MOLECULAR ANALYSIS OF JUVENILE HUNTINGTON DISEASE - THE MAJOR INFLUENCE ON (CAG)(N) REPEAT LENGTH IS THE SEX OF THE AFFECTED PARENT

Juvenile Huntington disease (HD), characterised by onset of symptoms b efore the age of 20 with rigidity and intellectual decline, is associa ted with a predominance of affected fathers. In order to investigate t he molecular basis for the observed parental effect, we have analysed the CAG trinucleotide repeat within the HD gene in 42 juvenile onset c ases from 34 families. A highly significant correlation was found betw een the repeat length and age of onset (r = - 0.86, p < 10(-7)) and it was determined that the sex of transmitting parent was the major infl uence on CAG expansion leading to earlier onset. Neither the size of t he parental upper allele, the age of parent at conception of juvenile onset child, nor the grandparental sex conferred a significant effect upon expansion. Affected sib pair analysis of CAG repeat length, howev er, revealed a high correlation (r = 0.91, p < 10(-7)). Furthermore, a nalysis of nuclear and extended families showed a familial predisposit ion to juvenile onset disease. This study demonstrates that the sex of transmitting parent is the major influence on trinucleotide expansion and clinical features in juvenile Huntington disease.