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The following is a summary of “Redefining the Pathogenic CAG Repeat Units Threshold in CACNA1A for Spinocerebellar Ataxia Type 6,” published in the February 2025 issue of Neurology Genetics by Hatano et al. 

Spinocerebellar ataxia type 6 (SCA6) results from CAG repeat units (RUs) expansion in CACNA1A. The pathologic threshold is debated, especially the lower limit. 

Researchers conducted a retrospective study to assess the pathologic significance of RUs in SCA6 and the impact of opposite alleles (OAs). 

They conducted an observational study on patients with suspected SCA who underwent SCA6 genetic testing. They analyzed CACNA1A RUs and age at onset (AAO). They examined family history positivity rates for different expanded allele (EA) RUs. They performed regression analyses for AAO estimation based on EA RUs. They investigated OA’s influence on AAO, focusing on cases with 21–22 EA RUs. 

The results showed that 2,768 participants were enrolled. Family history positivity increased above 19 RUs and plateaued at ≥23 RUs. Regression analysis showed that 96.20% of cases with ≥23 RUs, 90.67% with 22 RUs, 91.15% with 21 RUs, 61.54% with 20 RUs, and 33.33% with 19 RUs fell within the 95% prediction interval for AAO. No patients had ≤18 RUs. In the 21–22 RU group, OAs significantly influenced AAO, with ≥17 RUs having a significant effect. For ≥23 RUs, no significant OA effect was observed. Cases with 19–20 RUs had a higher OA prevalence with ≥19 RUs than those with ≥23 RUs. 

Investigators found that clinical manifestation likely required at least 19 RUs, with 19–20 RUs as an intermediate zone influenced by OAs. They observed that ≥23 RUs were sufficient for disease onset, while 21–22 RUs showed a complex EA-OA interplay. 

Source: neurology.org/doi/10.1212/NXG.0000000000200245