Diagnosing Wilson disease in the post-genomic era

Volume 1, Issue 3, November 2006

Dr Ching-Wan LAM, MBChB(CUHK), PhD(CUHK), FRCPA, FHKAM(Pathology)

Associate Professor, Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital


Resident Specialist, Division of Clinical Biochemistry, Department of Pathology, Queen Mary Hospital

Wilson disease (WD) (MIM # 277900) is an autosomal recessive disorder of copper transport. Clinical manifestations of WD vary widely. The age of onset ranges from three to more than 50 years of age. The initial onset of symptoms can be hepatic, neurological, psychiatric or as an acute haemolytic crisis. The prevalence of WD has been estimated to be approximately 1 in 30,000 in the Caucasian population. Although the prevalence of WD in the Hong Kong Chinese has not been investigated, based on our local experiences, WD is common and is the most common inherited liver disease in Hong Kong. In addition, investigators in Japan have suggested that the prevalence of WD in Asians might be higher than that reported in the U.S. and Europe.

In 1993, the gene responsible for WD was identified, and the gene product was predicted to be a copper binding P-type adenosine triphosphatase. The ATP7B gene, which consists of 21 exons, spans a genomic region of about 80kb and encodes a protein of 1465 amino acids. ATP7B is expressed primarily in the liver and kidney. The protein plays a dual function in the hepatocytes. One role is biosynthetic, delivering copper to apocaeruloplasm in within the Golginetwork. The other role of ATP7B is to transportexcess copper out of the cell and into the bilecanaliculus for subsequent excretion from the body with bile. ATP7B is localized in the trans-Golgi network of hepatocytes under low copper conditions, redistributes to cytoplasmic vesicles when cells are exposed to elevated copper levels, and then recycles back to the trans-Golgi network when copper is removed. Therefore, an ATP7B mutant will result in a reduction in the rate of incorporation of copper in to apocaeruloplasmin or a reduction in biliary excretion of copper, or both. For example, a WD mutant protein, R778L, has recently been shown to be extensively mislocalized, presumably to the endoplasmicreticulum. Defective biliary excretion leads to accumulation of copper in the liver with progressive liver damage and subsequent copper overflow to the brain, causing loss of coordination and involuntary moments. Deposition in the cornea produces Kayser-Fleischer rings, and accumulation in the other sites causes renal tubular damage, cardiomyopathy, hypoparathyroidism osteoporosis, and arthropathy, etc.

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