Six novel SACS mutations expand the autosomal recessive spastic ataxia of Charlevoix-Saguenay spectrum.

BACKGROUND: The clinical spectrum of autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) in Asian populations remains incompletely defined. We aimed to characterize the clinical, radiological, and genetic features of Japanese patients with ARSACS and to expand the mutational and phenotypic spectrum of this disorder. METHODS: We conducted a retrospective case series of patients diagnosed with ARSACS in our department between January 2016 and December 2023. Five patients from four families with biallelic SACS variants were identified. RESULTS: Genetic analysis revealed seven pathogenic SACS variants, of which six were novel. Clinical heterogeneity was notable, with age at onset ranging from 1 to 27 years. Four patients showed classical ARSACS-related neuroimaging findings, whereas one patient presented with a Charcot–Marie–Tooth disease (CMT)-mimicking phenotype characterized by predominant peripheral neuropathy, mild cerebellar involvement, and absence of the classical pontocerebellar magnetic resonance imaging features. CONCLUSIONS: The recognition of CMT-mimicking presentations supports considering ARSACS in the differential diagnosis of hereditary peripheral neuropathies, particularly in patients with additional cerebellar, pyramidal, or supportive neuroimaging features.