Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation
Massimo Pandolfo, Myriam Rai, Gauthier Remiche, Laurence Desmyter, Isabelle Vandernoot
Abstract
<h3>Objective</h3> To describe the clinical and molecular genetic findings in a family segregating a novel mutation in the <i>AIFM1</i> gene on the X chromosome. <h3>Methods</h3> We studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an <i>AIFM1</i> variant identified by CES and demonstrate its pathogenicity. <h3>Results</h3> The proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband9s mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the <i>AIFM1</i> gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband9s mother. The mutation did not cause quantitative changes in protein abundance. <h3>Conclusions</h3> Our report extends the molecular and phenotypic spectrum of <i>AIFM1</i> mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.