Six Novel SACS Mutations Expand the Autosomal Recessive Spastic Ataxia of Charlevoix–Saguenay Spectrum: From Classic to Charcot–Marie–Tooth Disease-Mimicking Phenotypes in a Single-Center Japanese Cohort

Background: Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) diagnosis traditionally relies on the classic triad; however, the spectrum in Asian populations remains undefined. We systematically characterized Japanese ARSACS to expand the mutational landscape and diagnostic boundaries. Results: We conducted a retrospective cohort study at a regional tertiary care hospital between January 2016 and December 2023, systematically reviewing 3,347 inpatients. ARSACS cases were identified through comprehensive multimodal assessments encompassing neurological, electrophysiological, ophthalmological, neuroimaging, and genetic evaluations. Among 3,347 patients at our single institution, we identified five ARSACS cases (four families), yielding hospital-based frequencies of 0.15% (all admissions), 1.83% (spinocerebellar degeneration), and 0.29% (peripheral neuropathy). Genetic analysis revealed seven pathogenic SACS variants, of which six were novel. Clinical heterogeneity was notable: onset ages ranged from 1 to 27 years, and phenotypes varied from classic ARSACS in four patients (with typical neuroimaging) to a Charcot–Marie–Tooth disease (CMT)-mimicking presentation in Case 5 (predominant peripheral neuropathy, minimal cerebellar involvement, absent characteristic magnetic resonance imaging features). Conclusions: Our identification of six novel SACS variants substantially expands the global ARSACS mutational spectrum and reveals unexpected phenotypic heterogeneity in Japanese patients. The discovery of CMT-mimicking presentations mandates inclusion of ARSACS in the differential diagnosis of hereditary peripheral neuropathies, potentially explaining previously undiagnosed cases.