Wilson disease, also referred to as hepatolenticular degeneration, is caused by excessive deposition of copper within the liver, the central nervous system predominately in the basal ganglia and putamen, kidney, placenta and cornea. Patients can present with a wide range of clinical symptoms including movement disorders, speech impediments, psychiatric disorders, renal dysfunction and hemolytic anemia. In the liver, excess copper can cause chronic hepatitis with subsequent cirrhosis and eventual liver failure. Accelerated hepatic injury associated with acute Wilsonian crisis can lead to rapid liver failure and commonly requires liver transplantation. Like hemochromatosis, excessive accumulation of a divalent metal, copper, results in chemical generation of reactive oxygen intermediates causing cellular injury and organ damage.

As with hemochromatosis, Wilson disease is an autosomal recessive disease with an incidence of 1 in 30,000 births affecting all patient populations. In 1993, the gene responsible for Wilson disease, WND, was rapidly identified on chromosome 13 after the gene responsible for Menkes disease, a pediatric disease of copper deficiency was cloned. WND, also referred to as ATP 7B, encodes for an ATP dependent copper transporter whose intracellular location and postulated functions are still being investigated. Unlike iron, copper balance is maintained by biliary excretion of excess copper into bile, from where it is eliminated in stool. The WND protein has been localized to the trans-Golgi apparatus, where it is thought to mediate the incorporation of copper into proteins, including cerruloplasmin, a serum protein with ferroxidase activity. In tissue culture models, excess copper causes redistribution of WND protein to a subplasma membrane compartment suggesting a possible role in excretion of excess copper either by direct endocytosis or by its participation in canalicular excretion of copper. Loss of normal WND function in Wilson disease leads to increase in urinary copper excretion, which is a characteristic feature of the disease.

With the identification of the WND gene, patients suspected of having the disease can now be identified by screening for mutations within the gene. Unlike hemochromatosis where one major and another minor mutation have been associated with the disease, careful study of patients with Wilson disease have found mutations throughout the gene limiting the practicality and commercial feasibility of searching for mutations in suspected individuals. To date, all Wilson disease patients are compound heterozygotes with only a common substitution of a histidine for glutamine (H1069Q) occurring in up to 35% of patients with Eastern European background. In addition to identifying the mutation, function of the mutated protein needs to be determined to eliminate normal variation in amino acid sequence, referred to as polymorphisms, from disease causing mutations. Mutations have been found within critical regions of this copper transporter protein, such as the ATP binding region, as well as a mutation such as H1069Q, which causes improper protein folding leading to rapid degradation. The lack of a common mutation for patients with this disease has significantly hampered the use of genotyping for making a diagnosis and identifying family members at risk for the disease.

Currently, a few centers with a research interest in Wilson disease are searching for mutations in the gene and performing haplotype analysis to identify family members who may be carriers of the disease. For patients with Wilson disease, it is important to contact investigators who are interested in correlating clinical presentation with precise localization of the mutations in the WND gene. To identify siblings who may also have mutations in the WND gene, haplotype analysis can be used if the mutations responsible for the disease are unknown. In this analysis, an allelic pattern of highly polymorphic markers located within the Wilson disease gene on the chromosome, which is approximately 80,000 base pairs long, are easily determined by PCR amplification of DNA isolated from white blood cells or a buccal smear. The pattern of polymorphic markers is compared to the Wilson disease patient and his siblings. Those siblings that share the same haplotype pattern of polymorphic markers are likely to have the disease as they share both copies of the mutated WND genes. Those patients identified before onset of disease can commence with lifelong copper chelation therapy to prevent complications of the disease.

In summary, Wilson disease is an autosomal recessive disease caused by multiple mutations located throughout the WND gene. At this time, the diagnosis of Wilson disease is made by clinical and biochemical evidence of excess copper storage and not by genotyping studies. Haplotype analysis or screening for mutations identified in a Wilson disease patient can be used to identify siblings that may be carriers of the disease before occurrence of the clinical complication of excess copper storage.