472##1973-7-1##Wilson's disease in the United Kingdom and Taiwan. I. General characteristics of 142 cases and prognosis. II. A genetic analysis of 88 cases.##
4732990##1973-6-15##[Wilson's disease of exclusively hepatic location (study of a family)].##
4712779##1973-6-1##Wilson's disease or chronic copper poisoning?##
4710011##1973-6-1##Wilson's disease and pregnancy. A case report.##
4712325##1973-5-23##[Radioactive copper in the diagnosis of Wilson's disease].##
4732090##1973-5-19##[Favorable results with an association of L-dopa and amantadine added to penicillamine in the treatment of Wilson's disease].##
4203314##1973-5-1##[Diagnostic and therapeutic aspects of Wilson's disease in the preclinical stage].##
4715528##1973-4-18##A biopsy case of Wilson's disease. Pathological changes in peripheral nerves.##
4611521##1973-3-1##Hepatic transplantation in Wilson disease.##
4700437##1973-3-1##The nature of the copper complexes in bile and their relationship to the absorption and excretion of copper in normal subjects and in Wilson's disease.##Copper in bile has been shown by electrophoresis to occur neither as free ions nor complexed to protein but to be associated with a component of the micellar complexes of bile. Solvent fractionation studies suggest that the bile salt components of the lecithin-bile salt complexes are the active binding agents. The effects of specific bile salts on the behaviour of copper during electrophoresis supports this possibility. The relationship of certain bile salts to the excretion of copper in man during the time that an external biliary fistula was functioning and to the intestinal absorption of copper in the rat was found to confirm this concept. The results show that copper in bile is associated with taurochenodeoxycholate and suggest an explanation for the elevated tissue copper levels found in Wilson's disease.
4786333##1973-3-1##[Detection of asymptomatic and preclinical forms of Wilson's disease by means of a test with 5,5-diphenylhydantoin (hydantoin Polfa)].##
4571542##1973-3-1##[Current views on the pathogenesis of Wilson's disease].##
4572145##1973-3-1##Metabolic effects of hepatic replacement in Wilson's disease.##
4632215##1973-2-23##[Long-term D-penicillamine therapy of Wilson's disease in childhood. Changes in blood coagulation and effects on the haematopoetic system].##
4683728##1973-1-27##[Wilson's disease in Switzerland. Clinical, genetic and biochemical studies].##
4683518##1973-1-20##[Wilson's disease in Switzerland. Clinical, genetic and biochemical studies].##
4800602##1973-1-1##Ophthalmologic and genetic aspects of Wilson's disease (hepatolenticular degeneration).##
4791768##1973-1-1##Observations on copper metabolism in Wilson's disease.##
4683859##1973-1-1##Lysosomal defect of hepatic copper excretion in Wilson's disease (hepatolenticular degeneration).##
4732021##1973-1-1##[Relationship between dermatoglyphics and Wilson's disease].##
4776667##1973-1-1##[1. Convulsive manifestations in Wilson's disease. Electro-clinical case study].##
4804125##1973-1-1##[Physiopathology of hepatolenticular degeneration (Wilson's disease)].##
4790777##1973-1-1##[Kinetics of radioactive copper in Wilson's disease].##
4694331##1973-1-1##[Serologic and hematologic findings in Wilson's disease].##
4641802##1972-12-29##[Diagnosis of the abdominal form of Wilson's disease].##
5082916##1972-11-1##A genetic study of Wilson's disease: evidence for heterogeneity.##
5083937##1972-11-1##Absorption of copper in homozygotes and heterozygotes for Wilson's disease and controls: isotope tracer studies with 67 Cu and 64 Cu.##
5083936##1972-11-1##Turnover studies of copper in homozygotes and heterozygotes for Wilson's disease and controls: isotope tracer studies with 67 Cu.##
4637346##1972-11-1##[Hemolytic anemia in Wilson's disease (hepato-lenticular degeneration)].##
4571815##1972-11-1##[Problems of hemolysis in Wilson's disease].##
5086789##1972-10-16##[Cr-51 labeled erythrocyte survival time in Wilson's disease].##
5076263##1972-9-30##Palmar dermatoglyphs in Wilson's disease.##
4673375##1972-9-1##A case of Wilson's disease with enormous cavity formation of cerebral white matter.##
4653120##1972-8-1##Renal abnormalities in heterozygotes for Wilson's disease: genes or copper?##
5038887##1972-7-1##A study of haemolysis in Wilson's disease.##
4636967##1972-7-1##[Diagnosis and differential diagnosis of hepatocerebral degeneration (Westphal-Strümpell-Wilson disease)].##
5048687##1972-6-30##[EEG changes under sodium diethyldithiocarbamate therapy in 2 cases of Wilson's disease].##
5025342##1972-5-1##Renal tubule and Wilson's disease.##
5031611##1972-5-1##Osteoarticular changes in Wilson's disease.##
4572368##1972-5-1##[Possible accidents due to penicillamine during treatment of Wilson's disease].##
5065238##1972-5-1##[Some observations on Wilson's disease].##
4666894##1972-5-1##[Cutis hyperelastica following prolonged administration of penicillamine in a patient with Wilson's disease].##
4111619##1972-4-15##Preparation of triethylenetetramine dihydrochloride for the treatment of Wilson's disease.##
5019448##1972-4-1##Glucose intolerance in Wilson's disease. Normalization after treatment with penicillamine.##
5019260##1972-3-31##[Wilson's disease. Etiopathogenetic, morphologic, clinical and therapeutic considerations, Case report].##
5024727##1972-3-1##Hypersplenism in Wilson's disease.##Thirteen patients with Wilson's disease were compared with seven cirrhotic and 13 normal controls to define better the haematological abnormalities in this condition. Hypersplenism (anaemia, leukopenia, thrombocytopenia, and reduced red cell survival) commonly occurred in patients with both Wilson's disease and cirrhosis. These abnormalities correlated with splenic enlargement. Despite reduced haematocrits, red cell mass was greater in these two groups than in normal controls. Plasma volume and the body haematocrit/peripheral haematocrit ratios were also greater in patients with Wilson's disease and cirrhosis. Increased splenic sequestration of (51)Cr-tagged red blood cells was not demonstrated in any subjects. The hypersplenism in patients with Wilson's disease is similar to that found in patients with cirrhosis from other causes.
5060150##1972-3-1##Osseous changes in Wilson's disease. A radiologic study of nine patients.##
4622917##1972-2-1##[Optic neuritis in a child with Wilson's disease].##
5057848##1972-1-1##Renal function in heterozygotes for Wilson's disease.##
5082973##1972-1-1##Copper dynamics in Wilson's disease.##
5021554##1972-1-1##Chronic hepatitis as a first manifestation of Wilson's disease.##
4122519##1972-1-1##[Verruciform perforating elastoma in a patient treated by penicillamine for Wilson's disease].##
5010331##1972-1-1##[Wilson's disease].##
5034317##1972-1-1##Hepato lenticular degeneration (Wilson's disease).##
4569009##1972-1-1##Evolution of the hepatic lesion in Wilson's disease (hepatolenticular degeneration).##
5140922##1971-12-11##[Copper-induced hemolysis in Wilson's disease].##
5149266##1971-11-1##Renal clearances of different amino acids in Wilson's disease before and after treatment with penicillamine.##
5315082##1971-9-1##Wilson's disease with reversible renal tubular dysfunction. Correlation with proximal tubular ultrastructure.##
5571499##1971-9-1##Studies with radioactive copper ( 64 Cu and 67 Cu); the incorporation of radioactive copper into caeruloplasmin in Wilson's disease and in primary biliary cirrhosis.##
5164552##1971-9-1##[Neurological evocation. Wilson's disease].##
4936856##1971-8-1##Neurological classics XXXVI. Wilson's disease (S.A. Wilson).##
5118239##1971-8-1##Wilson's disease.##
4106074##1971-8-1##[Electron microscopic observations on the so-called Opalski cells of the brain in Wilson's disease].##
5569040##1971-7-23##[Wilson's disease. 2 cases with damage to liver cells and renal tubules treated with penicillamine].##
5132826##1971-7-1##[On hepatolenticular degeneration (Wilson's disease). IV. A case with atypical clinical course, without the Kayser-Fleischer ring].##
5132825##1971-7-1##[On hepatolenticular degeneration (Wilson's disease). 3. Hepatic localization of Cu64: scintigraphic and dynamic study before and after treatment with BAL and D-penicillamine].##
5132824##1971-7-1##[On hepatolenticular degeneration (Wilson's disease). II. Treatment of 2 cases of Wilson's disease for 8 months with D-penicillamine].##
5132823##1971-7-1##[On hepato-lenticular degeneration (Wilson's disease). I. Detection and early diagnosis].##
5570318##1971-7-1##Metabolic studies in Wilson's disease. Evaluation of efficacy of chelation therapy in respect to copper balance.##
4997065##1971-7-1##Long-term therapy of Wilson's disease.##
5146408##1971-7-1##Abnormalities of the physiology of copper in Wilson's disease. 3. The excretion of copper.##
5207613##1971-7-1##The nursing care of a patient with Wilson's disease.##
5113445##1971-6-1##[Hematologic disorders in Wilson's disease (apropos of 2 personal cases)].##
5089893##1971-6-1##Abnormalities of the physiology of copper in Wilson's disease. II. The internal kinetics of copper.##
5104632##1971-6-1##[Renal function disorders in congenital metabolic abnormalities. 1. Renal function disorders in Wilson's disease].##
5553494##1971-5-20##Diagnosis of Wilson's disease.##
5554863##1971-5-1##Wilson's disease (hepatolenticular degeneration). Treatment with penicillamine and changes in hepatic trapping of radioactive copper.##
5554862##1971-5-1##Abnormalities of the physiology of copper in Wilson's disease. I. The whole-body turnover of copper.##
5547815##1971-4-1##The varied manifestations of Wilson's disease.##
5091812##1971-4-1##Studies with 35S-labelled DL-penicillamine in patients with Wilson's disease.##
4100432##1971-3-13##Orthotopic liver transplantation for Wilson's disease.##
5575151##1971-3-1##Management of hepatolenticular degeneration (Wilson's disease).##
5553728##1971-3-1##Tissue copper, zinc, and manganese levels in Wilson's disease: studies with the use of neutron activation analysis.##
4994070##1971-3-1##[Use of neutron activation analysis in the diagnosis and follow-up studies of Wilson's disease].##
4101505##1971-3-1##Inborn errors of metabolism in neurology (Wilson's disease, Refsum's disease and lipidoses).##
4328809##1971-3-1##Indications for orthotopic liver transplantation: with particular reference to hepatomas, biliary atresia, cirrhosis, Wilson's disease and serum hepatitis.##
4100034##1971-2-6##Lupus-like syndrome induced by D-penicillamine in Wilson's disease.##
5579428##1971-2-1##[Lupus erythematosus due to penicillamine associated with Wilson's disease].##
5579427##1971-2-1##[Lupoid syndrome due to D-penicillamine associated with Wilson's disease: clinical study of a case].##
4252937##1971-2-1##[Lupoid syndrome due to D-penicillamine associated with Wilson's disease: immunologic study by leukocyte migration test (L.M.T.)].##
5548560##1971-2-1##Copper kinetics in liver disease.##The plasma clearance and the liver uptake of intravenously administered (64)Cu were significantly impaired in four patients with Wilson's disease. These defects were unlikely to be simply expressions of the high liver copper concentration as the plasma clearance and hepatic uptake of (64)Cu were normal in four patients with primary biliary cirrhosis, in whom the liver copper concentration was raised to a degree comparable to that in Wilson's disease. The normal liver uptake and plasma clearance of (64)Cu in three patients with other forms of hepatocellular disease suggest that impaired liver cell function does not have a significant effect. The precise nature of the defect in copper transport in Wilson's disease remains to be elucidated; it is possible that delayed uptake of copper by the hepatic lysosomes may account for the toxic effects of the metal.
