Pediatric-onset spinocerebellar ataxia type 3 with dual ATXN3 and HTT gene mutations: a case report and literature-informed hypothesis

Abstract

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN3 gene, typically onsetting in adults aged 30-40 years. Pediatric-onset cases are extremely rare, and concurrent CAG repeat expansions in both ATXN3 and huntingtin (HTT) genes are even more exceptional. Herein, we report a 10-year-old female patient who presented with gait instability and dysarthria as initial symptoms. Diagnosis of SCA3 was confirmed by genetic and radiological evaluations. Genetic testing revealed biallelic CAG repeat lengths of 20 (normal) and 77 (expanded) in ATXN3, and 19 (normal) and 38 (expanded) in HTT. Imaging findings included mild cerebellar atrophy and bilateral tibial exostoses, consistent with her clinical phenotype. Integrated analysis of the case and a review of the literature indicated that the extreme CAG expansion in ATXN3 (77 repeats) is the primary determinant of the remarkably early onset in this patient. The concurrent HTT CAG expansion may also influence the phenotype, suggesting a potential complex interaction that warrants further investigation. This case report provides a clinical example of SCA3 complicated with concurrent ATXN3 and HTT mutations, offering preliminary clinical data for future large-sample studies on the correlation between these two mutations.

Keywords: ATXN3; HTT; SCA3; pediatric-onset; polyQ.