Family and molecular data for a fine analysis of age at onset in Huntington disease

We analyzed the data on age at onset and CAG size of 319 patients clinicall y diagnosed with Huntington disease (HD) and 86 presymptomatic subjects rec orded by four Italian Centers over the last 14 years. To overcome the probl em of different CAG numbers found in each subject, also in the same family, the data were analyzed in terms of deviations from the average exponential relationship between onset and CAG number. The subject's year of birth was also considered to quantify possible sampling biases, Observations between relatives were compared with those of the whole group. The deviations were equal, on average, in subjects who inherited their HD gene from their fath ers or mothers. Overall, our data argue in favor of a greater similarity ac ross the same generation than across successive generations. In particular, an excess of parents with later than expected age of onset was observed, p aralleled by a CAG-independent anticipation of onset in parent-child transm issions. These results can be interpreted in terms of a shared environment determining similar departures from the average GAG-onset relationship but also of a systematic effect that differentiates the two generations here ex amined. (C) 2000 Wiley-Liss, Inc.