5542280##1971-2-1##[Wilson's disease].##
4996661##1971-1-28##Comparison of immunologic and enzymatic methods for ceruloplasmin quantitation in Wilson's disease.##
5538633##1971-1-14##Diagnosis of Wilson's disease.##
5542178##1971-1-1##[Problems in the etiopathogenesis and laboratory diagnosis of hepatocerebral syndromes. 2. Current knowledge and views on the essence of so-called hepatolenticular degeneration (Wilson's disease)].##
5544049##1971-1-1##A radiometric assay of copper binding in biological fluids and its application to alimentary secretions in normal subjects and Wilson's disease.##
5101830##1971-1-1##[Treatment of Wilson's disease].##
5494103##1970-12-19##Heptolenticular degeneration (Wilson's disease) in an Australian Aboriginal.##
5495912##1970-12-17##Wilson's disease. A nursing study of the physical and psychological manifestations.##
5511397##1970-12-1##Renal function in Wilson's disease: response to penicillamine therapy.##
5480864##1970-12-1##The role of ceruloplasmin in iron metabolism.##The importance of ceruloplasmin in iron metabolism was studied in swine made hypoceruloplasminemic by copper deprivation. When the plasma ceruloplasmin level fell below 1% of normal, cell-to-plasma iron flow became sufficiently impaired to cause hypoferremia, even though total body iron stores were normal. When ceruloplasmin was administered to such animals, plasma iron increased immediately and continued to rise at a rate proportional to the logarithm of the ceruloplasmin dose. The administration of inorganic copper induced increases in plasma iron only after ceruloplasmin appeared in the circulation. Thus, ceruloplasmin appeared to be essential to the normal movement of iron from cells to plasma. Studies designed to define the mechanism of action of ceruloplasmin were based on the in vitro observation that ceruloplasmin behaves as an enzyme (ferroxidase) that catalyzes oxidation of ferrous iron. Retention of injected ferrous iron in the plasma of ceruloplasmin-deficient swine was significantly less than that of ferric iron, reflecting impaired transferrin iron binding. Rat ceruloplasmin, which has little ferroxidase activity, was much less effective than porcine or human ceruloplasmin in inducing increases in plasma iron. These observations suggest that ceruloplasmin acts by virtue of its ferroxidase activity. Eight patients with Wilson's disease were evaluated in order to investigate iron metabolism in a disorder characterized by reduced ceruloplasmin levels. Evidence of iron deficiency was found in six of these, and in five of the six, plasma ceruloplasmin was less than 5% of normal. In comparison, the two patients without evidence of iron deficiency had ceruloplasmin levels of 11 and 18% of normal. It is suggested that iron deficiency tends to occur in those patients with Wilson's disease who have the severest degrees of hypoceruloplasminemia, possibly because of defective transfer of iron from intestinal mucosal cells to plasma.
5514643##1970-12-1##Prevention of Wilson's disease--a long term follow-up.##
4195996##1970-10-10##Triethylene tetramine dihydrochloride in Wilson's disease.##
4378117##1970-10-1##Wilson's disease. Report of patient with osseous manifestations.##
4195789##1970-9-26##Ineffectiveness of L-dopa as supplement to penicillamine in a case of Wilson's disease.##
5455993##1970-9-1##Hemolytic anemia in Wilson's disease.##
5312232##1970-9-1##Effect of treatment on renal function in severe osteomalacia due to Wilson's disease.##A patient with Wilson's disease presented at the age of 41 with a neurological defect and gross osteomalacia secondary to a defect of renal tubular reabsorption. He also showed the unusual features of a renal stone in the presence of the Fanconi syndrome and a relatively low alkaline phosphatase level, possibly due to the additional inherited defect of hypophosphatasia. During four years of treatment with penicillamine and calciferol clinical improvement was spectacular. Details of amino-acid clearances before and after treatment are given, and the results suggest that, as in the brain and the liver, the function of the distal renal tubules may be restored in Wilson's disease when copper is removed.
5458332##1970-9-1##Muscle copper, zinc, and manganese levels in Wilson's disease: studies with the use of neutron-activation analysis.##
5502130##1970-9-1##[Copper in the anterior chamber in Wilson's disease].##
5316840##1970-8-22##[Disturbances of central vestibular function in Wilson's disease (hepatolenticular degeneration)].##
5472338##1970-7-1##Hemolysis in Wilson's disease. The role of glucose-6-phosphate dehydrogenase inhibition.##
4192136##1970-5-30##Treatment of Wilson's disease with L-dopa after failure with penicillamine.##
5446199##1970-5-2##[Determination of copper in the anterior chamber in Wilson's disease].##
5473254##1970-5-1##Changes in serum copper and PPD-oxidase in different diseases. II. Comparative studies in Wilson's disease schizophrenia and Parkinsonism.##
5452882##1970-5-1##Wilson's disease. Importance of the clinical laboratory in diagnosis and treatment.##
5315573##1970-4-1##[Wilson's disease. Report of a family with 4 cases of hepatolenticular degeneration].##
4986215##1970-4-1##Studies of pancreatic alpha cell function in normal and diabetic subjects.##The development of a glucagon radioimmunoassay with a relatively high degree of specificity for pancreatic glucagon made possible studies of alpha cell function in healthy nondiabetic subjects and in patients with diabetes mellitus. In the former group mean fasting plasma glucagon averaged 108 mumug/ml (SEM +/-10). In 12 juvenile-type diabetics fasting glucagon averaged 110 (+/-9) and in 33 adult-type diabetics the average was 114 (+/-8). The diabetic averages did not differ significantly from the nondiabetic subjects; however, when hyperglycemia was induced by glucose infusion in the nondiabetic subjects so as to simulate the fasting hyperglycemia of the diabetics, mean glucagon fell to 57 mumug (+/-8), which was significantly below the diabetic mean. In 28 healthy subjects the infusion of arginine elicited a rise in glucagon of at least 100 mumug/ml with a peak level averaging 331 mumug/ml (+/-22) at 40 min. This response to arginine was diminished but not abolished during hyperglycemia induced by simultaneous glucose infusion. In everyone of 45 diabetic subjects tested the infusion of arginine elicited a rise in glucagon of at least 140 mumug/ml to levels significantly greater than in nondiabetics. The peak glucagon level in juvenile-type diabetics averaged 458 mumug/ml (SEM +/-36) and in adult-type diabetics averaged 452 mumug/ml (SEM +/-38). The glucagon response to arginine was unrelated to duration of diabetes, to body weight, type of diabetic treatment, or to other known factors. Marked hyperresponsiveness of glucagon to arginine infusion was observed in two patients with advanced Kimmelsteil-Wilson disease. Glucagon levels were markedly elevated in certain patients with severe diabetic ketoacidosis before treatment with insulin. The findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome.
4998072##1970-4-1##Studies on ceruloplasmin in Wilson's disease.##
5443326##1970-4-1##[Laboratory changes and complications during long-term therapy of Wilson's disease using D-penicillamine].##
5429582##1970-4-1##[Penicillamine in the treatment of Wilson's disease. Clinical picture].##
4190630##1970-3-28##Bleeding oesophageal varices in patients with Wilson's disease.##
5467055##1970-3-2##Skin pigmentation in Wilson's disease.##
5417217##1970-3-1##[Therapy of neurologic manifestations of Wilson's disease using penicillamine].##
5434427##1970-3-1##Hepatolenticular degeneration (Wilson's disease).##
5413388##1970-2-1##Penicillamine-induced normalization of clinical signs, and liver morphology and histochemistry in a case of Wilson's disease.##
5462276##1970-2-1##[Electron microscopic observations on the cerebellar cortex of a case of Wilson's disease].##
5532793##1970-1-1##[Syndrome of &quot;epidermolysis bullosa with epidermal cyst&quot; appearing during Wilson's disease treated with penicillamine].##
5508491##1970-1-1##[1st case of Wilson's disease in Senegal].##
5312498##1970-1-1##[Digestive hemorrhages and surgical repercussions in Wilson's disease].##
5410330##1970-1-1##Skeletal changes in Wilson's disease. A radiological study.##
5415807##1970-1-1##Hepatolenticular degeneration (Wilson's disease): observations in 7 cases and review of the literature.##
4104602##1970-1-1##[Fine structural studies of the liver in Wilson's disease].##
4188283##1969-12-27##Management of penicillamine nephropathy in Wilson's disease: a new chelating agent.##
5364763##1969-12-7##[Current problems of Wilson's disease (hepatolenticular degeneration)].##
5351401##1969-12-1##Optical diffraction studies of crystalline structures in electron micrographs. II. Crystalline inclusions in mitochondria of human hepatocytes.##Unit cell dimensions of mitochondrial crystals were determined by optical diffraction analysis of electron micrographs of human liver biopsy specimens. Identical unit cells were found in pathologic material obtained from six patients with Wilson's disease, from one patient with sickle-cell hepatitis, and from two normal subjects. These measurements led to the conclusion that the crystals observed in patients and in normal subjects were probably chemically identical. Furthermore, the relatively large size of the unit cell limits the choices for its constituents to phospholipid micelles or to relatively large protein molecules.
