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Copper is an essential trace element with a well established mechanism for maintaining balance of the metal in the body, which is controlled by at least two genes. Disruption of one gene on the X chromosome determines a defect in the process of copper absorption, with consequent deficiency of available copper at the cellular level. This results in abnormalities of collagen formation and brain maturation, leading to early death. As yet there is no effective treatment. Disruption of the other copper controlling gene, located on chromosome 13, is associated with accumulation of excess copper in the body, first in the liver leading to cirrhosis, and then in the brain giving rise to destruction of the centre of motor control and, frequently, changes in personality. Copper excess can also cause renal damage, osteoarticular changes and joint pains. If the renal lesion leads to calcium loss in the urine and other tubular defects, there may be osteoporosis or, occasionally, osteomalacia with pathological fractures. In this disease, the abnormal stores of copper can be mobilised with chelating agents or depleted by the administration of zinc salts or thiomolybdate. This usually, but not invariably, leads to improvement or even complete reversal of symptoms. Brain lesions, as demonstrated by computed tomography or magnetic resonance imaging, may also resolve. The mechanism of this phenomenon is obscure but suggests that the long held doctrine that there is no recovery in the central nervous system may have to be reviewed.

In 51 families with Wilson disease, we have studied DNA haplotypes of dinucleotide repeat polymorphisms (CA repeats) in the 13q14.3 region, to examine these markers for association with the Wilson disease gene (WND). In addition to a marker (D13S133) described elsewhere, we have developed three new highly polymorphic markers (D13S314, D13S315, and D13S316) close to the WND locus. We have examined the distribution of marker alleles at the loci studied and have found that D13S314, D13S133, and D13S316 each show nonrandom distribution on chromosomes carrying the WND mutation. We have studied haplotypes of these three markers and have found that there are highly significant differences between WND and normal haplotypes in northern European families. These findings have important implications for mutation detection and molecular diagnosis in families with Wilson disease.