Motor system abnormalities in heterozygous relatives of a D90A homozygous CuZn-SOD ALS patient of Finnish extraction

Presently, 64 mutations in the gene encoding the enzyme CuZn-superoxide dis mutase have been found in a small fraction of amyotrophic lateral sclerosis patients worldwide. All but one of these mutations show autosomal dominant inheritance. In Scandinavia, the D90A mutation is inherited as an autosoma l recessive trait and patients have an easily recognizable characteristic p henotype with little variation among patients, even amongst different famil ies. Importantly, all D90A heterozygous relatives of Scandinavian D90A homo zygous patients have been reported as clinically unaffected. We have invest igated a Canadian family of Finnish extraction in which the D90A homozygous proband developed ALS with the characteristic phenotype. Remarkably, two D 90A heterozygous relatives show slight symptoms and signs of motor system i nvolvement, suggesting that the final phenotype of an individual with a CuZ n-superoxide dismutase mutation is shaped by the combination of the particu lar CuZn-SOD mutation, other polymorphic modifying genes elsewhere in the g enome, stochastics and possible environmental factors. (C) 1999 Published b y Elsevier Science B.V. All rights reserved.