5374545##1969-11-1##The psychiatric presentation of Wilson's disease (hepatolenticular degeneration) with an etiologic explanation.##
4187038##1969-11-1##EEG changes in Wilson's disease.##
5358609##1969-11-1##Effect of cortisone on the faecal excretion of copper in neonatal rats: a new model for the study of Wilson's disease.##
5365473##1969-11-1##[Determination of Cu by activation analysis in liver punctates in Wilson's disease].##
4980975##1969-10-1##Wilson's disease: the role of penicillamine.##
5355538##1969-10-1##Studies with radioactive copper (64Cu and 67Cu): abdominal scintiscans in patients with Wilson's disease.##
5262012##1969-9-30##Interruption of the tryptophan-nicotinic acid pathway by penicillamine-induced pyridoxine deficiency in patients with Wilson's disease and in experimental animals.##
4185700##1969-9-1##EEG changes in Wilson's disease.##
5345090##1969-9-1##Wilson's Disease.##
4979739##1969-8-1##Treatment of hepatolenticular degeneration. (Wilson's disease).##
5824791##1969-7-31##[Hepatolenticular degeneration, Wilson's disease. A characteristics case with remission under penicillamine therapy].##
4898805##1969-7-31##[Hepatolenticular degeneration. Wilson's disease].##
5790274##1969-7-12##&quot;Sunflower cataract&quot; in Wilson's disease.##
4182791##1969-7-5##The influence of genetic and acquired liver defects on radio-copper turnover in Wilson's disease.##
5375675##1969-7-1##[Motometric studies in the diagnosis and observation of the course of Wilson's disease].##
4902749##1969-6-30##[Wilson's disease treated with thalamolysis].##
5376168##1969-6-19##[Wilson's disease: hepatocerebral degeneration. 2. Clinical findings and therapy].##
5816831##1969-6-1##[Effect of sulfhydryl compounds on excretion of heavy metals, with special reference to organic mercury poisoning and Wilson's disease].##
5805577##1969-6-1##[Early diagnosis and prevention of Wilson's disease].##
5807434##1969-5-15##[Iron and copper metabolism in hemochromatosis and Wilson's disease. Studies on relatives of patients].##
5795695##1969-5-14##[Penicillamine treatment of Wilson's disease].##
5807505##1969-5-1##Coagulation abnormalities in Wilson's disease.##
5770104##1969-5-1##Normal manganese turnover in Wilson's disease.##
4979093##1969-4-15##Identification of ceruloplasmin in human liver cells by fluorescent antibodies and absence of this protein in Wilson disease.##
5815702##1969-4-1##[Electron microscopic observations on the cerebrum in a case of Wilson's disease].##
5764894##1969-3-7##[Therapy of Wilson's disease].##
5386346##1969-3-1##[Clinical study of a case of Wilson's disease with observations on the hepatic ultrastructure].##
5785018##1969-3-1##Detection of the heterozygote of Wilson's disease.##
4306792##1969-3-1##A mechanism for the action of penicillamine in the treatment of Wilson's disease.##
4308098##1969-3-1##Cytochrome oxidase deficiency in Wilson's disease: a suggested ceruloplasmin function.##The hypothesis is advanced that ceruloplasmin functions in enzymatic transfer of copper to copper-containing enzymes, such as cytochrome oxidase. To test this hypothesis, leucocytes from Wilson's disease patients, heterozygous carriers, and normal subjects were assayed for cytochrome-oxidase activity. The data reported here show markedly reduced levels of activity in Wilson's disease cases and moderate reductions in heterozygous individuals relative to normal controls. These observations and a close correlation between the level of cytochrome-oxidase activity in the leucocytes and ceruloplasmin in the serum tend to support the hypothesis.
5767059##1969-2-1##Wilson's disease.##
4178768##1969-1-4##Diagnosis of Wilson's disease in children with liver disease. A report of two families.##
5401571##1969-1-1##[Hepatic ultrastructure in Wilson's disease].##
5384189##1969-1-1##[Pemphigus in a patient treated with penicillamine for Wilson's disease].##
4242275##1969-1-1##[Late cutaneous lesions due to penicillamine in a patient with Wilson's disease].##
5771745##1969-1-1##[De Toni-Debre-Fanconi syndrome in Wilson's disease].##
4246638##1969-1-1##[Clinical, therapeutic and isotopic study of familial Wilson's disease: desensitization to penicillamine D].##
5404531##1969-1-1##[2 cases of Wilson's disease with hepatic precession in biliary lithiasis].##
5385889##1969-1-1##[Wilson's disease or hepatolenticular degeneration].##
5374484##1969-1-1##Treatment of Wilson's disease (hepatolenticular degeneration) with penicillamine and low-copper diet.##
4984978##1969-1-1##Studies of peptide maps of ceruloplasmin in Wilson's disease.##
5732473##1968-12-15##[Present concepts of copper physiology and Wilson's disease].##
5756864##1968-12-10##[Presymptomatic and hepatic forms of Wilson's disease in childhood. Long-term therapy with D-penicillamine].##
4177374##1968-12-1##Changes in the distribution of hepatic copper in relation to the progression of Wilson's disease (hepatolenticular degeneration).##
5711646##1968-12-1##[Wilson's disease treated by penicillamine: favorable effect].##
5732518##1968-12-1##[Wilson's disease (hepatolenticular degeneration)].##
5704622##1968-11-30##[Functional disorders of the renal tubules in Wilson's disease].##
5697385##1968-11-1##Use of whole-body counter to study body retention of radiocopper in Wilson's disease.##
5730464##1968-11-1##[Osteoarthropathies in Wilson's disease].##
5738558##1968-10-31##[Aspects of chemical pathology in 2 cases of Wilson's disease].##
5743244##1968-10-1##[Physiopathological and therapeutic considerations on a case of Wilson's disease].##
5706614##1968-10-1##Toxic reactions to penicillamine in patients with Wilson's disease.##
5675366##1968-9-1##Mitochondrial and fatty changes in hepatocytes of patients with Wilson's disease.##
5683354##1968-9-1##Hereditary hepatolenticular degeneration (Wilson's disease). Report of the first case in Jamaica.##
5747556##1968-8-15##[On a case of Wilson's disease].##
5662784##1968-8-1##Prophylaxis for Wilson's disease.##
5244534##1968-8-1##Prevention of Wilson's disease.##
5727320##1968-7-1##[Does molybdenum play a role in Wilson's disease?].##
5742073##1968-7-1##What Wilson's disease and its treatment have taught us about the metabolism of copper. Observations in 27 cases.##
5691595##1968-7-1##Iron metabolism in Wilson's disease. Kinetic studies with iron.##
5656291##1968-6-29##Controversy in Wilson's disease.##
5656240##1968-6-1##Multiple intrasplenic arterial aneurysms in Wilson's disease.##
4171778##1968-5-18##Penicillamine for tubular dysfunction in Wilson's disease.##
5646242##1968-5-16##Prophylaxis of Wilson's disease.##
5646241##1968-5-16##Prophylaxis of Wilson's disease.##
4171810##1968-5-11##Prevention of Wilson's disease by penicillamine?##
4384740##1968-5-1##Psychiatric aspects of Wilson's disease (hepatolenticular degeneration): results of psychometric tests during long-term therapy.##
4880081##1968-5-1##[Abdominal form of Wilson's disease. Detection of copper in the tissues by X fluorescence].##
5641165##1968-4-18##Prophylactic treatment of Wilson's disease.##
4171128##1968-4-13##Effect of penicillamine on failure of renal acidification in Wilson's disease.##
5642962##1968-4-1##Defective urinary acidification in Wilson's disease.##
5690128##1968-4-1##The liver-thigh 64Cu ratio in Wilson's disease.##
5655947##1968-3-1##Treatment of Wilson's disease.##
5746721##1968-3-1##[Wilson's disease or hepatolenticular degeneration].##
5642287##1968-3-1##Wilson's disease presenting with rickets.##
5635648##1968-2-15##Editor's choice: Wilson's disease.##
5635646##1968-2-15##Prevention of Wilson's disease in asymptomatic patients.##
5745277##1968-2-1##[Treatment of Wilson's disease].##
5688753##1968-2-1##Wilson's disease in India. II. Biochemical and pathogenetic considerations in patients, parents, and siblings.##
5695072##1968-2-1##[Effects of the combined administration of glutathione and D-penicillamine on the urinary copper excretion in Wilson's disease].##
5760555##1968-1-1##[Genetic, anatomo-clinical and therapeutic remarks on two cases with Wilson's disease].##
4895955##1968-1-1##[Possibilities of treating Wilson's disease by stereotaxic thalamolysis].##
5308488##1968-1-1##Wilson's disease: an abnormal cellular defect?##
5697340##1968-1-1##Neutron activation analysis ofr copper in biological material applied to Wilson's disease.##A method for the neutron activation analysis of copper in biological material is described and applied to the diagnosis and management of four cases of Wilson's disease. Results obtained for serum and urine are in agreement with values obtained by established colorimetric techniques. The method described can estimate 10(-9) g. copper to within 10% and this sensitivity has allowed the determination of copper from biopsy material such as liver, spleen, hair, and nail.
