Wilson disease.

Wilson disease is an inherited disorder of copper metabolism. Progress has been made in establishing the location of the gene on the long arm of chromosome 13, and in finding nearby probes that can be used to identify affected sibs of newly diagnosed patients. However, the gene has not been cloned, and the molecular nature of the defect remains unknown. The cause of the disease is a failure to excrete unneeded and excessive copper in the bile for loss in the stool. This may be due to a failure to excrete copper packaged in ceruloplasmin into the bile. Clinically, patients usually present during the second to fourth decades of life with liver, neurologic, or psychiatric disease, but the diagnosis is often missed or delayed. Once a diagnosis of Wilson disease is considered, reliable studies of copper variables can be carried out. After diagnosis, patients must receive anticopper treatment for the rest of their lives, to reduce copper levels and prevent copper reaccumulation. For life-long maintenance therapy, we recommend zinc acetate because of its complete efficacy and lack of toxicity; it acts by blocking copper absorption. For initial therapy of the acutely ill patient, no currently available therapy has proven to be ideal. A chelator-type drug, either penicillamine or trien, can be used for the initial therapy of patients who present with liver disease; transition to zinc acetate can then be made after a few months. For the initial therapy of acutely ill patients who present with neurologic disease, chelation should be avoided because neurologic worsening frequently occurs, probably due to redistribution of copper which temporarily raises the levels of copper in the brain. For initial treatment, zinc therapy is also not ideal because it is relatively slow-acting. A new experimental drug, tetrathiomolybdate, shows promise in the initial treatment of patients with Wilson disease. The major challenges ahead include closing the remaining therapeutic hiatuses, cloning and expressing the gene to understand its function, and improving clinical diagnosis so that therapy can be instituted as quickly as possible.