To examine correlates of SCA6 and SCA27B onset and severity using a patient survey.

Spinocerebellar ataxias (SCA) are rare neurodegenerative disorders affecting the cerebellum and brainstem, causing progressive imbalance and motor incoordination. They arise through diverse genetic mutational mechanisms, yet mutation severity only partly explains clinical features, suggesting environmental, non-germline or polygenic influences. Few epidemiologic studies have investigated risk factors.

283 participants with SCA6 and 127 with SCA27B completed an online survey (2024-2025). Age of symptom onset was modeled using Cox proportional hazards regression. Disease severity was measured using the Patient Reported Outcome Measure of Ataxia (PROM-Ataxia), and quartiles were modeled using ordinal logistic regression. Separate models for each subtype were adjusted for sex, education, race, and CAG/GAA repeat lengths. Age and age of onset were also included in the severity models. Additional covariates of interest were added separately, including indicators of childhood head trauma risk, toxin and pesticide exposures, hepatitis and herpes simplex virus (HSV), and birth characteristics. Disease severity models also examined current alcohol, tobacco and marijuana use.

Sex, race, and longer CAG repeats were significantly associated with earlier SCA6 onset. Earlier onset for SCA27B was associated with longer GAA repeats, concussion before age 25, pesticide exposure, and HSV infection, with marginal associations with contact sport participation and active childhood/adolescence.

For disease severity, age and age of onset were significantly associated for both SCA subtypes. Education, race and current alcohol and marijuana use were significantly associated with SCA6 severity. An active childhood/adolescence, pesticide exposure, and current alcohol use were marginally associated with SCA27B severity.

Genetics primarily influence SCA6 onset, while environmental exposures like head trauma, pesticide exposure, HSV infections and exercise may affect SCA27B disease onset and severity. Environmental factors could serve as intervention targets, particularly for SCA27B.