5634999##1968-1-1##The renal clearance of amino acids in a patient with Wilson's disease during penicillamine treatment.##
5656546##1968-1-1##Experimental Wilson's disease in primates.##
5689924##1968-1-1##Wilson's disease in India. I. Geographic, genetic, and clinical aspects in 16 families.##
4180784##1968-1-1##[Electron microscopic observation of the liver in Wilson's disease].##
5709960##1968-1-1##Prevention of Wilson's disease in asymptomatic patients.##
5697565##1968-1-1##[Anatomo-clinical study of a case of Wilson's disease treated with chelating agents for 5 years].##
5733267##1968-1-1##[Genetic and biochemical studies in 4 siblings with Wilson's disease].##
5704721##1968-1-1##[A case of Wilson's disease with peculiar manifestations].##
4873428##1967-12-15##[New views on the etiology, diagnosis and therapy of Wilson's disease].##
6082645##1967-12-1##Oral roentgenographic changes in Wilson's disease.##
6069299##1967-11-1##Seizures in Wilson's disease.##
6081668##1967-11-1##[Hepatic changes in the neurological form of Wilson's disease].##
5630545##1967-10-1##[Contribution to the clarification of the pathogenesis of osteopathies in Wilson's disease. (Hepatolenticular degeneration)].##
4166824##1967-9-16##Presymptomatic Wilson's disease.##
6054323##1967-9-15##[Long-term treatment of Wilson's disease with D-penicillamine. Report on 20 cases].##
6038297##1967-9-1##Wilson's disease with aseptic meningitis and penicillamine-related cheilosis.##
5610733##1967-8-25##[Juvenile form of Wilson's disease with mainly hepatic character].##
6062332##1967-8-1##[Mental disorders in Wilson's disease and the effect on them of penicillamine therapy].##
4961748##1967-8-1##Hemolytic anemia associated with Wilson's disease.##
6027596##1967-7-1##Intake-excretion studies of fat and nitrogen in 7 patients with hepatolenticular degeneration (Wilson's disease).##
6027683##1967-7-1##Comparative metabolism of copper and zinc in patients with Wilson's disease (hepatolenticular degeneration).##
6027022##1967-6-30##[On the course and therapy of a juvenile Wilson's disease case].##
5624888##1967-6-10##[Metabolism in Wilson's disease. Whole body counting of 64Cu].##
6026104##1967-6-1##Ceruloplasmin in Wilson's disease.##Ceruloplasmin was highly purified from one patient with Wilson's disease and partially purified from a second unrelated patient. The highly purified ceruloplasmin was indistinguishable from normal ceruloplasmin by electrophoresis, tryptic peptide map, oxidase activity, and copper, amino acid, and sugar composition. The partially purified ceruloplasmin was indistinguishable electrophoretically from normal ceruloplasmin. With penicillamine therapy, ceruloplasmin disappeared from the serum of the first patient; it reappeared after the drug was discontinued. The significance of this observation in regard to the basic defect in Wilson's disease is discussed.
6028804##1967-6-1##Studies on levels of penicillamine-induced cupriuresis in heterozygotes of Wilson's disease.##
5625390##1967-6-1##[Genetical and epidemiological studies of Wilson's disease in Japan].##
5619464##1967-5-2##[Liver lesions in preclinical Wilson disease. Importance of case-finding].##
6022752##1967-4-1##Studies on azide, caeruloplasmin and copper in relation to Wilson's disease.##
6041972##1967-4-1##The liver in Wilson's disease. Some histochemical and histological aspects.##
5600109##1967-4-1##The broad field of neuropathology. A. 1,000 brain &quot;tumours&quot;, B. The encephalitides, C. Wilson's disease in India.##
5336999##1967-3-1##The physiology of copper in man and its relation to Wilson's disease.##
6031801##1967-2-25##Metabolic pathways of red blood cell copper in normal humans and in Wilson's disease.##
6018274##1967-2-23##Hemolytic anemia in Wilson's disease.##
4163882##1967-2-8##Studies with radioactive copper (64Cu and 67Cu) in relation to the natural history of Wilson's disease.##
6050435##1967-2-1##[Study of psychiatric disorders in a case of familial Wilson's disease].##
5335185##1967-2-1##Problems in Wilson's disease.##
5610947##1967-2-1##[Does the Jirasek-Zulzer-Wilson disease exist?].##
6017170##1967-1-14##A screening test for Wilson's disease and its application to psychiatric patients.##Varied modes of onset make the early diagnosis of Wilson's disease difficult. A deficiency of serum ceruloplasmin, usually characteristic of the disease, was used as the basis for a screening test. Simple test materials and provision for handling about 50 plasma samples simultaneously made this test feasible for large-scale screening.The screening test was applied to 336 persons hospitalized for psychiatric disorders, to detect patients with Wilson's disease before the classical symptoms appeared. Two patients with ceruloplasmin levels below the normal limits were detected but did not have Wilson's disease. Further application of the screening test to relatives of patients known to have Wilson's disease and to individuals with any symptoms of the disease (hepatic disease, extrapyramidal dysfunction, psychiatric disorders, behaviour problems in children) would aid in early diagnosis and more effective treatment.
6015900##1967-1-1##Picture of the month. Wilson's disease (hepato-lenticular degeneration).##
6031446##1967-1-1##[Interviews with a young boy with Wilson's disease. Relation of the patient with copper and the physicians].##
6043357##1967-1-1##Quantitative topography of copper in Wilson's disease and in porto-systemic encephalopathy.##
6050251##1967-1-1##[Study of the copper of the aqueous humor in a family with Wilson's disease].##
4166971##1967-1-1##[A contribution to the morphological study of &quot;atypical glial cells&quot; in Wilson's disease. On the findings with silver impregnation methods].##
5620588##1967-1-1##[Urine copper determination in Wilson's disease during therapy].##
5620587##1967-1-1##[Experiences with long-term therapy of Wilson's disease].##
5620586##1967-1-1##[Wilson's disease. Introduction to current problems (early diagnosis and therapy)].##
4227557##1967-1-1##[Criminal behavior disorders in Wilson's disease].##
21105526##2010-11-26##New oral chelating agent for treatment of Wilson's disease.##
5954673##1966-12-1##Hypercalciuria in hepatolenticular degeneration (Wilson's disease).##
5927925##1966-12-1##Nephrotic syndrome in the course of treatment of Wilson's disease with DL-penicillamine.##
5998503##1966-12-1##[Metabolism of serotonin in Wilson's disease].##
5332750##1966-11-19##Ocular correlates of inborn metabolic defects.##The eye provides unique opportunities for the detection, during life, of deposits of storage substances and other characteristic changes resulting from inborn metabolic defects. The cornea shows the macromolecular polysaccharides of Hurler's disease, the cystine crystals in cystinosis, and the copper deposits of Wilson's disease. The sclera shows characteristic pigmentation in alcaptonuria. The iris shows the lack of pigmentation in various types of albinism. The lens is cataractous in galactosemia and dislocated in homocystinuria. The vitreous is opacified in familial amyloidosis. The retina shows different and characteristic deposits with the diseases of Tay-Sachs, Niemann-Pick, metachromatic leukodystrophy, and Farber's lipogranulomatosis. The retinal veins show pronounced tortuosity with Fabry's disease. There is some evidence that optic neuropathy occurs in glucose-6-phosphate dehydrogenase deficiency. Curiously, few abnormalities in the eye have been described in subjects with the glycogen storage diseases.
5924028##1966-11-11##A mathematical model for copper metabolism and its relation to Wilson's disease.##
5922366##1966-11-1##Copper content of saliva of normal subjects and treated Wilson's disease patients.##
5922363##1966-11-1##Influence of penicillamine on the turnover of I-131-labeled ceruloplasmin in Wilson's disease.##
6009456##1966-10-1##[Bone changes in Wilson's disease].##
5914113##1966-9-1##Radiocopper studies in patients with Wilson's disease and their relatives.##
5331489##1966-9-1##Copper metabolism in Wilson's Disease.##
5976806##1966-9-1##[Blood coagulation disorders in Wilson's disease].##
5976062##1966-9-1##A case of Wilson's disease.##
5946252##1966-6-1##[Preclinical detection of Wilson's disease].##
5936452##1966-5-1##Wilson's Disease presenting as pancytopenia: splenectomy in management.##
5963235##1966-4-23##Active copper transport in mammalian tissues--a possible role in Wilson's disease.##
5910562##1966-4-1##Experimental copper poisoning and Wilson's disease.##
5951974##1966-3-14##Wilson's disease (hepatolenticular degeneration) and pregnancy.##
5904434##1966-3-1##Hepatolenticular degeneration. (Wilson's disease).##
5908198##1966-3-1##[Wilson's disease: determination of minerals in ocular tissues].##
5937104##1966-3-1##[Clinical and endocrine aspects of Wilson's disease (hepatolenticular degeneration)].##
5904503##1966-2-1##Electron probe microanalysis of liver in Wilson's disease. Simultaneous assay for copper and for lead deposited by acid phosphatase activity in lysosomes.##
6014815##1966-1-1##[Hepatolenticular degeneration. Wilson's disease. New case contribution].##
5994294##1966-1-1##[Electromyographic findings in a case of Wilson's disease].##
5994293##1966-1-1##[Therapeutic considerations on Wilson's disease].##
4964272##1966-1-1##[Wilson's disease (hepatolenticular degeneration)].##
5954284##1966-1-1##The effects of penicillamine therapy on uric acid metabolism in Wilson's disease.##
5848709##1965-12-1##Studies with radiocopper (64Cu) in Wilson's disease: dynamics of copper transport.##
5894519##1965-12-1##[Clinical and biochemical aspects in Wilson's disease in several families].##
5884683##1965-11-12##[Hepatocerebral degeneration (Wilson's disease). 2. Therapy].##
5887817##1965-11-5##[Hepatocerebral degeneration (Wilson's disease). I. Pathogenesis, clinical aspects, electroencephalogram].##
4221490##1965-11-1##Increased brain radiocopper uptake in Wilson's disease.##
5878841##1965-11-1##Clinical and physiologic implications of thalamic surgery for disorders of sensory communication. 2. Intention tremor, dystonia, Wilson's disease and torticollis.##
5838405##1965-10-1##Studies on copper, caeruloplasmin and cirrhosis in relation to Wilson's disease.##
5881766##1965-10-1##[On the early diagnosis of Wilson's disease].##
5895380##1965-10-1##[Therapeutic effects of penicillamine on Wilson's disease].##
5318498##1965-10-1##Dietary copper in Wilson's disease.##
5841019##1965-9-1##Wilson's disease in an Indian boy.##
5851771##1965-9-1##[Recent acquisitions in the study of Wilson's disease].##
14319259##1965-8-6##[LABORATORY DIAGNOSIS OF WILSON'S DISEASE].##
5295758##1965-8-1##Wilson's disease. An electron microscope study.##
5323121##1965-8-1##[Wilson's disease].##
14341840##1965-8-1##WILSON'S DISEASE PRESENTING AS AN ACUTE HAEMOLYTIC ANAEMIA.##
14338401##1965-7-1##WILSON'S DISEASE. (A CASE REPORT).##
14339732##1965-7-1##CHEMICAL THERAPY OF WILSON'S DISEASE.##
14328025##1965-6-1##THE LOCALIZATION OF COPPER IN THE PERICANALICULAR GRANULES (LYSOSOMES) OF LIVER IN WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION) .##
14295512##1965-6-1##THE NEPHROTIC SYNDROME AS A COMPLICATION OF PENICILLAMINE THERAPY FOR HEPATOLENTICULAR DEGENERATION (WILSON'S DISEASE).##
14318784##1965-6-1##[CONTROL OF THE COURSE IN FAMILIAL WILSON'S DISEASE (KAYSER-FLEISCHER RING, SUNFLOWER CATARACT, VITREOUS BODY PIGMENTATION)].##
14293521##1965-6-1##COPPER BALANCE STUDIES DURING THE TREATMENT OF PATIENTS WITH WILSON'S DISEASE.##
14338689##1965-6-1##[A CASE OF FAMILIAL HEPATOLENTICULAR DEGENERATION (WILSON'S DISEASE)].##
5843373##1965-6-1##[Wilson's disease with deceptive onset (hematuria followed by portal hypertension syndrome)].##
5836853##1965-6-1##[Wilson's disease (degeneratio hepatolenticularis)].##
14298567##1965-5-16##[WILSON'S DISEASE].##
14298566##1965-5-16##[ON WILSON'S DISEASE. (HEPATOLENTICULAR DEGENERATION)].##
14288982##1965-5-1##COPPER BALANCE STUDIES IN WILSON'S DISEASE; OBSERVATIONS ON THE EFFECT OF PENICILLAMINE, CARBACRYLAMINE RESINS, AND POTASSIUM SULFIDE.##
5834270##1965-4-30##[Early detection and treatment of Wilson's disease].##
5834268##1965-4-30##[Trial of treatment of Wilson's disease with sodium diethyl-dithio-carbamate].##
5834267##1965-4-30##[Renal accidents in 2 cases of Wilson's disease treated with penicillamine].##
5317932##1965-4-24##[Hepatolenticular degeneration or Wilson's disease. Results of treatment].##
14264484##1965-4-10##[DO CHELATING AGENTS CURE WILSON'S DISEASE?].##
5827295##1965-4-1##Wilson's disease with rickets.##
14280605##1965-4-1##TREATMENT OF HEPATOLENTICULAR DEGENERATION (WILSON'S DISEASE) IN THE ASYMPTOMATIC STAGE.##
14266590##1965-3-26##[WILSON'S DISEASE IN THE FORM OF A PANHEMOCYTOPENIA].##
14285074##1965-3-25##A GENETIC ASPECT OF WILSON'S DISEASE IN JAPAN.##
14275039##1965-3-6##FINGERPRINT PATTERNS IN HUNTINGTON'S CHOREA AND PARKINSON'S DISEASE.##In the course of a continuing search for means of predicting Huntington's chorea before the onset of neurological symptoms, a study of fingerprint patterns was undertaken, using the technique employed by Hodges and Simon in the investigation of patients with Wilson's disease. Fingerprint patterns of 61 patients with Huntington's chorea and 50 with Parkinson's disease were compared with norms established by Scotland Yard. Although an increased incidence of the &quot;whorl&quot; pattern was seen in the left second and third fingers in patients with Huntington's chorea, this finding could not be interpreted as having diagnostic or prognostic value as it was found also in some normal subjects and in occasional cases of Parkinson's disease. The pattern supposedly characteristic of Wilson's disease was also seen in persons with Huntington's chorea.
