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

Abstract

We analyzed the data on age at onset and CAG size of 319 patients clinically diagnosed with Huntington disease (HD) and 86 presymptomatic subjects recorded by four Italian Centers over the last 14 years. To overcome the problem 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 fathers or mothers. Overall, our data argue in favor of a greater similarity across the same generation than across successive generations. In particular, an excess of parents with later than expected age of onset was observed, paralleled by a CAG-independent anticipation of onset in parent-child transmissions. These results can be interpreted in terms of a shared environment determining similar departures from the average CAG-onset relationship but also of a systematic effect that differentiates the two generations here examined.

CAG repeat lengths ≥ 335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse

“…Whether CAG repeats beyond 200 are progressively less harmful in HD is uncertain. Repeats above 60 invariably cause the rapidly progressing juvenile-onset form of HD, with rigidity as the presenting symptom (Huntington’s Disease Collaborative Research Group,1993; Stine et al,1993; Squitieri et al, 2000), and repeats in the 100–150 range yield an age of onset of 2–5 years (Huntington’s Disease Collaborative Research Group, 1993; Furtado et al, 1996; Squitieri et al, 2000; Gambardella et al, 2001; Nahhas et al, 2005; Papapetropoulos et al, 2005; Wojaczynska-Stanek et al, 2006). The rare HD victims found to possess >200 CAG repeats, however, also show an age of onset of 2–3 years, and one case with a 265-repeat HD allele presented at 4 years of age with the typically adult-onset symptom of chorea (Nance et al,1999; Milunsky et al, 2003; Seneca et al, 2004).…”

Reduced penetrance alleles for Huntington's disease: a multi-centre direct observational study

“…As sib-sib pairs tend to have a similar age at onset for given expanded repeat sizes, 11 we assessed the possible bias introduced by the inclusion of first degree relative pairs (sib-sib and parent-child) by randomly selecting one of the pair for exclusion from the survival analysis. There was no significant difference in the results obtained, suggesting that their inclusion did not introduce major bias.…”

Indexing disease progression at study entry with individuals at‐risk for Huntington disease

“…There is an inverse relationship between CAG repeat length and age of HD diagnosis with longer lengths being associated with earlier diagnosis. Various statistical models have been developed to account for this phenomenon [Andresen et al, 2007a, 2007b; Andrew et al, 1993; Brinkman et al, 1997; Gutiérrez and MacDonald, 2002, 2004; Langbehn et al, 2004, 2010; Langbehn and Paulsen, 2007; Lucotte et al, 1995; Maat-Kievit et al, 2002; Rubinsztein et al, 1996, 1997; Squitieri et al, 2000; Stine et al, 1993]. …”