Wilson disease

Matthew Lorincz MD PhD (Dr. Lorincz of the University of Michigan has no relevant financial relationships to disclose.)
AHM M Huq MD PhD, editor. (Dr. Huq of Wayne State University has no relevant financial relationships to disclose.)
Originally released July 11, 1994; last updated July 10, 2017; expires July 10, 2020

This article includes discussion of Wilson disease, copper toxicosis, hepatolenticular degeneration, progressive lenticular degeneration, and pseudosclerosis of Westphall-Strumpell. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The history of Wilson disease is a microcosm of the history of neurology, beginning with seminal clinical observations by the man whose name the disease bears, followed by pioneering work translating copper deficiencies in sheep to human treatment, and continuing on to identification of causative gene mutations. Amongst neurodegenerative disease, it is unusual in that treatments can prevent and cure Wilson disease if they are given appropriately. Despite a long history, Wilson disease remains an important disease that is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson disease progresses to hepatic failure or severe neurologic disability and death. Those adequately treated have a normal life span. In this article, the author discusses the neurologic features of Wilson disease, its diagnosis, and new treatment options.

Key points

 

• Wilson disease is caused by mutations in ATP7B that result in abnormal copper metabolism, and subsequent excess free copper is toxic.

 

• The most common clinical manifestations of neurologic Wilson disease include variable combinations of dysarthria, dystonia, tremor, and parkinsonism.

 

• Recognition of the disorder is important because effective treatment can prevent or improve disease features.

 

• The most useful screening procedure is a 24-hour urine copper test. In symptomatic Wilson disease the 24-hour urine copper is always elevated to a value greater than 100 µg per 24 hours (normal is 50 µg or less).

 

• The aim of treatment is to reduce the amount of toxic free copper. Currently available agents in the United States include zinc acetate and trientine. Clinical trials suggest tetrathiomolybdate may be the preferred agent for initial treatment for neurologic Wilson disease, but it is not currently FDA approved.

Historical note and terminology

The historical landmark paper in this disease was written in 1912 by Samuel Alexander Kinnier-Wilson, an American neurologist working at The National Hospital at Queen Square in London (Wilson 1912; Compston 2009). He described a neurologic disorder associated with progressive lenticular degeneration and cirrhosis of the liver that came later to be known as Wilson disease, or hepatolenticular degeneration. The disease described by Wilson was one dominated by juvenile age at onset with dystonia and contrasted from the form of disease described by Westpahl in 1883 as pseudosclerotic, which had a young adult age of onset and symptomatically consisted principally of tremor and dysarthria. Only later was parkinsonism recognized as a major clinical feature of Wilson disease. Kayser and Fleischer described the corneal copper deposits associated with the disease, which later became known as Kayser-Fleischer rings. Several authors have described excess copper deposition, but Cumings was the first to postulate an etiologic role for copper and suggested that chelation therapy might be of benefit. A low biliary excretion of copper was later shown to be responsible for a failure to regulate copper balance, and the disease was found to be inherited as an autosomal-recessive disorder. Landmarks in treatment have included the development of penicillamine, trientine, and zinc therapies (Walshe 2009). The gene for Wilson disease has been identified and an animal model of Wilson disease has provided insights into pathogenesis (Bull et al 1993; Tanzi et al 1993; Yamaguchi et al 1993).

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