PNPT1 – Spinocerebellar Ataxia Type 25

Autosomal dominant spinocerebellar ataxia type 25 (SCA25) is associated with heterozygous pathogenic variants in PNPT1 (HGNC:23166) leading to childhood-onset progressive cerebellar ataxia often accompanied by sensorineural hearing loss and neuropathy. Two unrelated probands have been reported: an 11-year-old boy with severe hearing impairment and childhood-onset ataxia carrying a 3′ splice site variant c.2014-3C>G (PMID:39729134), and a 20-month-old Brazilian girl with progressive ataxia, cerebellar atrophy, and sensory neuropathy harboring a truncating variant c.2068del (p.Arg690GlyfsTer5) (PMID:39899068). In the latter family, the variant segregated with mild polyneuropathy in the father. No formal functional assays of these SCA25‐associated variants have been reported beyond in silico splice and truncation predictions.

ClinGen classification for the PNPT1–SCA25 association is Limited based on two probands, one additional affected relative, and absence of replication or mechanistic studies. Genetic evidence is Limited, reflecting two unrelated AD cases with predicted deleterious splice‐site and truncating variants and minimal segregation. Functional evidence is Limited, as no direct biochemical or model organism data confirm pathogenicity in SCA25.

Altogether, existing data support a provisional gene–disease link that warrants further functional validation and broader case series. Clinicians should consider PNPT1 screening in early‐onset ataxia with hearing loss.

References

• Cerebellum (London, England) • 2024 • Unravelling Heterogeneity: A Rare PNPT1 Variant in Childhood-Onset Spinocerebellar Ataxia with Sensorineural Hearing Loss. PMID:39729134
• Cerebellum (London, England) • 2025 • Unveiling Spinocerebellar Ataxia 25: First Case Report of a Brazilian Family. PMID:39899068

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