Expanding the Spectrum of AFG3L2 Mutations: A Case with Late-Onset Autosomal Recessive Spinocerebellar Ataxia from Iran

Abstract

Spastic ataxia type 5 (SPAX5) is a rare autosomal-recessive neurodegenerative disorder caused by AFG3L2 mutations affecting the mitochondrial m-AAA protease complex. previously reported cases presented in early childhood with seizures and developmental delay. We report a 38-year-old woman with progressive gait ataxia, dystonia, dysmetria, scanning speech, and hyperreflexia. Brain MRI revealed cerebellar atrophy, while metabolic studies were normal. Genetic testing identified a homozygous AFG3L2 variant (c.2176G > T; p.Val726Phe) consistent with SPAX5. Family history included two mildly affected children. Unlike previously described early-onset SPAX5 cases, this patient exhibited adult-onset, slowly progressive symptoms without seizures or cognitive delay, suggesting partial preservation of protease activity. The p.Val726Phe substitution may retain residual function, accounting for the milder phenotype. This case, the first genetically confirmed SPAX5 from Iran, expands the clinical spectrum of AFG3L2-related disorders and emphasizes considering this diagnosis in adult-onset ataxia.