INITIAL THERAPY OF WILSON'S DISEASE

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Background: Wilson's disease is an autosomal recessive disorder that affects 1 in 30,000 individuals regardless of ethnicity. Penicillamine was the first oral agent developed for treatment of these patients, however treatment with Penicillamine for neurologic manifestations of Wilson's disease causes neurologic worsening in 10-50% during the initial phase of treatment. While many recover with continued treatment, some patients are left with permanent severe disabilities. Two other oral chelating agents have been utilized for treatment of Wilson's disease, tetrathiomolybdate (TM), an experimental drug under evaluation, and Trientine, an alternative agent approved for use in Penicillamine intolerant patients. Zinc is another oral agent that acts by blocking copper absorption, however its onset of action is slow and therefore is less likely to be efficacious in the initial phase of treatment. Study Objective: The objective of the study is to determine the best initial mode of therapy for patients with neurologic manifestations of Wilson's disease by comparing tetrathiomolybdate (TM), an experimental copper-chelator with Trientine. The design of the study is to give patients either TM or trientine along with zinc, an agent that itself blocks copper absorption but does not directly remove copper stores. The effectiveness of these regimens will be determined biochemically by monitoring for reductions in non-ceruloplasmin bound copper and in urine copper excretion, and for normalization of abnormal liver functions if present at the outset. Patients will also be monitored clinically by neurologic and speech examinations performed on a weekly basis for the eight weeks of treatment. Hematologic and biochemical screening will be performed weekly; to exclude drug toxicity. Patients will be withdrawn from the protocol if they manifest neurologic worsening over a two week period of examination or if serious hematologic or biochemical abnormalities occur. Following this treatment, patients will be maintained on zinc therapy and monitored biannually or more frequently as necessary. Patients to be enrolled in this study will either have been suspected of having Wilson's disease as the etiology of their neurologic disease, and the evaluation for this disorder completed as part of the study, or have been diagnosed as having Wilson's disease with appropriate testing and treated for less than two weeks with Penicillamine.