Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin

Abstract Background AIFM1encodes a mitochondrial flavoproteinwith a dual role (NADH oxidoreductaseand regulator of apoptosis), which uses riboflavinas a cofactor. Mutations in the X-linked AIFM1were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathyand an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1mutations (one of which is novel) who display distinct phenotypes including progressive ataxiawhich partially improved with riboflavintreatment. Methods For both patients trio whole exome sequencingwas performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxiawas 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 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexiaand cardiomyopathy. Two deleterious missense mutations were found in the AIFM1gene: p. Met340Thr mutation located in the FAD dependent oxidoreductasedomain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxiascore, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. Conclusion AIFM1mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.