14323829##1965-3-1##[WILSON'S DISEASE].##
14256542##1965-3-1##WILSON'S DISEASE (HEPATO-LENTICULAR DEGENERATION): A BRIEF REVIEW.##
14285068##1965-2-25##CLINICAL AND PATHOLOGICAL ASPECTS OF WILSON'S DISEASE IN CASES OF ONE AND THE SAME FAMILY.##
14309926##1965-2-1##[WILSON'S DISEASE WITHOUT NEUROLOGICAL SYMPTOMS].##
14276559##1965-1-1##WILSON'S DISEASE.##
5857077##1965-1-1##Changes of some clotting factors in hepatolenticular degeneration (Wilson's disease).##
14252337##1965-1-1##EFFECT OF ADRENOCORTICAL STEROIDS ON THE HYPERCALCIURIA OF WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION).##
14236007##1964-12-1##HEPATO-LENTICULAR DEGENERATION (WILSON'S DISEASE) TREATED BY PENICILLAMINE.##
5829369##1964-12-1##Wilson's disease (hepato-lenticular degeneration). Changing clinical concepts.##
14196726##1964-10-1##TISSUE COPPER PROTEINS IN WILSON'S DISEASE. INTRACELLULAR DISTRIBUTION AND CHROMATOGRAPHIC FRACTIONATION.##
14216172##1964-10-1##[IMPROVEMENT IN WILSON'S DISEASE IN A 17-YEAR-OLD GIRL WITH CONTINUOUS PENICILLAMINE THERAPY].##
14220911##1964-10-1##STUDIES WITH RADIOCOPPER (64CU) IN WILSON'S DISEASE: THE LIVER/THIGH RATIO.##
14210920##1964-10-1##[CURRENT ASPECTS OF WILSON'S DISEASE].##
14225643##1964-10-1##[ARTHROPATHIES IN WILSON'S DISEASE].##
14226649##1964-9-19##[WILSON'S DISEASE AND ITS TREATMENT].##
14202497##1964-9-1##WILSON'S DISEASE AS A GASTROENTEROLOGIC PROBLEM.##
14205672##1964-9-1##[PIGMENTATION OF THE CHAMBER ANGLE IN WILSON'S DISEASE AND EXFOLIATIO LENTIS].##
14248470##1964-7-6##[A CONTRIBUTION TO WILSON'S DISEASE FROM A CLINICAL AND MORPHOLOGICAL VIEWPOINT].##
14169457##1964-6-1##BASAL COPPER EXCRETION IN WILSON'S DISEASE.##
14191274##1964-6-1##ENDOGENOUS COPPER CLEARANCE IN WILSON'S DISEASE: A STUDY OF THE MODE OF ACTION OF PENICILLAMINE.##
14143829##1964-6-1##WILSON'S DISEASE.##
14194539##1964-6-1##GENETICAL STUDIES OF WILSON'S DISEASE. 3. GENETICAL AND EPIDEMIOLOGICAL STUDIES OF WILSON'S DISEASE IN MIKURA ISLAND.##
14129061##1964-5-28##HEPATOLENTICULAR DEGENERATION (WILSON'S DISEASE). TWO DIFFERENT COMPONENTS.##
14159455##1964-5-1##THE MICRODETERMINATION OF BIOLOGICAL COPPER WITH OXALYLDIHYDRAZIDE.##Methods are described for the determination of microgram quantities of biological copper in aqueous medium as the intensely coloured oxalyldihydrazide-acetaldehyde complex (molar extinction coefficient 23,000 to 23,500). The methods are applicable on a routine basis to any biological material, in particular to serum, urine, or tissues, such as liver, brain, or kidney. In the case of urine a simple semi-quantitative screening method is also described. For quantitative work copper is liberated from serum by acid extraction and protein precipitation, and from urine and tissues by a rapid wet-ashing procedure. Recoveries of added copper from urine are quantitative. Precision is high although day-to-day control with standards and blanks is desirable. The methods are applied in an investigation of the diurnal variations in a normal man and in two cases of Wilson's disease.
14129796##1964-4-18##RENAL LESIONS IN WILSON'S DISEASE.##
5851345##1964-4-1##Infantile familiar cirrhosis, due to Wilson's disease without neurologic manifestations.##
14141837##1964-4-1##D-PENICILLAMINE, WITH PARTICULAR RELATION TO WILSON'S DISEASE.##
14147228##1964-4-1##[WILSON'S DISEASE TREATED BY PENICILLAMINE].##
14140246##1964-2-28##[WILSON'S DISEASE (HEPATOCEREBRAL DEGENERATION) IN CHILDREN].##
14124700##1964-2-1##NEPHROTIC SYNDROME ASSOCIATED WITH PENICILLAMINE THERAPY OF WILSON'S DISEASE.##
14160082##1964-2-1##FAMILIAL HEPATIC COPPER STORAGE DISEASE: A VARIANT OF WILSON'S DISEASE.##
14126723##1964-2-1##[LONG-TERM USE OF BAL IN WILSON'S DISEASE WITH SPECIAL REFERENCE TO THE OBSERVATION OF CHANGES IN BLOOD COPPER AND LIVER TISSUE].##
14156393##1964-1-1##WILSON'S DISEASE, AN INBORN ERROR OF METABOLISM AND A MODEL OF DEGENERATIVE CENTRAL NERVOUS SYSTEM DISEASE.##
14126932##1964-1-1##[2 CASES OF WILSON'S DISEASE, WITH SPECIAL REFERENCE TO THERAPY AND THE DANGER OF FURTHER PROGRESS OF THE DISEASE].##
14243537##1964-1-1##[ON WILSON'S DISEASE].##
14294239##1964-1-1##[HEPATOCEREBRAL DEGENERATION IN CHILDHOOD (WILSON'S DISEASE)].##
14294237##1964-1-1##[COPPER METABOLISM AND WILSON'S DISEASE].##
14090776##1963-12-1##EXCRETION OF DOPAMINE, CATECHOLAMINE METABOLITES AND 5-HYDROXYINDOLEACETIC ACID IN HEPATOLENTICULAR DEGENERATION (WILSON'S DISEASE).##
14157269##1963-12-1##CLINICAL AND PATHOLOGICAL CHARACTERISTICS IN WILSON'S DISEASE IN CASES UNDER TEN YEARS OF AGE.##
14096317##1963-11-1##[STUDIES ON THE URINARY EXCRETION OF FREE AMINO ACIDS IN NERVOUS DISEASES IN CHILDHOOD. 3. ON URINARY FREE AMINO ACIDS IN WILSON'S DISEASE].##
14056737##1963-10-1##MEDICAL GRAND ROUNDS FROM THE UNIVERSITY OF ALABAMA MEDICAL CENTER. CASE 9: WILSON'S DISEASE.##
14057643##1963-9-1##LIVER CELL LYSOSOMES IN WILSON'S DISEASE: ACID PHOSPHATASE ACTIVITY BY LIGHT AND ELECTRON MICROSCOPY.##
14073714##1963-9-1##STUDY OF WILSON'S DISEASE IN TAIWAN.##
14057196##1963-9-1##[WILSON'S DISEASE. HISTORICAL PROGRESS IN ITS STUDY, AND FUTURE RESEARCH WITH SPECIAL REFERENCE TO ABNORMALITIES OF COPPER METABOLISM].##
14044316##1963-8-31##PENICILLAMINE AND MIXED DISULPHIDE EXCRETION IN WILSON'S DISEASE.##
14044277##1963-8-17##CHELATING AGENTS IN WILSON'S DISEASE.##
13998657##1963-7-1##Studies on the oxidase properties of ceruloplasmin: factors in normal and Wilson's-disease serum affecting oxidase activity.##
14091678##1963-7-1##[OUR EXPERIENCE IN THE TREATMENT OF WILSON'S DISEASE WITH PENICILLAMINE].##
13991539##1963-6-29##Wilson's disease and the concentration of caeruloplasmin in serum.##
14054466##1963-6-1##[CLINICAL AND HUMORAL ASPECT OF THE SPLENIC FORM OF WILSON'S DISEASE. PRESENTATION OF A CASE].##
14017232##1963-5-3##[Study of ceruloplasmin in Wilson's disease].##
14014351##1963-5-3##[Arthropathies of Wilson's disease].##
14014350##1963-5-3##[Our experience with the treatment of Wilson's disease by penicillamine].##
13977562##1963-5-1##Metabolic aspects of Wilson's disease: a review.##
13991538##1963-5-1##The dual role of the liver in Wilson's disease.##
14023283##1963-4-1##[On the therapy of Wilson's disease].##
14049950##1963-4-1##A GENETIC, BIOCHEMICAL AND CLINICAL STUDY OF WILSON'S DISEASE AMONG CHINESE IN TAIWAN.##
14065806##1963-3-22##[THE LIVER IN HEPATOLENTICULAR DEGENERATION (WILSON'S DISEASE). REVIEW OF 4 CASES].##
13983986##1963-3-2##The diagnosis of Wilson's disease in asymptomatic patients.##
13998516##1963-3-1##Possible importance of altered steroid metabolism in etiology of Wilson's disease. Preliminary report.##
13994934##1963-2-1##[Wilson's disease with preceding hepatic and hematological symptoms in a 10-year-old child].##
13940485##1963-2-1##Uptake of radiocopper by the liver. A study of patients with Wilson's disease and various control groups.##
13997625##1963-2-1##Biochemical reactions of copper within neural mitochondria, with consideration of the role of the metal in the pathogenesis of Wilson's disease.##
13994646##1963-2-1##Tissue copper levels in Chinese patients with Wilson's disease.##
13935542##1963-1-1##[Ocular manifestations of Wilson's disease treated by penicillamine].##
13971614##1963-1-1##[Treatment of Wilson's disease with penicillamine and guajacuran].##
13993254##1963-1-1##[Wilson's disease. Apropos of a case with complete ocular symptomatology].##
13987179##1963-1-1##Wilson's disease: a case with almost total loss of white matter.##
13973797##1963-1-1##The pathophysiology of Wilson's disease.##
13940148##1963-1-1##[On the correlations between liver and brain in the picture of Wilson's disease].##
13991537##1963-1-1##Ceruloplasmin test for Wilson's disease.##
