Mutations in AIFM1 cause a potentially treatable X-linked childhood cerebellar ataxia

Abstract

Objective: AIFM1 is mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked gene AIFM1 were reported accompanied by two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males with very different phenotypes including progressive ataxia which significantly improved with riboflavin treatment. Methods: For both patient trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with 200 mg riboflavin/day for 12 month. The ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. Results: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia and sensorineural hearing loss. Two missense mutations, predicted to be highly pathogenic were found in the AIFM1 gene: p. Met340Thyr (located in the FAD dependent oxidoreductase domain) and p.Thr141Ile (located in a highly conserved DNA binding motif). Ataxia score (ICARS), decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment with riboflavin. Conclusion: AIFM1 mutations cause childhood cerebellar ataxia, which may be treatable in some patients with high dose riboflavin. Response to treatment might be influenced by the position of mutation.