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

Abstract

Background: The 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.

Methods: We 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.

Results: For 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.

Conclusions: These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.

Clinicaltrialsgov, number: NCT01037777 and NCT00136630 for the French patients.

Keywords: Movement disorders (other than Parkinsons).

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Figures

Figure 1

Conditional probability density function of age at onset for different current ages (CA) (t). The figures are drawn for SCA2 data with a repeat number of the expanded allele of 37 for an individual at birth (solid), or at a current age of 30 (medium dash), 40 (short dash) or 45 (short dash dot). Based on a log linear parametric model, the estimation of the mean age at onset from birth was 43 years (γG: 3.7428,: 0.2516) (vertical dashed line). As the distribution is log-normal the mode is neither the mean nor the median. SCA, spinocerebellar ataxias.

Figure 2

Median age at onset according to the genotype and the current age of the presymptomatic individual. (A) SCA1 genotype, (B) SCA2 genotype, (C) SCA3 genotype, (D) SCA6 genotype. For all panels, the x axis is the number of repeats for the expanded alleles, and the y axis the estimated age at onset. For SCA1 and SCA6 genotypes, each sub-panel representing different repeats numbers of the shorter allele are depicted. Curves are plotted from birth and for an individual of 25/30/35/40/45 years old. SCA, spinocerebellar ataxias.