14272232##1963-1-1##COPPER BALANCE STUDIES IN WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION). OBSERVATIONS ON THE EFFECT OF PENICILLAMINE, CARBO-RESIN AND POTASSIUM SULFIDE.##
14272206##1963-1-1##THE INTRACELLULAR DISTRIBUTION AND CHROMATOGRAPHIC SEPARATION OF COPPER PROTEINS IN WILSON'S DISEASE.##
14024225##1962-12-1##Wilson's disease.##
13998658##1962-11-1##[Hepatolenticular degeneration (Wilson's disease); unsolved problems].##
13935602##1962-10-26##Wilson's disease.##
13994451##1962-10-12##[Iron deficiency syndrome in hepatolenticular degeneration (Wilson's disease)].##
13974111##1962-10-4##[Hepatic and metabolic aspects of progressive hepatolenticular degeneration or Wilson's disease].##
13938907##1962-10-1##Wilson's disease.##
14031483##1962-10-1##Ceruloplasmin, copper and Wilson's disease.##
13963787##1962-10-1##Relationship between fingerprint patterns and Wilson's disease.##
14067922##1962-9-28##STUDY OF WILSON'S DISEASE IN TAIWAN.##
20327250##2010-3-24##Birth of a Viable Child to a Mother with Wilson's Disease.##
14018626##1962-9-15##[Therapy of Wilson's disease].##
14497986##1962-9-1##Hepatocellular changes in Wilson's disease. Histochemical and electron microscopic studies.##
13912922##1962-9-1##The liver in juvenile Wilson's disease.##
13973459##1962-9-1##[Clinico-biological considerations on a case of Wilson's disease with normal ceruloplasmin levels].##
13913237##1962-8-25##Whole body scanning in medicine. II. Clinical aspects.##Various kinds of scans were performed on 439 patients, using several types of radioactive substances. Using I(131), functioning metastases were demonstrated in 11 of 26 patients with follicular or papillary thyroid cancer; in three of these patients the results of scans were a decisive influence in attempting radioiodine therapy. Radioiron scans demonstrated extramedullary hematopoiesis in patients with polycythemia vera, myelofibrosis, and myelophthisic anemia. Radiocopper studies showed abnormal concentration in the kidneys in two patients with Wilson's disease. Radioactive strontium localized in bone metastases in at least four patients with malignant disease. Liver and kidney scans, using I(131)-Rose Bengal and Hg(203)-Neohydrin respectively, have been useful in the management of patients suffering from malignant disease, renal hypertension, and certain other disorders.
13906230##1962-8-1##The electroencephalogram in hepatolenticular degeneration (Wilson's disease).##
14475962##1962-7-1##Wilson's disease and the Fanconi syndrome.##
20327144##2010-3-24##Birth of a Viable Child to a Mother with Wilson's Disease.##
14040172##1962-6-1##Wilson's disease.##
14038010##1962-6-1##Wilson's disease. The presenting symptoms.##
13899920##1962-4-1##Treatment of Wilson's disease (hepatolenticular degeneration) with DL-penicillamine.##
14479334##1962-3-1##The determination of copper in biological materials by flame spectrophotometry.##A method for the determination of the copper content of biological materials by flame spectrophotometry is described. The effects of interference by ions such as sodium and phosphate were eliminated by isolating copper as the dithizonate in CCl(4). Results obtained for the urinary excretion of copper by a patient with Wilson's disease before and after treatment with penicillamine are reported.
13892274##1962-1-1##Calcium and phosphorus metabolism in Wilson's disease.##
13882607##1962-1-1##The metabolism of copper and Wilson's disease.##
13984170##1962-1-1##[Wilson's disease of hepatic form in the child and its treatment].##
14471779##1961-12-6##Copper metabolism in Wilson's disease, Laennec's cirrhosis and hemachromatosis: studies with radiocopper (Cu64).##
14491888##1961-12-1##Copper content of hair and nails in Wilson's disease (hepatolenticular degeneration).##
13866167##1961-11-1##Wilson's disease.##
13869965##1961-9-1##[The use of penicillamine as a diagnostic aid in hepatolenticular degeneration (Wilson's disease)].##
13737275##1961-8-1##Cerebrocuprein I copper in the brain in Wilson's disease. A preliminary report on yields of copper in subfractions obtained in the course of modified isolation procedure.##
13898276##1961-7-1##[Study of the serum copper-oxidase activity in 8 families affected by Struempell-Wilson disease (hepatolentricular degeneration)].##
13781801##1961-6-1##Morphologic alterations produced by copper in neural tissues with consideration of the role of the metal in the pathogenesis of Wilson's disease.##The injection into the cerebrospinal fluid of cats of 52 to 208 gamma of copper in the form of an albumin complex or as cupric sulfate, was followed by small elevations in the content of metal in the neural tissues, but regularly and promptly produced persistent quadriplegia and conspicuous histologic changes. Smaller amounts of copper caused less, or no, neurologic manifestations or histologic alterations. The earliest lesions were essentially unaccompanied by inflammation and were initially characterized by hydropic swelling of the myelin sheaths. They progressed rapidly to focal necrosis of all parenchymal components with marked degeneration of myelin and axis cylinders in the peripheral margins of the spinal cord, brain stem, mid-brain, and cerebrum. These histologic changes did not occur in neural tissues incubated in vitro in solutions of the copper-albumin complex. They did not appear in animals injected intraventricularly with ferric sulfate or saccharated iron. Considered together, the findings make it clear that copper in concentrations comparable to those present in the neural tissues of patients with Wilson's disease has the property of profoundly altering neural function and causing conspicuous morphologic alterations.
13686753##1961-5-26##Excretion of dopamine in diseases of basal ganglia.##The urinary excretion of catecholamines has been measured in 32 patients with disorders of the basal ganglia. Sixteen patients with Parkinsonism (idiopathic, postencephalitic, and arteriosclerotic types) had a significantly lower amount of dopamine in the urine during a 24-hour period than a group of 24 normal control subjects. In a group of 16 patients with various striatal syndromes the excretion of dopamine and epinephrine was significantly higher than normal. Norepinephrine excretion was similar in the three groups. The lowest mean value of urinary dopamine was found in postencephalitic Parkinsonism; the highest occurred in Wilson's disease.
13695800##1961-5-1##[On the biochemical pathology of Wilson's disease. New observations on the action of alpha-liponic acid].##
16810973##1961-5-1##A family study of the biochemical defects in Wilson's disease.##Estimations of serum copper, serum ceruloplasmin (immunochemical), and urinary amino-acids excretion (quantitative and chromatographic) in 44 healthy relatives of patients with Wilson's disease (39 from one family) are reported. Each technique revealed some abnormal individuals. Good agreement was obtained between the serum copper and serum ceruloplasmin estimations and between the quantitative and chromatographic estimations of amino-acid excretion. Some individuals were abnormal to one or other of the pairs of tests only. These results cast doubt on the hypothesis that the symptoms of Wilson's disease are secondary to a quantitative (or qualitative) abnormality of ceruloplasmin. They also suggest that the mode of inheritance of the biochemical defects may be more complicated than that of a simple recessive mutant gene. Two of the relatives (one pregnant and one immediately post-partum) had a high serum copper level, as is expected in pregnancy, but normal serum ceruloplasmin. This suggests that the mechanism of control of the serum ceruloplasmin concentration may, normally, depend on the serum copper concentration.
13735975##1961-5-1##[Metabolism of iron and copper, action of chelators and therapeutic possibilities in Wilson's disease and hemochromatosis].##
13782931##1961-4-1##Pyruvate metabolism in Wilson's disease.##
16695860##1961-4-1##DETECTION OF THE HETEROZYGOUS CARRIER OF THE WILSON'S DISEASE GENE.##
13736303##1961-4-1##Metabolic balance studies in a patient with Wilson's disease and hypercalcuria.##
13686754##1961-4-1##An early defect in Wilson's disease.##
13736377##1961-3-11##[The effect of some estrogens on the serum copper content, especially in Wilson's disease].##
13704653##1961-3-1##Effect of estrogens on copper metabolism in Wilson's disease.##
13684224##1961-3-1##[Diagnosis and genetic aspects of Wilson's disease in childhood].##
13907399##1961-1-1##[Wilson's disease or hepatocerebral degeneration].##
13772042##1961-1-1##[Essential hepatorenal form of Wilson's disease in a brother and a sister and its treatment with penicillamine].##
13899919##1961-1-1##Treatment of Wilson's disease (hepatolenticular degeneration) with DL-penicillamine.##
13747429##1960-12-15##Environmental treatment of a hereditary illness: Wilson's disease.##
13708400##1960-11-1##[Physiopathological study of a case of Wilson's disease. Treatment with penicillamine].##
13741432##1960-11-1##The heterogeneity of caeruloplasmin nd the enzymatic defect in Wilson's disease.##
13777141##1960-10-1##[Wilson's disease (hepatolenticular degeneration)].##
13688052##1960-9-1##[Aminoaciduria in Wilson's disease].##
13695799##1960-9-1##[Experiments on the pathogenesis of Wilson's disease. 4. The action of alpha-lipoic acid on the metabolism of copper and proteins in cases of hepatolenticular degeneration (recent observations)].##
13747430##1960-8-1##The long term management of hepatolenticular degeneration (Wilson's disease).##
14445906##1960-7-23##The course of Wilson's disease (hepatolenticular degeneration) during pregnancy and after delivery.##
20326321##2010-3-24##Penicillamine in Wilson's Disease.##
19970989##2009-12-9##Nephrotoxic Properties of Copper under Experimental Conditions in Mice: With Special Reference to the Pathogenesis of the Renal Alterations in Wilson's Disease.##
13793439##1960-5-1##Changes in hepatic structure in Wilson's disease.##
13850169##1960-5-1##The renal biopsy in Wilson's disease.##
13695801##1960-5-1##[On the pathogenesis and therapy of Wilson's disease. The effect of alpha-lipoic acid (preliminary communication)].##
14442586##1960-5-1##The pathogenesis and clinical significance of the liver disease in hepatolenticular degeneration (Wilson's disease).##
13798965##1960-4-15##[Disorders of transport processes as causes of diseases and of disease symptoms (based on examples of jaundice, hemochromatosis and Wilson's disease and of iron deficiency anemia)].##
13808058##1960-4-1##Studies on copper metabolism. XXIX. A critical analysis of serum copper and ceruloplasmin concentrations in normal subjects, patients with Wilson's disease and relatives of patients with Wilson's disease.##
13792199##1960-4-1##A rapid screening test for deficiency of plasma ceruloplasmin and its value in the diagnosis of Wilson's disease.##
13797909##1960-4-1##A genetical analysis of thirty families with Wilson's disease (hepatolenticular degeneration).##
13796576##1960-4-1##[Recent findings on Wilson's disease].##
13824031##1960-3-10##Wilson's disease in a Swedish family: a follow-up study.##
13809737##1960-3-1##[On a case of Wilson's disease associated with epileptic manifestations].##
14433511##1960-2-13##[The copper content of some organs in Wilson's disease].##
14417516##1960-2-1##Effect of D,L-penicillamine on the urinary excretion of copper and calcium in hepatolenticular degeneration (Wilson's disease).##
13842679##1960-1-23##Treatment of Wilson's disease with penicillamine.##
13822431##1960-1-1##[Wilson's disease and splenomegaly. Recent acquisitions and report of a case].##
13853564##1960-1-1##[On Wilson's disease. Also a contribution on penicillamine therapy].##
14439030##1959-12-26##Caeruloplasmin in Wilson's disease.##
13800662##1959-12-1##The effect of pregnancy on hepatolenticular degeneration (Wilson's disease).##
14439031##1959-12-1##Skeletal changes in Wilson's disease (hepato-lenticular degeneration).##
14417517##1959-11-1##Hypercalciuria in hepatolenticular degeneration (Wilson's disease).##
13842678##1959-11-1##Changing concepts of the pathogenesis of Wilson's disease.##
14442585##1959-11-1##The liver in Wilson's disease.##
19867166##2009-10-30##THE DEPOSITION OF EXOGENOUS COPPER UNDER EXPERIMENTAL CONDITIONS WITH OBSERVATIONS ON ITS NEUROTOXIC AND NEPHROTOXIC PROPERTIES IN RELATION TO WILSON'S DISEASE.##Goldfish kept in water containing ionized copper and a detergent added with the aim of decreasing coagulation of the mucus on the gills, took in and retained this metal in their brains, livers, and kidneys, in concentrations comparable to those that occur naturally in Wilson's disease, as chemical assays disclosed. Histochemical studies made it clear that much copper had accumulated within the large neurons, principally in those of the telencephalon and anterior horn region of the spinal cord and in the tubular epithelial cells of the kidneys, the nuclei of the parenchymal cells of the liver, the sarcoplasm of the skeletal muscle, and in the epithelial covering of the gills. The intraneuronal deposition of copper was regularly associated after a time with conspicuous cytologic changes, notably contraction and hyperchromaticity of the nerve cells with tortuosity and fragmentation of the axis cylinders and lysis and loss of neurons. The accumulation of metal in the renal epithelium was frequently accompanied by necrosis and was regularly associated with hyperplasia and calcification of the epithelial cells of the larger renal tubules in all goldfish kept for prolonged periods in copper-rich water. The deposition of copper in the liver was not accompanied by consistent cytologic changes. The similarity of the cytologic alterations induced in the central nervous systems by copper and those that occur naturally in hepatolenticular degeneration in human beings provides evidence that copper itself plays an important role in the pathologic alterations of the brain in Wilson's disease.
13850168##1959-10-31##[The renal biopsy in Wilson's disease].##
14441876##1959-10-1##Observations on ceruloplasmin in Wilson's disease.##
13852382##1959-9-26##The action of chelating agents in Wilson's disease.##
13657357##1959-6-4##Wilson's disease, portal hypertension and intrahepatic vascular obstruction.##
14444631##1959-6-1##[The effects of penicillamine and versenate in the treatment of Wilson's disease and lead poisoning].##
13656852##1959-3-31##[Clinical and biological study of a case of Wilson's disease in pure hepatic form in an infant; favorable effects of therapy with chelating agents].##
13675376##1959-3-1##[A hallucinatory psychosis in the Westphal-Strümpell-Wilson disease].##
13636806##1959-2-25##Wilson's disease; report of a case with normal serum ceruloplasmin level.##
13631994##1959-2-7##Hepatolenticular degeneration (Wilson's disease); a case diagnosed biochemically before clinical manifestations.##
13631993##1959-2-7##Hepatolenticular degeneration (Wilson's disease) and juvenile cirrhosis in the same family.##
13605315##1959-1-1##Current views on the pathogenesis and treatment of Wilson's disease.##
13705436##1959-1-1##[Renal biopsy and Wilson's disease].##
13829813##1959-1-1##[Hemolytic crises as an early manifestation of Wilson's disease. A contribution to the pathogenesis of hepatocerebral degeneration].##
13667351##1959-1-1##[Clinical and biological study of Wilson's disease with pure hepatic form in an infant; successful results of therapy with chelating agents].##
13623851##1959-1-1##Genetic aspects of Wilson's disease.##
13606076##1958-12-1##Trace metal patterns in disease states. II. Copper storage diseases, with consideration of juvenile cirrhosis, Wilson's disease, and hepatic copper of the newborn.##
13589061##1958-11-1##WILSON'S disease.##
13575563##1958-9-1##Copper metabolism in normal adults and in clinically normal relatives of patients with Wilson's disease.##
13581042##1958-8-15##[Wilson's disease with special reference to biochemical disorders].##
13561110##1958-7-1##Hepatocerebral dysfunction.##The neurological manifestations associated with acquired liver disorders of various types may present difficult diagnostic problems until the condition is far advanced. Bizarre psychological and motor disorders occur when the central nervous system is affected by liver disease. The clinical features may in some ways resemble those of Wilson's disease, but such features as remitting coma, fetor hepaticus and seizures in &quot;cholemia,&quot; and a Kaiser-Fleischer ring in hepatolenticular degeneration help to distinguish the two conditions. The biochemical abnormalities found in all types of hepatocerebral dysfunction may be quite similar one to another. While many studies suggest that the whole problem is simply the result of brain intoxication by a substance such as ammonia, other lines of evidence indict several factors in intermediate cerebral and liver metabolism. The treatment involves use of substances which may relieve certain blocks in biochemical processes, supplementary vitamins, low protein intake and strict avoidance of all neuro- and hepatotoxins.
