Analysis of the Age of Onset in Spinocerebellar Ataxia Type 7 (SCA7)

Abstract

Introduction Spinocerebellar Ataxia Type 7 (SCA7) is a neurodegenerative disease, caused by a CAG repeat expansion in the ATXN7 gene. It is characterized by progressive ataxia and a distinctive cone-rod dystrophy. The age of onset of symptoms (AO) varies widely and it has been established that the number of CAG repeats is its main modifier, showing a strong inverse correlation. The low prevalence of SCA7 has limited the precise characterization of its natural history, which in turn hinders a specific and accurate genetic counseling for patients and their families.

Objective To describe and model the SCA7-free survival and the effect of the number of CAG repeats on it in a cohort of individuals with SCA7.

Methodology A total cohort of 183 individuals was analyzed, composed of 157 symptomatic patients and 26 carriers of the expansion in a presymptomatic state. Initially, a correlation analysis was performed between the number of CAG repeats and the AO in the 157 symptomatic cases, fitting different regression models. Subsequently, the 26 presymptomatic (censored) cases were incorporated to perform a survival analysis using the Kaplan-Meier method and the construction of SCA7-free survival tables. The individuals were stratified into 7 groups according to their number of CAG repeats, and the survival curves were compared using the Log-rank test with Bonferroni correction. Finally, Cox proportional hazards models were used to evaluate the effect of the CAG repeats and other covariates. Given the violation of the proportional hazards assumption (Schoenfeld test), a Cox model with B-splines was implemented.

Results Power regression was the model with the best fit for the correlation between CAG repeats and AO (R² = 0.884, p < 0.001), indicating that 88.4% of the variability in the age of onset is explained by the number of repeats. The overall median age of onset in the complete cohort (n=183) was 34.10 years (95% CI: 29.36-36.61). The stratified analysis showed a median disease-free survival of 82.62 years for the group with 34-36 repeats, which drastically decreased to 3.60 years for the group with 100 or more repeats (p < 0.001). The univariate Cox models confirmed that only the CAG repeats were a significant predictor of the AO. The B-spline model revealed a complex non-linear relationship, identifying a threshold around 45 repeats, below which the effect is much lower and above which the risk increases drastically until stabilizing in very large expansions.

Conclusions The number of CAG repeats is the main and most potent predictor of the age of onset in SCA7, explaining the great majority of its variability. The demographic variables studied did not show a significant modifying effect.

Keywords: Spinocerebellar Ataxia Type 7, Disease-Free Survival Analysis, Cox Model.