Objective: To describe the clinical and genetic characteristics of patients with SACS-related ataxia in an Arab population.

Background: Pathogenic variants in the SACS gene cause autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS), a rare neurodegenerative disorder characterized by early-onset cerebellar ataxia, pyramidal signs, and peripheral neuropathy. Data from highly consanguineous Middle Eastern populations remain limited.

Method: We conducted a retrospective case series of 13 patients with genetically confirmed SACS variants. Demographic, clinical, and genetic data were collected, including age of onset, neurological manifestations, family history, and molecular findings. Genetic diagnosis was established using ataxia gene panels, whole-exome sequencing (WES), or whole-genome sequencing (WGS). Variants were classified according to ACMG criteria.

Results: Thirteen patients were identified (8 males, 61.5%; 5 females, 38.5%), all of Arab ethnicity. Consanguinity was present in 10/13 (76.9%), and 12/13 (92.3%) reported a family history of similar illness. Mean age at first symptom was 2.1 years (median 1), with mean age at ataxia onset of 2.5 years (median 1.8). Mean age at diagnosis was 8.5 years (median 10), and mean current age was 16.4 years (median 14). Genetic analysis revealed 11 homozygous variants (84.6%) and 2 compound heterozygous variants (15.4%). Mutation types included frameshift (53.8%), nonsense (23.1%), and missense variants (7.7%), while compound heterozygous cases carried frameshift/missense variants. According to ACMG classification, 9 variants (69.2%) were pathogenic and 4 (30.8%) were variants of uncertain significance. Diagnostic approaches included WES in 9 patients (69.2%), ataxia gene panels in 3 (23.1%), and WGS in 1 (7.7%). Clinically, gait ataxia was present in all patients (100%), followed by upper limb ataxia in 8 (61.5%), lower limb ataxia in 6 (46.2%), and truncal ataxia in 4 (30.8%). Dysarthria and spasticity occurred in 7 patients each (53.8%). Additional features included muscle weakness (38.5%), seizures (38.5%), cognitive impairment (30.8%), learning disorders (30.8%), and axonal neuropathy (30.8%).

Conclusion: SACS-related ataxia in this cohort demonstrates early onset, high rates of consanguinity, and prominent gait ataxia with variable neurological involvement.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-characteristics-of-sacs-related-ataxia-a-case-series-of-13-patients-from-a-consanguineous-arab-population/