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INTRODUCTION

Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, which encodes a membrane-bound, copper-transporting ATPase. Clinical manifestations are caused by copper toxicity and primarily involve the liver and the brain. Because effective treatment is available, it is important to make this diagnosis early.

The frequency of Wilson’s disease in most populations is about 1 in 30,000–40,000, and the frequency of carriers of ATP7B mutations is ~1%. Siblings of a diagnosed patient have a 1 in 4 risk of Wilson’s disease, whereas children of an affected patient have about a 1 in 200 risk. Although a large number of inactivating mutations have been reported in the ATP7B gene, mutation screening for diagnosis is now available, and a definitive diagnosis can be obtained in 50–75% of patients, depending on the population. DNA haplotype analysis can be used to genotype siblings of an affected patient. A rare multisystem disorder of copper metabolism with features of both Menke’s and Wilson’s diseases has been reported. It is termed the MEDNIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia) syndrome and is caused by mutations in the AP1S1 gene, which encodes an adaptor protein necessary for intracellular trafficking of copper pump proteins ATP7A (Menke’s disease) and ATP7B (Wilson’s disease).

PATHOGENESIS

ATP7B protein deficiency impairs biliary copper excretion, resulting in positive copper balance, hepatic copper accumulation, and copper toxicity from oxidant damage. Excess hepatic copper is initially bound to metallothionein; liver damage begins as this storage capacity is exceeded, sometimes by 3 years of age. Defective copper incorporation into apoceruloplasmin leads to excess catabolism and low blood levels of ceruloplasmin. Serum copper levels are usually lower than normal because of low blood levels of ceruloplasmin, which normally binds >90% of serum copper. As the disease progresses, nonceruloplasmin serum copper (“free” copper) levels increase, resulting in copper buildup in other parts of the body (e.g., in the brain, with consequent neurologic and psychiatric disease).

CLINICAL PRESENTATION

Hepatic Features

Wilson’s disease may present as hepatitis, cirrhosis, or hepatic decompensation. Patients typically present in the mid- to late teenage years in Western countries, although the age of presentation is quite broad and extends into the fifth decade of life. An episode of hepatitis may occur—with elevated serum aminotransferase levels, with or without jaundice—and then spontaneously regress. Hepatitis often recurs, and most of these patients eventually develop cirrhosis. Hepatic decompensation is associated with elevated serum bilirubin, reduced serum albumin and coagulation factors, ascites, peripheral edema, and hepatic encephalopathy. In severe hepatic failure, hemolytic anemia may develop because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson’s disease a likely diagnosis.

Neurologic Features

The neurologic manifestations of Wilson’s disease typically occur in patients in their early twenties, although the ...

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