Expanded ATXN10 Alleles in Neurodegenerative Disorders: A Case Series and Review of the Literature

Spinocerebellar ataxia type 10 (SCA10 or ATX-ATXN10) is typically attributed to large intronic ATTCT repeat expansions in ATXN10, yet interpretation is complicated by repeat interruptions, reduced penetrance, and assay limitations.

We describe three patients referred for SCA10 evaluation in whom ATXN10 repeat-primed PCR (RP-PCR) reported ">32 repeats, probable pathogenic." Targeted long-read sequencing (LRS) identified two individuals with intermediate, mixed repeat tracts (~100-150 repeats) and one individual with a very large, highly pure ATTCT expansion (~1127 repeats). Each phenotype was explained by an alternative disorder: spastic ataxia syndrome caused by biallelic pathogenic FA2H variants (HSP/ATX-FA2H), full-penetrance ATXN3 CAG expansion consistent with SCA3/ATX-ATXN3, and clinically established MSA-C.

We identified three studies reporting four ATX-ATXN10 cases coexisting with Huntington's disease (one case) and SCA2/ATX-ATXN2 (three cases).

Our three cases suggest that intermediate ATXN10 alleles in the 100-150 range may not be pathogenic and large ATXN10 expansions remain probably pathogenic in most patients with a compatible autosomal-dominant ataxia phenotype. Comprehensive genetic testing beyond RP-PCR is necessary for accurate diagnosis.