INSTABILITY OF CAG REPEATS IN HUNTINGTONS-DISEASE - RELATION TO PARENTAL TRANSMISSION AND AGE-OF-ONSET

Huntington's disease (HD) has recently been found to be caused by expa nsion of a trinucleotide (CAG) repeat within the putative coding regio n of a gene with an unknown function. We report here an analysis of HD mutation and the characteristics of its transmission in 36 HD familie s. CAG repeats on HD chromosomes were unstable when transmitted from p arent to offspring. Instability appeared more frequent and stronger up on transmission from a male than from a female, with a clear tendency towards increased size. We have also found a significant inverse corre lation (p = 0.0001) between the age of onset and the CAG repeat length . The observed scatter would, however, not allow an accurate individua l prediction of age of onset. Three juvenile onset cases analysed had an HD mutation of paternal origin. In at least two of these cases a la rge expansion of the HD allele upon paternal transmission may explain the major anticipation observed. Our results suggest that several feat ures of the expansion mutation in HD are similar to those previously o bserved for mutations of similar size in spinobulbar muscular atrophy and in myotonic dystrophy, and to those observed more recently in spin ocerebellar ataxia type 1 and in dentatorubropallidoluysian atrophy, f our diseases also caused by expansion of CAG repeats.