The DNA segment CAG (cytosine adenine guanine) repeat causes SCA3/MJD. Its length in the ATXN3 gene determines the age at onset of clinical symptoms. However, the expanded CAG repeat length’s association with disease progression rate is unclear. This study aims to deepen understanding through quantitative assessments.

The study’s objective is to relate SCA3/MJD onset and progression with CAG repeat. 82 Dutch patients underwent annual evaluations for 15 years. A linear growth curve model was used for the International Cooperative Ataxia Rating Scale (ICARS) analysis. The progression rates were analyzed using observed and predicted AO based on CAG repeat length. They were also tested to relate CAG expansion length with residual age at onset(RAO).

The average ICARS scores increased by 2.57 points per every disease year. CAG repeat length positively correlated with rapid ICARS progression. CAG repeat length and RAO were combined as co-modifiers. It explained 47% of the inter-patient variation in progression.

The expanded CAG repeat length in ATXN3 is a major cause of the clinical decline. The data suggests that these related molecular mechanisms lead to both disease onset and the progression rate. This data on SCA3/MJD modifiers helps in designing future clinical trials.

Ref: https://onlinelibrary.wiley.com/doi/10.1002/ana.25919