13550994##1958-6-21##Acute case of Wilson's disease (hepatolenticular degeneration).##
13572697##1958-6-1##The diagnosis and treatment of Wilson's disease.##
13550045##1958-6-1##Chelating agents in the treatment of hepatolenticular degeneration (Wilson's disease).##
13591856##1958-6-1##[Starch gel electrophoresis of human blood &amp; ceruloplasmin identification in normal subjects as well as in homozygote &amp; heterozygote subjects for Wilson's disease gene].##
13537727##1958-4-25##[Wilson's disease as a metabolic problem].##
13521109##1958-4-1##Roentgenographic abnormalities of the skeletal system in Wilson's disease (hepatolenticular degeneration).##
13541603##1958-4-1##Some aspects of the relation of ceruloplasmin to Wilson's disease.##
13540356##1958-3-23##[Pure hepatic form of Wilson's disease in infant; successful therapy with chelating agents].##
13555098##1958-3-1##[Pure hepatic form of Wilson's disease in an infant; effect of therapy with chelators].##
13502081##1958-2-22##Azure lunulae; an unusual change in the fingernails in two patients with hepatolenticular degeneration (Wilson's disease).##
13501866##1958-2-1##Renal complications with diabetes mellitus; Kimmelstiel-Wilson's disease.##
13517688##1958-2-1##NEW HYPOTHESES concerning Wilson's disease.##
13503211##1958-1-11##Effects of penicillamine and dimercaprol on turnover of copper in patients with Wilson's disease.##
13499340##1958-1-1##[Recent findings on hepatocerebral degeneration (Wilson's disease)].##
13500467##1957-11-1##Abnormalities of copper metabolism in Wilson's disease; a preliminary report.##
13526501##1957-10-1##[Amino acid studies in Wilson disease].##
13494696##1957-10-1##A clinical and biochemical study of hepatolenticular degeneration (Wilson's disease).##
13501528##1957-9-1##[A case of Wilson's disease; new pathogenetic &amp; therapeutic concepts].##
13517092##1957-9-1##[High tension electrophoretic studies on urine in a child with Wilson's disease].##
13472982##1957-8-1##Wilson's disease; report of ten cases.##
13463081##1957-8-1##Exchange of ceruloplasmin copper with ionic Cu64 with reference to Wilson's disease.##
13439005##1957-7-1##Effect of estrogen therapy on ceruloplasmin concentration in a man with Wilson's disease.##
13449163##1957-7-1##Renal function in Wilson's disease.##
13429888##1957-5-25##Wilson's disease.##
13417659##1957-5-11##WILSON'S disease.##
13410964##1957-5-1##Wilson's disease; an inborn error of metabolism with multiple manifestations.##
13426540##1957-5-1##Hepatolenticular degeneration (Wilson's disease).##
13437876##1957-5-1##[Biochemistry and pathogenesis of Wilson's disease].##
13466748##1957-3-1##[Biochemical &amp; histological study of Wilson's disease in siblings of a strict anatomoclinical homotype].##
13400241##1957-2-7##Hepatolenticular degeneration (Wilson's disease) as a form of idiopathic cirrhosis.##
13398686##1957-2-1##Copper transport and excretion in normal subjects and in patients with Laennec's cirrhosis and Wilson's disease: a study with CU64.##
13393844##1957-1-1##An unusual case of Wilson's disease.##
13381211##1957-1-1##Brain copperprotein fractions in the normal and in Wilson's disease.##
13452294##1957-1-1##[Wilson's disease &amp; the pregnancy-puerperium cycle].##
13362281##1956-10-1##Penicillamine, a new oral therapy for Wilson's disease.##
13389010##1956-10-1##Wilson's disease; hepatolenticular degeneration.##
13392950##1956-9-22##[Metabolic disorders in hepatolenticular affections, Wilson's disease and pseudosclerosis].##
13377617##1956-9-15##[Tests of ceruloplasmin substitution in hepatocerebral degeneration (Wilson's disease)].##
13429351##1956-9-1##Psychological impairment in Wilson's disease.##
13358643##1956-7-1##[Diagnosis and differential diagnosis of Wilson's disease (with the aid of a family examination)].##
13313537##1956-5-1##The mechanism of copper deposition in the liver in hepatolenticular degeneration (Wilson's disease).##
13295696##1956-3-1##Some aspects of kidney function in hepatolenticular degeneration (Wilson's disease).##
13279157##1956-1-7##Wilson's disease; new oral therapy.##
13375611##1956-1-1##[Wilson's disease].##
13359521##1956-1-1##Relation of ceruloplasmin and plasma copper to hepatolenticular degeneration (Wilson's disease).##
13389829##1956-1-1##[A case of Wilson's disease of Kehrer's abdominal variety].##
13337942##1956-1-1##[A case of hepatolenticular degeneration (Wilson's disease)].##
13283835##1955-9-1##[Review of hepatolenticular degeneration (Wilson's disease) and presentation of two cases].##
13269211##1955-8-1##Treatment of Kimmelstiel-Wilson disease and related conditions.##
13244952##1955-8-1##FURTHER studies on copper in Wilson's disease.##
14360851##1955-5-1##Contribution to study of Wilson's disease.##
14368026##1955-4-1##Metabolic studies in Wilson's disease using Cu64.##
14363037##1955-2-1##Aspects of copper metabolism in Wilson's disease.##
13217518##1955-1-1##Wilson's disease, chronic form; clinical-pathological observations in a brother and sister.##
13298377##1955-1-1##[Wilson's disease; neurological signs three years after onset of hypersplenomegalic cirrhosis].##
13206477##1954-11-1##Pathogenesis of hepatocerebral disease. II. Histochemical study of copper of liver and brain in Wilson's disease.##
13212412##1954-11-1##The absorption and excretion of radiocopper in hepato-lenticular degeneration (Wilson's disease).##
13203840##1954-10-1##COPPER metabolism and amino acid excretion in Wilson's disease.##
13221960##1954-9-1##Observations on insulin requirement in Kimmelstiel-Wilson disease.##
14356319##1954-9-1##[Therapy of Wilson's disease].##
13180528##1954-8-1##Metabolism of copper in Wilson's disease and in normal subjects; studies with Cu-64.##
13191516##1954-7-1##[Wilson's disease: hepatolenticular degeneration; new therapeutic and pathogenic conception].##
13176818##1954-7-1##COPPER and amino acids in Wilson's disease.##
13194680##1954-7-1##Uric acid in two patients with Wilson's disease (hepatolenticular degeneration).##
13178810##1954-6-12##Diabetic retinopathy and Kimmelstiel-Wilson disease; fundus examination of 110 diabetics.##
13143089##1954-3-1##The amino acid content of the blood and urine in Wilson's disease.##
13143088##1954-3-1##Abnormalities of copper metabolism in Wilson's disease and their relationship to the aminoaciduria.##
13131080##1954-2-1##Dimercaprol in the pre-neurological stage of Wilson's disease (hepatolenticular degeneration).##
14362945##1954-1-1##[Metabolic disorders in Wilson's disease].##
13118383##1954-1-1##The histopathology of Wilson's disease; a study with silver carbonate.##
13204007##1954-1-1##[Aminoacid metabolism and Wilson disease].##
13134284##1954-1-1##Localization of Cu64 in serum fractions following oral administration: an alteration in Wilson's disease.##
13168597##1954-1-1##[Various modern biological investigations on Wilson's disease; study of two cases].##
13216832##1954-1-1##Copper metabolism in Wilson's disease.##
13104417##1953-12-1##On the relationship of urinary copper excretion to the aminoaciduria in Wilson's disease (hepatolenticular degeneration).##
13168151##1953-11-1##[Treatment of Wilson's disease with 2,3-dimercaptopropanol].##
13092113##1953-10-1##Genetic and biochemical aspects of Wilson's disease.##
13050229##1953-6-1##Wilson's disease (hepatolenticular disease); a family study.##
13131739##1953-1-1##[Retinopathia diabetica proliferans in diabetic glomerulosclerosis (Kimmelstiel-Wilson disease)].##
13135170##1953-1-1##[Considerations on Wilson's disease; genealogic, clinical, and metabolic investigations on 60 members of one family].##
13101417##1953-1-1##[Kernicterus, Wilson's disease and Rh factor; anatomopathological findings and pathogenetic observations].##
13029295##1952-11-1##Hepatolenticular degeneration; Wilson's disease; a report of five cases, with commentary.##
12994898##1952-10-31##Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease).##
14914748##1952-4-1##The familial nature of the amino-aciduria of Wilson's disease (hepatolenticular degeneration).##
12995078##1952-3-1##[Study on prothrombin in neurological diseases; vitamin K test of prothrombin curve in a case of Wilson's disease].##
14920926##1952-1-31##[Acute form of hepatolenticular degeneration (Wilson's disease); clinical and pathologico-anatomical study].##
12978560##1952-1-1##A case of acute hepatolenticular degeneration (Wilson's disease); clinical and pathological study.##
14898306##1952-1-1##Two types of Wilson's disease; hepato-lenticular degeneration; case reports.##
13004628##1952-1-1##[Abnormal movements in Wilson's disease in a child].##
14950047##1952-1-1##[Hepatocerebral degeneration: Westphal-Strümpeli pseudosclerosis; Wilson's disease; hepatolenticular degeneration; abdominal Wilson's disease].##
14882450##1951-12-13##The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson's disease).##
14892632##1951-10-1##[Three cases of familial Wilson's disease; importance of flocculation test, ocular signs in portal forms].##
14830233##1951-4-1##Copper excretion in the urine of normal individuals and of patients with hepatolenticular degeneration (Wilson's disease).##
14827152##1951-2-1##A case of Wilson's disease with Kayser Fleischer ring.##
14930558##1951-1-1##[Thomalla-Wimmer's type of Wilson disease].##
14913592##1951-1-1##The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson's disease).##
14773648##1950-8-1##[Wilson's disease].##
15439905##1950-8-1##AMINO acid excretion in liver disease and Wilson's disease.##
15438535##1950-5-26##[Diabetes mellitus and vascular disease; Kimmelstiel-Wilson disease].##
16695797##1950-3-1##INVESTIGATION OF THE AMINOACIDURIA IN WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION): DEMONSTRATION OF A DEFECT IN RENAL FUNCTION.##
15413439##1950-2-24##Intercapillary glomerulosclerosis (Kimmelstiel-Wilson's disease).##
14789471##1950-1-1##Paper chromatographic analysis of amino acid excretion in Wilson's disease.##
15411892##1950-1-1##[Heredity in hepatolenticular degeneration and the problem of the intrinsic relations between Westphal-Strumpell's pseudosclerosis and Wilson's disease; the nosologic location of Kehrer's &quot;abdominal-Wilson&quot; within hepatolenticular degeneration].##
14805355##1950-1-1##[Wilson's disease].##
18122158##1948-10-1##Trichostrongylus infestation and extrapyramidal lesion; exogenous Wilson's disease?##
18875448##1948-6-1##Amino-aciduria in hepato-lenticular degeneration (Wilson's disease).##
20344688##2010-3-27##Wilson's disease.##
20323258##2010-3-24##Wilson's Disease.##
20322385##2010-3-24##Parathyroid Insufficiency in Wilson's Disease.##
19991123##2009-12-9##Wilson's Disease with Kayser-Fleischer Ring.##
20320260##2010-3-24##A Hepato-cerebral Syndrome: Wilson's Disease.##
19989647##2009-12-9##Kayser-Fleischer Ring in Cornea in two Cases of Wilson's Disease (Progressive Lenticular Degeneration).##
21611342##2011-5-26##THE BIOLOGICAL SIGNIFICANCE OF EXTRAPYRAMIDAL SYNDROMES, APROPOS A CASE OF WILSON'S DISEASE IN THE ADULT: Second contribution to the biology of extrapyramidal affections.##