Recessive AFG3L2 Mutation Causes Progressive Microcephaly, Early Onset Seizures, Spasticity, and Basal Ganglia Involvement

Abstract

Background Mutations in AFG3L2, a gene encoding a subunit of the mitochondrion m-AAA protease, cause spinocerebellar ataxia type 28 and recessive spastic ataxia type 5. Neuroimaging shows cerebellar atrophy. Methods Retrospective review of the patient charts including their clinical evaluation and molecular genetic, neurodiagnostic, and neuroradiological investigations. Results We describe five members of a large consanguineous family with a severe mitochondrial disease phenotype in the form of regression of the developmental milestones in the first year of life, refractory epilepsy, progressive microcephaly, increased blood lactate, basal ganglia involvement, and premature death. Exome sequencing showed homozygous mutation of the AFG3L2 gene in all individuals: c.1714G>A (p.Ala572Thr). Conclusions Our findings add to the phenotypic, neuroradiological, genetic, and biochemical spectrum of AFG3L2 mutations.