Predictability of age at onset in Huntington disease in the Dutch population

As previously described, the age at onset of Huntington disease (HD) ranges from 2 to 80 years, with a mean between 46.0 and 48.9 years. The number of repeats, in the causal CAG repeat expansion, is inversely related to the age at onset and accounts for 50%-77% of the variation in age at onset. We analyzed a Dutch cohort of 755 individuals retrospectively to assess the probability of onset for any given CAG repeat. The repeat size is the major determinant of age at onset, with a correlation of -0.74, stronger (-0.84) in paternal than in maternal inheritance (-0.64), consistent with increased repeat expansion and stronger anticipation in the paternal line. The age at onset within families was more similar than could be explained by the resemblance of the repeat size of persons in the same family. We hypothesized that if environmental factors were principally responsible for this familial aggregation, one would expect a greater correlation for sibs than for parents and children. This was not found to be the case. These observations suggest that genetic factors may play a greater role in the onset of HD than a shared environment. Finally, we discuss several explanations for the fact that the Dutch median age at onset for all expanded repeat sizes studied is significantly later, by about 10 years, than that found in a Canadian study.

• View at Publisher
• View at Pubmed
• View at Scopus
• View at Web of Science