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Wilson disease

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Wilson disease is an inherited autosomal recessive disorder of copper balance leading to hepatic damage and neurological disturbance of variable degree. The defective gene, ATP7B, encodes a hepatic copper-transporting protein, which plays a key role in human copper metabolism. Our knowledge of the genetic basis of Wilson disease has increased dramatically; however, understanding of genotype–phenotype correlation and multifarious effects of copper toxicity as basis for targeted and individualised therapy strategies is still insufficient. Clinical manifestations are related to copper accumulation predominantly in the liver and brain and include hepatic disease ranging from mild hepatitis to acute liver failure or cirrhosis and/or neurological symptoms such as dystonia, tremor, dysarthria, psychiatric disturbances. Mixed presentations occur frequently. Early recognition by means of clinical, biochemical or genetic examination and initiation of therapy with copper chelators, zinc salts or even liver transplantation in cases of acute and chronic liver failure are essential for favourable outcome.

Section snippets

Copper balance and pathogenesis of Wilson disease

Daily uptake of copper in the proximal parts of the small intestine ranges between one and two milligrams, this amount is adequate for the needs of the human body. *[9], [10] In the blood copper is bound to amino acids (e.g. histidine) or proteins (e.g. albumin) and transported to the liver and peripheral tissues. [11] Due to its redox potential copper is essential for many physiological processes and serves as co-factor for important metabolic enzymes such as cytochrom c oxidase (mitochondrial

Inheritance and epidemiology of the ATP7B gene defect

The worldwide prevalence is estimated one in 30,000 and even higher in certain populations with consanguinity. The gene frequency in the healthy population is about one in 90. [21] ATP7B is located on the long arm of chromosome 13 (13q14–q21). To date more than 300 different mutations have been identified in the large ATP7B gene (cDNA: 4.4 kbp) (http://www.wilsondisease.med.ualberta.ca/database.asp). [22] Only few of these mutations were already functionally characterised. [23], [24], [25], [26]

Clinical presentation

Symptoms, clinical course and outcome of Wilson are highly variable. In principle, the main features – the hepatic and the neurologic form – can be distinguished, but many patients present with a mixture of both. Usually after an asymptomatic early life period predominant hepatic forms (manifestation between eight and 18 years) appear several years earlier than the neurologic forms (manifestation during early adulthood). [28], *[29], [30], [31] Late onset of symptomatic Wilson disease may occur

Diagnosis

Diagnostic delays appear frequently particularly in predominant neurologic manifestation of Wilson disease and result in poor clinical outcome. [36] Recognising Wilson disease is challenging. The clinician’s alertness and screening for Wilson disease in patients with suspect neurologic symptoms or unknown liver disease may prevent an unfavourable course of this treatable disease. A summary of diagnostic steps in different clinical situations is shown in Fig. 3.

Therapeutic strategies

All Wilson disease patients – even in the presymptomatic stage – need lifelong drug therapy. In general pharmacological treatment alternatives include copper chelators and zinc salts. Essential for long-term success of pharmacological treatment for Wilson disease is the patients’ adherence. Currently only liver transplantation is able to cure the disease (hepatic form). However, transplantation is only mandatory in some special situations (see below).

Conflict of interest

None.

Acknowledgement

This work was supported by the German Research Foundation (DFG HU 932/3-2).

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