Huntington disease mutation in Venezuela: age of onset, haplotype analyses and geographic aggregation.

The aggregation of patients with Huntington's disease (HD) around Lake Maracaibo, Zulia State, Venezuela, is widely recognized, but the epidemiology of HD in the whole country is relatively unstudied. We have examined 279 individuals from 60 unrelated affected families residing in various areas of Venezuela for the presence of CAG repeats and other features associated with HD. The number of expanded repeats in 139 carriers varied from 35 to 112. Based on our examination of 71 symptomatic individuals, we developed a log-transformed regression equation, y= -0.0238x + 2.6616, to enable the prediction of age of onset in asymptomatic carriers. Intragenic haplotypes were constructed with two VNTRs (variable number of tandem repeats) and two SNPs (single nucleotide polymorphisms) in the promoter region as well as CCG repeat and Delta2642 polymorphisms to assess kinship between families. In 43 of 45 tested families, the haplotype on the mutated chromosome was 1;G;C;7;(A). The other haplotypes observed, 1;G;C;7;(B) and 4;G;C;7;(A), were of Peruvian and French origins, respectively. The geographic source of the first affected ancestor was assessed in 54 families from 15 different states. Residents of the states of Miranda, Lara and Táchira, excluding those of Zulia, had a mutated allele prevalence five- to ninefold higher than that of other areas. A low (approx. 1/200,000) prevalence, a wide-spread distribution with aggregation in some states and a likely remote European Caucasoid origin are defining epidemiologic features of HD in Venezuela.