Objective: The aim was to model the evolution of ataxia and neurological symptoms in SCA1, SCA2, SCA3, and SCA6 over the entire disease span and to determine the sensitivity to change of clinical outcome assessments (COAs) in the conversion period 5 years prior and after ataxia onset.

Background: Studies considering the entire disease span from the early pre-ataxia to the late ataxia stage especially the time of conversion to ataxia are lacking. To fill this gap, we combined and jointly analysed the data of the longitudinal RISCA and EUROSCA studies which recruited ataxic and non-ataxic SCA 1, 2, 3, and 6 mutation carriers in different diseases stages.

Method: We used mixed-effect models to analyse evolution of SARA, SARAaxial, SCAFI and INAS and tested for a linear, quadratic, and cubic effect of time to choose the model that best fitted the data. We applied multivariable modelling to identify factors associated with progression of the SARA. In the time interval 5 years prior and after ataxia onset we assessed the sensitivity to change of COAs by calculating sensitivity to change ratio (SCS).

Results: Data of 2740 visits of 677 participants were analysed. Evolution of all COAs was best fitted with complex mixed models based on linear, quadratic and cubic time effects. R² values indicating quality of the fit ranged between 0.90 and 0.97 for SARA, SARAaxial, and SCAFI, and 0.70 and 0.82 for INAS. Repeat length of the expanded allele was associated with faster progression in SCA1, SCA2, and SCA3, but not SCA6. There was no association of sex and repeat length of the shorter allele with progression in any SCA subtype.

In SCA1, SCA2, and SCA3, SARA had the highest SCS of all COAs with a mean of 1.211 (95% CI: 1.209,1.212) in SCA1, 0.938 (0.963,0.940) in SCA2 and 1.227 (1.224, 12,30) in SCA3 followed by SARAaxial. In SCA6, SCS of SARAaxial (0.377 [0.374,0.380]) was higher than that of SARA (0.349 [0.346,0.352]). In all genotypes, SCAFI had the third highest and INAS the lowest SCS.

Conclusion: Our data have important implications for the understanding of disease progression in SCA1, SCA2, SCA3, and SCA6 across the lifespan. Furthermore, our study provides useful information for the design of interventional trials, in particular interventions aimed at modifying the disease course in pre-ataxic mutation carriers close to ataxia onset and patients in an early disease stage.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disease-progression-of-spinocerebellar-ataxia-types-1-2-3-and-6-before-and-after-ataxia-onset-a-joint-analysis-of-two-longitudinal-cohort-studies/