The recurrent SACS gene p.Arg272His hotspot expands the neurodevelopmental and cognitive spectrum of ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by pathogenic variants in the SACS gene. While traditionally defined by a motor triad, emerging evidence suggests a broader phenotypic spectrum that includes significant cognitive involvement. We describe a 16-year-old Sicilian female, born to consanguineous parents, and homozygous for missense variant c.815G > A (p.Arg272His). Alongside the classical triad of progressive cerebellar ataxia, pyramidal spasticity, and demyelinating sensorimotor polyneuropathy, the patient exhibited mild intellectual disability (ID) with a Full-Scale Intelligence Quotient (IQ) of 60. Additional clinical markers included early-onset axial hypotonia and marked retinal nerve fiber layer thickening on optical coherence tomography. Longitudinal neuroimaging over 13 years documented progressive cerebellar vermis atrophy and the emergence of pontine transverse fiber hyperintensity. Comparison with previously published patients carrying the identical homozygous variant strongly supports p.Arg272His as a recurrent mutational hotspot involving a highly conserved functional residue within the SIRPT1 domain of sacsin, likely critical for mitochondrial homeostasis and neuronal cytoskeletal organization. Importantly, comparison with previously reported patients suggests that cognitive impairment and intellectual disability may represent recurrent and potentially under-recognized features among individuals carrying the p.Arg272His variant, although the limited number of reported cases precludes definitive genotype-phenotype conclusions. This case adds longitudinal clinical, neuroimaging, ophthalmological, and neuropsychological data to the limited literature on patients carrying the p.Arg272His variant, supporting further investigation of genotype-phenotype relationships in ARSACS. We advocate for the integration of standardized neuropsychological assessments into the routine diagnostic workup for ARSACS to ensure comprehensive patient management.