Abstract
OBJECTIVES: Apoptosis-inducing factor mitochondria-associated 1 (AIFM1) gene encodes a mitochondrial flavoprotein that mediates caspase-independent programmed cell death. We report a novel AIFM1 variant in 2 siblings with early-onset hearing loss and progressive cerebellar ataxia. METHODS: We evaluated the clinical features, brain MRI scans, EMG studies, and whole genome sequencing (WGS). RESULTS: Sibling A is a 19-year-old man with auditory neuropathy at age 15 years, who subsequently developed optic atrophy, progressive gait and limb ataxia, peripheral neuropathy, and ambulation with cane by age 17 years. Brain MRI was normal. Sibling B is a 13-year-old boy with auditory neuropathy diagnosed at 7 and gait instability at 13, with rapid development of peripheral neuropathy, cerebellar ataxia, muscle weakness and atrophy needing wheelchair for mobility, and neuromuscular respiratory failure requiring noninvasive ventilation. Brain MRI showed mild cerebellar atrophy. Initial EMGs showed axonal neuropathy in both and diffuse chronic and active anterior horn cell disorder later in Sibling B. WGS revealed an X-linked, maternally inherited novel AIFM1 variant (c.1299C>G p. Ile433Met). DISCUSSION: AIFM1 variants should be considered in patients with hereditary cerebellar ataxia and auditory neuropathy. We highlight a novel AIFM1 variant and its phenotypic intrafamilial variability expanding the knowledge of the genetic spectrum of AIFM1-related diseases.