Wilson's Diseases Research Articles

Silver in sugar particles and systemic argyria

A 79-year-old man developed a grey-brown discolouration of his skin over 3 years; the pigmentation was most striking in the sun-exposed areas of his face, neck, and the backs of his hands. Lunulae of his nail beds were blue (figure). Tests for Wilson's diseases, haemochromatosis, bismuth toxicity, and renal insufficiency were negative. He was not taking any medicines that could lead to photosensitivity, nor did he use cosmetics.

Book reviews

Book reviewed in this article:Tetrahydrobiopterin: Basic Biochemistry and Role in Human Disease By Seymour Kaufman Baltimore, MDRehabilitation Studies Handbook Edited by Barbara A Wilson and DL McLellanNeuromuscular Diseases During Development Edited by F Cornelio, G Lanzi, E Fedrizzi London: John LibbeyVisibly Different: Coping with Disfigurement Edited by Richard Lansdown, Nichola Rumsey, Eileen Bradbury, Tony Carr, James PartridgeCognitive Developmental Therapy with Children By Tammie Ronen. Chichester: John Wiley

Copper transport and metabolism: An update

Molecular understandings of copper transport and metabolism have advanced significantly in the past 10 years. In this review we examine two areas where the new information has been particularly rapid and the insights more profound: membrane copper transport and the ferroxidase function of ceruloplasmin. The first is highlighted by discoveries of the genes for Menkes and Wilson's diseases and the realization that both disease genes encode membrane-bound P-type ATPases. The second is a strong confirmation through genetic and clinical evidence that ceruloplasmin has an obligatory function in iron metabolism. J. Trace Elem. Exp. Med. 11:163–176, 1998. © 1998 Wiley-Liss, Inc.

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.

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).

P433 Evaluation of the pyramidal tract function in Wilson's diseases with magnetic brain stimulation

P433 Evaluation of the pyramidal tract function in Wilson's diseases with magnetic brain stimulation

An international symposium on Wilson's and Menkes' diseases.

An international symposium on Wilson's and Menkes' diseases.

An international symposium on Wilson's and Menkes' diseases

An international symposium on Wilson's and Menkes' diseases

Positron-emission tomography in tardive dyskinesia.

Cerebral glucose metabolic rates were determined in normal control subjects (n = 26) and schizophrenic patients with tardive dyskinesia (n = 14). Globus pallidus and primary motor cortex (precentral gyrus) metabolic values divided by those of the cerebral hemispheres were significantly increased in the patient group. A similar metabolic pattern has not been reported for schizophrenic patients without tardive dyskinesia, and the abnormalities were demonstrated despite the normal appearance of the basal ganglia on X-ray CT. The findings differed markedly from the reduced metabolic rates of the basal ganglia previously identified in other choreiform disorders, including Huntington's and Wilson's diseases. The findings suggest that tardive dyskinesia is characterized by increased pallidal synaptic activity resulting from either altered striatopallidal input or increased pallidal interneuron firing.

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.

Motor dysfunction in HIV-infected patients without clinically detectable central-nervous deficit

Motor tests were performed in 50 HIV-infected patients in all stages according to the current CDC classification, but without any clinically evident central nervous system deficit, and the results compared with an age-matched control group. Patients were excluded from the study if there was alcohol or drug abuse, fever and/or opportunistic cerebral infection. The parameters tested were postural tremor of the outstretched hands, most rapid voluntary alternating index finger movements (MRAM) and rise time of most rapid index finger extensions (MRC). Whereas tremor peak frequencies did not differ significantly in the patients and controls, MRAM and rise times of MRCs showed significant slowing in the patient group. Morphologically, the motor test performance of the HIV-infected patients was similar to that of patients with manifest basal ganglia disease (Parkinson's, Huntington's and Wilson's diseases). MRI scans of all patients were normal. It is concluded that in HIV-infected patients there is a very early subclinical central nervous system affection, especially of the basal ganglia, which is detectable with appropriate, quantitative motor function tests. These functional abnormalities precede the structural alterations in the MRI scans.

Metallothionein--aspects related to copper and zinc metabolism.

Metallothionein is a cysteine-rich, low molecular weight protein that binds zinc, copper and cadmium. It is inducible in liver, kidney and intestine by glucocorticoids, changes in the dietary zinc supply, acute administration of various metals, food restriction, infection, stress and endotoxin treatment. Regulation of synthesis involves altered gene expression. The protein is fairly rapidly degraded when zinc is the primary metal species bound, but the degradation rate is diminished when cadmium or copper are bound as well. The net result of metallothionein production seems to be accumulation of bound metal and/or intracellular metal redistribution. The accumulation of copper in various tissues of individuals with Menkes' and Wilson's diseases may be related to altered metallothionein turnover. The physiological function is not clear, but the response of metallothionein to hormonal stimuli is suggestive of an important role in cellular metabolism.

A family with vitelliform macular dystrophy. Best's disease.

In a family of 84 members macular lesions were observed in 16 out of 75 examined individuals. The typical egg yolk lesion was seen in three cases while the remaining bore evidence of the polymorphous nature of the disease. Electro‐oculography (EOG) was performed on 11 affected individuals. EOG showed pathological changes in 10 of these. In one case the changes were localized to an eye which ophthalmoscopy had shown to be normal. EOG was performed on a further nine members of the family in whom ophthalmoscopy was normal. The values were subnormal in four of these. The significance of EOG in cases of macular degeneration is accentuated. Fluorescein angiography in colour was performed on two individuals. Hepatolenticular degeneration (Wilson's disease) had previously been diagnosed in members of one branch of this family. A possible connection between Best's and Wilson's diseases is advocated in the discussion.

Ocular manifestations of congenital metabolic diseases

SummaryThe analysis of the ocular manifestations encountered in some inherited disorders of metabolism demonstrated their frequency and diagnostic values in this type of diseases. The inborn errors of metabolism analyzed are : cystinosis. Wilson, Hurler and Fabry diseases, galactosemia, haemocystnuria. alcaptonuria, albinism, familial amaurotic idiocy, Niemann-Pick disease, metachromatic leuco-dystrophy and Farber disease.

Contribution à l'étude des aminoaciduries pathologiques

The author has studied the urinary elimination of the amino acids, and compared the results with those obtained in some diseases (leukemia, diabetes, Hodgkin's, Wilson's and Fanconi's diseases, reticulosarcoma, multiple myeloma, etc.). It appeared that in some of those diseases the elimination has considerably changed.