Spinocerebellar ataxia, autosomal recessive type 23 (SCAR23) with compound TDP2 variants: clinical, molecular, and...

Spinocerebellar ataxia, autosomal recessive type 23 (SCAR23) is an ultra-rare inherited disorder caused by biallelic Loss-of-Function (LoF) variants in TDP2, a nuclear enzyme involved in DNA double-strand breaks repair. To date, only 12 cases with homozygous variants and complex neurological phenotypes have been reported.

We describe a 20-year-old male presenting with cerebellar ataxia, drug-resistant epilepsy, mild intellectual disability, and recurring craniofacial traits observed in SCAR23. Additional findings included polycythemia and a pituitary hamartoma. Clinical exome sequencing (CES) identified two novel TDP2 nonsense variants. In silico and structural analyses indicated that both variants affect highly conserved residues in the catalytic domain. Longitudinal video-oculography confirmed downbeat nystagmus (DBN), while static stabilometry captured subtle postural changes over 12 months not detected by routine clinical examination, highlighting the utility of quantitative digital assessments.

This case expands the genotypic spectrum of SCAR23 and highlights recurring facial traits that may aid recognition. The coexisting SHOX deletion (i.e., Leri-Weill syndrome) was considered unrelated to the neurological phenotype. Digital assessments provided objective measures of motor function over time.

Our findings broaden the clinical and molecular characterization of SCAR23 and illustrate the potential of digital biomarkers for longitudinal monitoring. Despite the lack of functional validation and the inherent limitations of a single-case report, these observations provide valuable insights for future research in this ultra-rare disorder.