STUB1 Mutations as Possible Genetic Modifiers in Spinocerebellar Ataxia Type 8.

BACKGROUND: Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited expansion disorder with highly variable penetrance. ATXN8OS/ATXN8 expanded alleles have been identified in association with other types of hereditary ataxias, pointing to a possible genetic synergism. OBJECTIVES: We aimed to further investigate the molecular background of patients with SCA8 diagnosis. METHODS: Patients were selected from our cohort of 346 families. A total of 14 probands with SCA8 underwent additional investigation through exome sequencing. RESULTS: Pathogenic heterozygous STUB1 variants were found in 21.4% of SCA8 patients (3 of 14) compared to only 0.5% in the non-SCA8 group (1 of 222), indicating a statistically significant association (P < 0.05). CONCLUSIONS: The findings reported in this study might suggest a genetic synergism between STUB1 and ATXN8OS/ATXN8 expanded alleles. Further studies are needed to validate this observation and better define the clinical impact of this genetic interaction. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population.

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.