Abstract
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder due to mutations in the SACS gene. While the typical phenotype is characterized by cerebellar ataxia, spasticity, and peripheral neuropathy, more reports are published of atypical and late-onset presentations, also lacking typical cerebellar signs of the disease, which can mimic Charcot-Marie-Tooth disease (CMT). We report a 58-year-old Chinese male with a 12-year history of progressive gait instability and lower limb weakness, who also exhibited retinal degeneration. Remarkably, in contrast to the majority of ARSACS patients, he had no significant spasticity, thus expanding the phenotypic spectrum. Genetic analysis identified a pathogenic compound heterozygous mutation in SACS: a novel frameshift variant (c.178del, p.Asp60ThrfsTer8) in exon 4, unreported in ClinVar, and a missense variant (c.4723 C > T, p.Arg1575Trp) in exon 10, documented in ClinVar with conflicting interpretations. The exceptionally late onset in this patient suggests that the c.178del frameshift may partially preserve sacsin function, thereby delaying disease manifestation. MLPA analysis excluded CMT1/HNPP-related rearrangements, confirming an ARSACS diagnosis. Familial segregation further supported autosomal recessive inheritance, emphasizing the importance of family screening. Given this, our case suggests a potential extended therapeutic window in late-onset ARSACS and may need to be included in future therapeutics efforts, emphasizing the importance of identifying such atypical forms. This observation highlights the importance of thorough genetic testing in achieving a correct diagnosis and providing treatment for patients with undiagnosed progressive ataxia.