Genetic Heterogeneity in Wilson Disease: Lessons from Rare Alleles

In 1912, S.A. Kinnier Wilson (1877-1937) described the condition that now bears his name [1, 2]. As a neurologist, he was interested in the progressive deterioration of the nervous system seen with this condition, but the involvement of the liver and the familial clustering of cases also intrigued him. In the previous decade, Mendel's laws had been rediscovered and Garrod had interpreted alkaptonuria and other disorders as both inborn errors of metabolism and an expression of Mendelian recessive traits. Wilson disease was thought from early on to be recessively inherited from two heterozygous parents. Because of marked clinical variability within families, however, confirmation of this theory by pedigree analysis took more than five decades. The term used by Wilson, hepatolenticular degeneration, acknowledged the pleiotropic nature of the condition: It was presumed that the underlying cause of the disease had multiple effects on the phenotype. An explanation for the pathogenesis and pleiotropy of Wilson disease began to emerge in 1913, when increased copper deposition was found in the liver and, subsequently, in other affected organs. During much of this century, the extent of pleiotropy seen in Wilson disease has expanded, so that multiple organs and tissues must be scrutinized by the managing physician [3, 4]. For example, clinical diagnosis of Wilson disease is aided by the presence of Kayser-Fleischer rings in the cornea or azure lunulae in the fingernails.

In Wilson disease, as in most metabolic diseases, effective treatment can evolve despite ignorance of cause as long as some aspects of the condition's …