Age at onset prediction in spinocerebellar ataxia type 3 changes according to population of origin

Background and purpose: In spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population-specific models to predict AO. Methods: This was a parametric survival modelling study. Results: The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population-specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population-specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group. Conclusions: Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population-dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins.