Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

Abstract

BackgroundThe most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset.MethodsWe combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age.ResultsFor SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age.ConclusionsThese estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.ClinicalTrials.gov, numberNCT01037777 and NCT00136630 for the French patients.

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…The extent of the increase in arborization was proportional to CAG repeat length (which governs the SCA1 phenotype, with more repeats producing more severe disease and earlier onset) (33)(34)(35)36). In other words, the patients who showed earlier disease onset had more BC collaterals than those patients with milder, later-onset disease in the fifth or sixth decade of life ( Figure 3, B and C).…”

Neurochemical abnormalities in premanifest and early spinocerebellar ataxias

“…onset using a recently developed statistical model. 41 The premanifest mutation carriers who were classified by DWD as SCA had estimated time to onset of 10 years or less (Fig 6), indicating that neurochemical abnormalities may be detectable up to 10 years before onset of ataxia. FIGURE 5: SCA classification based on distance-weighted discrimination.…”

Repeat expansion diseases

“…In both SCA6 and SCA1, the size of the normal repeat contributes modestly to age of onset (135a and b), and the size of the normal SCA6 repeat may be a modifier of disease onset in SCA2 (111). Moreover, at the SCA2 locus, repeats at the high end of the normal range are an important genetic risk factor for ALS.…”