We searched the MEDLINE database from January, 1966, to June, 2006, for specific topics in relation to the search terms “Wilson disease” or “Wilson's disease” in combination with the terms “genetic”, “liver disease”, “neurology”, and “psychiatric”. We largely selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy, and selected those we
SeminarWilson's disease
Section snippets
Hepatic pathology
In the early stages of the disease, diffuse cytoplasmic copper accumulation can be seen only by special immunohistochemical stains for detecting copper, which are not routinely available. This early accumulation of copper is associated with macrosteatosis, microsteatosis, and glycogenated nuclei which are features that can be seen in various other disorders—eg, nonalcoholic steatohepatitis.2 The ultrastructural abnormalities range from enlargement and separation of the mitochondrial inner and
Molecular pathogenesis
The gene responsible for Wilson's disease (on chromosome 13) was identified almost simultaneously by three separate laboratories.8, 9, 10, 11 The gene (ATP7B) is highly expressed in the liver, kidney, and placenta. ATP7B encodes a transmembrane protein ATPase (ATP7B), which functions as a copper-dependent P-type ATPase. The ATP7B transporter has dual synthetic and excretory roles, functioning in the transport of copper into the trans-Golgi compartment, for incorporation into the plasma protein
Clinical applications of Wilson's disease genetics
The Human Genome Organisation (HUGO) database for Wilson's disease lists roughly 300 different mutations described in the disease, which are distributed across the ATP7B gene. As a result, the distribution of ATP7B genotypes is complex and most patients are compound heterozygotes, having two different mutations of the ATP7B gene. In general, a few mutations predominate, depending on the population tested. Therefore, in molecular diagnosis, selected exons are chosen for initial screening
Clinical manifestations and range of disease
The clinical range of Wilson's disease is wide, and knowledge of the various disease presentations is important (panel 1). In broad terms, patients can present acutely with liver failure, haemolysis, or both, or more chronically with liver disease, neurological disease, or both.
Patients who first present with neurological or psychiatric signs tend to be older than those with hepatic features alone. Most patients with CNS involvement are believed to have liver disease at the time of presentation
Establishing a diagnosis
There is no one test for the diagnosis of Wilson's disease (panel 2). The diagnostic challenge is that the symptoms are often non-specific and the disease affects many different organ systems, which results in confusion with other disorders. The diagnosis is easy to establish in individuals with neurological symptoms, K-F rings, and a low caeruloplasmin concentration. The absence of K-F rings does not necessarily exclude the possibility of this disease but in patients with predominantly
Family screening
First-degree relatives must be screened for Wilson's disease. The probability of finding a homozygote in siblings is 25% and in the children is roughly 0·5%. Liver function tests, serum copper and caeruloplasmin concentration, and urinary copper analysis are done for relatives. If necessary, investigations should be extended to test for K-F rings. 24-h urinary copper might be difficult to interpret in Wilson's disease heterozygotes.
The diagnosis could remain contentious when individuals without
Treatment
The drug treatment of Wilson's disease is based on the use of copper chelators to promote copper excretion from the body, or zinc to reduce copper absorption, or both. Liver transplantation is successful for patients with liver failure that is unresponsive to medical treatment.
Wilson's disease was progressive and fatal until 1951, when the first chelating agent dimercaprol given intramuscularly was used. In 1956, John Walshe90 reported the clinical benefit of the orally active chelator
The future
Why is there a need for a cure for a disease that has available medical therapy? Patients faced with a lifelong need for medication and physicians faced with the results of non-adherence to therapy are the two main arguments.
Genetic therapy and hepatocyte transplantation represent future curative treatments for Wilson's disease, along with currently available liver transplantation.115 However, both cell and liver transplants need immunosuppression to maintain grafted cells. Future use of
Search strategy and selection criteria
References (118)
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The cytopathology of metal overload
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Gastroenterology
(1968)- et al.
Prognosis of Wilsonian chronic active hepatitis
Gastroenterology
(1991) - et al.
Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease
Biochem Biophys Res Commun
(1993) - et al.
Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion
Gastroenterology
(2000) - et al.
Localization of the Wilson's disease protein in human liver
Gastroenterology
(1999) - et al.
Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines
Gastroenterology
(2003) - et al.
The role of the invariant His-1069 in folding and function of the Wilson's disease protein, the human copper-transporting ATPase ATP7B
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(2003) - et al.
Copper-dependent protein-protein interactions studied by yeast two-hybrid analysis
Biochem Biophys Res Commun
(2004) - et al.
The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein
J Biol Chem
(2003)
Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs
Crit Rev Oncol Hematol
Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease
Mol Genet Metab
The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis
J Hepatol
Molecular diagnosis of Wilson disease
Mol Genet Metab
Non-radioactive detection of five common microsatellite markers for ATP7B gene in Wilson disease patients
Mol Cell Probes
Severe hepatic Wilson's disease in preschool-aged children
J Pediatr
Role of genetic testing in liver transplantation for Wilson's disease
Transplant Proc
Kayser-Fleischer-like rings in patients without Wilson's disease
Gastroenterology
Ocular findings in pediatric systemic disease
Pediatr Clin North Am
Wobbly handwriting
Lancet
Clinical, CT and evoked potential manifestations in Wilson's disease with cerebral white matter involvement
Clin Neurol Neurosurg
EEG spectral analysis and topographic mapping in Wilson's disease
J Neurol Sci
Wilson's disease: a longitudinal study of psychiatric symptoms
Biol Psychiatry
The interaction of motor, memory, and emotional dysfunction in Wilson's disease
Biol Psychiatry
Cardiac Wilson's disease
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Successful pregnancies and abortions in symptomatic and asymptomatic Wilson's disease
J Neurol Sci
Endocrine studies of the ovulatory disturbances in Wilson's disease (hepatolenticular degeneration)
Fertil Steril
A practice guideline on Wilson disease
Hepatology
Wilson's disease in patients with liver disease: a diagnostic challenge
Gastroenterology
Menkes disease and Wilson disease: two sides of the same copper coin. Part I:Menkes disease
Eur J Paediatr Neurol
Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease
Clin Gastroenterol Hepatol
Studies on levels of penicillamine-induced cupriuresis in heterozygotes of Wilson's disease
Metabolism
Wilson's disease. New oral therapy
Lancet
The management of penicillamine nephropathy in Wilson's disease. A new chelating agent
Lancet
Treatment of Wilson's disease with zinc: XV. Long-term follow-up studies
J Lab Clin Med
Penicillamine and pyridoxine requirements in man
Lancet
Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver
Brain
Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis
Hepatology
Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis
Nat Med
Changes in the distribution of hepatic copper in relation to the progression of Wilson's disease (hepatolenticular degeneration)
Am J Pathol
Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus
Proc Natl Acad Sci USA
The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene
Nat Genet
The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene
Nat Genet
Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development
Proc Natl Acad Sci USA
The copper transporter CTR1 provides an essential function in mammalian embryonic development
Proc Natl Acad Sci USA
COMMD1 (MURR1) as a candidate in patients with copper storage disease of undefined etiology
Clin Genet
Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease
Arch Neurol
Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease
Clin Genet
Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: genotype
Clin Genet
A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations
Eur J Neurol
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