To describe a unique phenotype associated with a novel genetic variant of AIFM1 gene and review the literature of AIFM1-related disorders.

The AIFM1 gene is located on chromosome X and encodes the AIF (Apoptosis-Inducing Factor) protein, which plays a significant role in programmed cell death and oxidative phosphorylation. AIFM1 mutations have been reported with multiple clinical phenotypes, including Cowchock syndrome, X-linked deafness-5, spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy, and combined oxidative phosphorylation deficiency resulting in a severe mitochondrial encephalomyopathy. Cowchock syndrome, in particular, is an X-linked recessive disorder with progressive neurologic dysfunction and highly variable features including hearing loss, progressive sensorimotor axonal neuropathy, cognitive impairment, cerebellar signs, and spasticity.

Case Report

We report a 37-year-old man with no relevant family history who exhibited characteristic features of Cowchock syndrome but in addition had ophthalmologic and psychiatric findings. His phenotype included slowly progressive ataxia, tremor, nystagmus, dysarthria, axonal neuropathy, intellectual disability, sensorineural hearing loss, ocular motor apraxia, visual impairment secondary to optic atrophy, and mood and behavior disorder. He carried a clinical diagnosis of spinocerebellar ataxia (SCA) initially and his brain MRI demonstrated cerebellar vermis atrophy. Evaluation for lysosomal enzyme, glycogen storage and VLCFAs disorders, Frataxin and Aprataxin genes disorders, SCA, Lesch-Nyhan syndrome, and Fragile X has been unremarkable. Comprehensive genetic testing for hereditary hearing loss identified a novel and de novo hemizygous missense mutation of AIFM1 gene, Allele 1: NM_ 001130846:c.211G>A, p.Val71Ile. Given the complicated phenotype, management consisted of collective efforts of several departments including neurology, ophthalmology, otolaryngology, psychiatry, genetics, orthopedics, physical and occupational therapy, and speech pathology.

Our report shows a unique phenotype and a novel genetic variant that expands the molecular and phenotypic spectrum of AIFM1-related disorders.