Pathogenesis and Pathophysiology. Wilson's disease (WD), or hepatolenticular degeneration, is an autosomal recessive disorder of copper metabolism. The specific genetic biochemical defect appears to be an abnormality of a copper-binding, membrane-associated adenosine-triphosphatase-associated protein, and the allele for this protein has been localized to the long arm of chromosome 13. y It is postulated that most of the symptoms result from excess deposition of copper in tissues, particularly in the brain and liver.
Epidemiology and Risk Factors. This rare neurodegenerative movement disorder occurs in approximately 1 in 40,000 people. Although the disorder may not become clinically evident until the fourth or fifth decade of life, the initial presentation most often appears in the early twenties. '751
Clinical Features and Associated Disorders. Clinical features are age-dependent. Children with WD exhibit a typical facies (so-called sardonic smile), behavioral abnormalities, and various motor disorders. '77' These include tremor (particularly in a wing-beating position), dystonia, rigidity, postural instability, dysarthria, and ataxia. Some patients also exhibit mental and behavioral changes and seizures. Almost all patients show evidence of hepatic dysfunction. Ihe adult patient usually presents with parkinsonian features, dystonia, athetosis, and slow (myorhythmic) or coarse postural (so-called wing-beating) tremor. In adults, the neurological symptoms predominate over the hepatic dysfunction, and the disorder appears to be less rapidly progressive. Approximately a third of patients present with psychiatric symptoms. Ihese range from irritability and loss of impulse control to mania and depression, sometimes with catatonic symptoms.
Ihe clinical hallmark of the disorder is the presence of a brownish-golden ring at the corneal rim (Kayser-Fleischer ring), which is due to the deposition of copper in the cornea. This sign is seen in almost all patients with neurological or psychiatric manifestations of WD, although slit-lamp examination is sometimes necessary to detect the copper deposition.^' Other ocular abnormalities seen in
Wilson's disease include "sunflower" subcapsular cataracts, retinitis pigmentosa, optic nerve atrophy, and loss of smooth pursuit.
Differential Diagnosis. Ihe differential diagnosis of WD depends on the phenotypical presentation. In children, evaluation usually centers around hepatic disorders, whereas in adults, diagnostic considerations center around the type of movement disorder seen (tremor, chorea, dystonia, or parkinsonism). Although Kayser-Fleischer rings are extremely helpful in confirming this diagnosis clinically, they are also seen in patients with silver intoxication, primary biliary cirrhosis, Addison's disease, carotinemia, and chalcosis as a result of unilateral trauma to the eye with copper-containing foreign bodies. y
Evaluation. All patients should be evaluated by an ophthalmologist for the presence of the Kaiser-Fleischer ring. Decreased serum ceruloplasmin (less than 20 mg/dl) in 90 percent of patients, increased urinary copper excretion (more than 100 pg/ml), impaired hepatic and renal function, hemolytic anemia, and aminoaciduria may also be present. In most cases a 24-hour urinary copper screen will detect elevated urinary copper levels (more than 100 pg/ 24 hours). If these tests are not diagnostic, liver biopsy should be performed with copper measurements (copper greater than 200 pg/g dry weight). '74' I2-weighted MRI scans may show the "face of the panda" sign in the midbrain due to hypodensity of the superior colliculi and hyperdensity in the medial substantia nigra and tegmentum. Fluorodopa PET scans are abnormal in symptomatic patients, demonstrating evidence of nigrostriatal damage.
Management. Because good recovery of hepatic and neurological function is possible in most patients, treatment must be instituted quickly. Ihe goal of therapy is to reduce copper intake by means of a low-copper diet and increase copper excretion. D-Penicillamine is the chelating agent most often used; its side effects are potentially serious but preventable. Ihese include nephrotic syndrome, fever, thrombocytopenia, dermatitis, vitamin B 6 deficiency, seizures, and zinc deficiency, which causes impairment of taste and smell. Pyridoxine should be administered along with penicillamine. Some investigators suggest using tetrathiomolybdate, a drug that both blocks copper absorption and binds to bloodborne copper, as an initial therapy. In addition, zinc acetate may be used as a maintenance therapy because of its low potential for serious side effects other than gastrointestinal effects. Dietary education about foods containing high levels of copper should be undertaken, and specific restrictions should be placed on liver and shellfish. '77' In patients who have sustained severe liver damage at the time of treatment, liver transplantation may be considered but remains controversial.
Since the disorder is inherited as an autosomal recessive trait, it is important to screen other members of the family with a neurological examination, serum ceruloplasmin level, and slit-lamp examination of the cornea. Ihe clinical manifestations of the disorder and progression of disease may be prevented by early institution of copper chelation therapy.
Prognosis and Future Perspectives. If WD is recognized early in the course of the illness and is treated aggressively with initial and maintenance chelation therapy, it is potentially a curable disorder. Without treatment, patients progress to disability and death. Ihe gene for Wd has been identified on chromosome 13, but several mutations within the gene have been found, and therefore, DNA testing is not yet practical. y
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