Objective: The aim was to study the evolution of disability in spinocerebellar ataxias type 1, 2, 3, and 6 (SCA1, 2, 3, 6) and to identify factors that influence transition into higher disability stages.

Background: SCA1, 2, 3, and 6 are autosomal dominantly inherited ataxia disorders which lead to increasing disability. A number of cohort studies assessed the progression rates of these diseases over several years by repeated administration of clinical scales, such as SARA, but an understanding of the development of disability over the entire disease spans is lacking.

Method: We analyzed longitudinal data of ataxic and non-ataxic SCA 1, 2, 3, and 6 mutation carriers from the RISCA [1] and EUROSCA [2,3] cohort. To study the evolution of disability, we used the following staging system: stage 0 (no gait difficulties), stage 1 (gait difficulties), stage 2 (loss of independent gait, as defined by permanent use of a walking aid or reliance on a supporting arm), and stage 3 (confinement to wheelchair) [4]. Transitions between stages were analyzed using a multistate model with proportional transition hazards[5]. Based on the hazard estimates, transition probabilities and the expected lengths of stay in each of the stages were calculated [6]. We further studied the effect of sex and CAG repeat length on progression.

Results: Data of 3138 visits in 677 participants were analyzed. Mean SARA scores for SCA1, 2, 3, and 6 ranged from 1.9 to 2.6 in stage 0, 10.8 to 12.8 in stage 1, 19.8 to 24.8 in stage 2, and 29.7 to 34.3 in stage4. Modelling allowed to determine the genotype-specific likelihood to be in a certain stage at a given age, and the duration of each stage. CAG repeat length was associated with faster progression in SCA1 (HR: 1.11, 95% CI: 1.062-1.164), SCA2 (1.16, 1.075-1.245), and SCA3 (1.08; 1.016-1.156). In SCA6, female sex was associated with faster progression (1.67, 1.077-2.577).

Conclusion: Our study provides a comprehensive view of disease evolution in SCA1, 2, 3, and 6 based on the prospective assessment of disability stages which are of immediate relevance for affected individuals. Our data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.

References: 1 Jacobi et al. Lancet Neurol. 2020 Sep;19(9):738-747. 2 Jacobi et al. Lancet Neurol. 2015 Nov;14(11):1101-8. 3 Diallo et al. Lancet Neurol. 2018 Apr;17(4):327-334. 4 Klockgether et al. Brain. 1998 Apr;121 ( Pt 4):589-600. 5 Putter et al. (2007). Statistics in Medicine 26, 2389–2430. 6 Beyersmann et al. Demographic Research 2014, 30(62), 1681-1696.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evolution-of-disability-in-spinocerebellar-ataxias-type-1-2-3-and-6/