EFFECT OF TRINUCLEOTIDE REPEAT LENGTH AND PARENTAL SEX ON PHENOTYPIC VARIATION IN SPINOCEREBELLAR ATAXIA-I

Trinucleotide repeat expansion has been found in 64 subjects from 19 f amilies: 57 patients with SCA1 and 7 subjects predicted, by haplotype analysis, to carry the mutation. Comparison with a large set of normal chromosomes shows two distinct distributions, with a much wider varia tion among expanded chromosomes. The sex of transmitting parent plays a major role in the size distribution of expanded alleles, those with >54 repeats being transmitted by affected fathers exclusively. Our dat a suggest that alleles with >54 repeats have a reduced chance of survi val; these appear to be replaced in each generation by further expansi on of alleles in the low- to medium-expanded repeat range, preferentia lly in male transmissions. Detailed clinical follow-up of a subset of our patients demonstrates significant relationships between increasing repeat number on expanded chromosomes and earlier age at onset, faste r progression of the disease, and earlier age at death.