Age at onset variance analysis in spinocerebellar ataxias: A study in a Dutch–French cohort

Abstract

In dominant spinocerebellar ataxias (SCAs), the issue of whether non-CAG dependent factors contribute to onset age remains unsettled. Data on SCA genotype, onset age, normal/expanded CAG repeat length, sex of the patient and transmitting parent, and family details were available from 802 patients. Based on the model [log(10) (age at onset) = k - b CAG(exp) + epsilon], we examined changes in adjusted R(2) and residual standard error following incorporation of the other factors in this model. The expanded repeat explained 44.3 to 74.9% of onset age variance, although this was less than 50% in SCA3 and SCA6, implicating a large effect of non-CAG factors. The relation between onset age and CAG repeat was similar for SCA1, 3, 6, and 7, but different for SCA2, pointing to different polyglutamine effects in SCA2. For SCA2 and SCA3, 17.1 and 45.5% of onset age variance, respectively, were explained by currently (unidentified) familial factors. We found a significant contribution of the nonexpanded allele in SCA1 and SCA6. Besides polyglutamine motif (determined by the expanded CAG repeat length), we identified the following age at onset modifiers: protein context in SCA2; familial factors in SCA2 and SCA3; and the nonexpanded CAG repeat in SCA1 and SCA6.

Molecular Pathogenesis of Spinocerebellar Ataxia Type 6

“…For example, individuals with a glutamine repeat of 20 begin to exhibit symptoms in their 70s, while individuals with a repeat length of 30 glutamines begin to exhibit symptoms as early as 30 years old. 12 The findings of the SCA6 mutation in humans and the spontaneous mouse mutant leaner Cterminal ␣1A splice mutation strongly suggest that genetic mutation of the C-terminus has significant functional consequences.…”

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

“…The Genetic Modifiers of Huntington's Disease (GeM‐HD) genome‐wide association study (GWAS)6 found two genome‐wide loci associated with age at motor onset in HD on chromosomes 15 and 8, with two independent signals at the same locus on chromosome 15. A few SCA genetic modifiers have been proposed3, 5, 7, 8, 9 and no GWAS have been reported.…”

Non-Mendelian Genetic Aspects in Spinocerebellar Ataxias (SCAS): The Case of Machado-Joseph Disease (MJD)

“…The reported incompleteness of the genotype-phenotype correlation, observed in MJD as well as in other SCAs, confirms the involvement of non-CAG factors in the explanation of the phenotype, that can either be genetic or environmental (van de Warrenburg et al, 2005). For MJD, the hypothesis that an important fraction of the residual of the disease onset (after accounting for the CAG repeat size) is of genetic nature has been reinforced (DeStefano et al, 1996;van de Warrenburg et al, 2005).…”

“…For MJD, the hypothesis that an important fraction of the residual of the disease onset (after accounting for the CAG repeat size) is of genetic nature has been reinforced (DeStefano et al, 1996;van de Warrenburg et al, 2005). The few studies that attempted to identify MJD modifiers have used candidate gene approaches; Jardim et al (2003), in a study that considers the effect of the CAG tract at several expansion loci (namely SCA2, SCA6 and DRPLA), only found a correlation between the severity of fasciculations and the size of the CAG tract at the SCA2 locus.…”