Unveiling Spinocerebellar Ataxia 25: First Case Report of a Brazilian Family.

Abstract

Spinocerebellar ataxia type 25 (SCA25) is a rare autosomal dominant disorder caused by heterozygous pathogenic variants in the PNPT1 gene, primarily affecting the critical S1 RNA-binding domain. This study reports the first Brazilian and South American family with SCA25. To describe the clinical, genetic, and molecular findings in a family with a novel PNPT1 variant and compare them with previously reported cases. Clinical evaluation, neuroimaging, and genetic testing were performed on affected family members. The proband underwent clinical exome sequencing, with Sanger confirmation of the identified variant. Computational tools, including SpliceAI, were used to predict the molecular consequences of the variant. The proband, a 1-year-8-month-old girl, presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. Genetic testing identified a novel heterozygous truncating variant in PNPT1 (c.2068del; p.?), inherited from her father, who was mildly affected with polyneuropathy but no ataxia. SpliceAI predicted significant splicing disruptions, including intron retention or exon skipping, leading to a frameshift (p.(Arg690Glyfs*5)) and likely triggering nonsense-mediated decay or post-translational degradation. These findings align with previously reported PNPT1 variants associated with SCA25, which exhibit phenotypic variability and incomplete penetrance. This report expands the clinical and genetic spectrum of SCA25 and highlights the importance of considering this condition in the differential diagnosis of progressive ataxias. Further studies, including RNA and protein analyses, are required to confirm the molecular consequences of the PNPT1:c.2068del variant and to advance our understanding of the pathophysiology of SCA25.