Evolution of disability in spinocerebellar ataxias type 1, 2, 3, and 6

Abstract

Objective: The aim was to study the evolution of disability in spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3, 6). Methods: We analyzed data of two longitudinal cohorts (RISCA, EUROSCA) which recruited ataxic and non-ataxic SCA1, SCA2, SCA3, and SCA6 mutation carriers. To study disability, we used a five-stage system for ataxia defined by walking ability (stages 0–3) and death (stage 4). Transitions were analyzed using a multi-state model with proportional transition hazards. Based on the hazard estimates, transition probabilities and the expected lengths of stay in each stage were calculated. We further studied the effect of sex and CAG repeat length on progression. Results: Data of 3138 visits in 677 participants were analyzed. Median SARA scores for SCA1, SCA2, SCA3, and SCA6 ranged from 1.5 (interquartile range [IQR] = 0.0–3.5) to 3.5 (IQR = 1.4–6.1) in stage 0, 11.5 (IQR = 9.6–14.0) to 13.8 (IQR = 11.0–16.0) in stage 1, 19.0 (IQR = 17.0–21.0) to 23.8 (IQR = 19.5–27.0) in stage 2, and 28.5 (IQR = 26.0–32.5) to 34.0 (IQR = 32.6–37.1) in stage 3. Modeling allowed to calculate the subtype-specific probability to be in a certain stage at a given age and duration of each stage. CAG repeat length was associated with faster progression in SCA1 (HR, 95% CI: 1.1, 1.1–1.2), SCA2 (1.2, 1.1–1.3), and SCA3 (1.1, 1.0–1.2). In SCA6, female sex was associated with faster progression (1.7, 1.1–2.6). Interpretation: Our data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.