DIAGNOSIS OF WILSON DISEASE USING DNA MARKERS

Abstract

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The basic defect in WD is unknown, but the gene has been assigned to chromosome 13 at q14-q21 by using closely linked markers.

Clinical presentation of WD is variable. Symptomatic patients have a high urinary copper output and decreased serum ceruloplasmin. Atypical or presymptomatic patients may not be diagnosed by these criteria. Distinction from heterozygotes can also be difficult. A liver biopsy is almost always conclusive, but is invasive. Therefore the incorporation of 67Cu into ceruloplasmin (absent in WD) has been advocated as a non-invasive diagnostic test.

Nevertheless a genetic diagnosis is more desirable. So we used 12 DNA markers from the 13q14-q21 region to study 6 patients with a questionable diagnosis of WD. We could confirm the diagnosis in 2 of them. However in the remaining 4 individuals, all previously classified as having WD (based on a moderately increased urinary copper excretion, a somewhat increased liver copper, a low ceruloplasmin and no incorporation of 67Cu), the diagnosis had to be revised. Our present results reveal that they are in fact heterozygotes.

This demonstrates that DNA markers can now be used to establish the diagnosis of WD. Moreover copper isotope studies can be abnormal in heterozygotes with a low ceruloplasmin.

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