AFG3L2 is the gene encoding the mit

AFG3L2 is the gene encoding the mitochondrial m-AAA protease subunit. The heterozygous mutations in AFG3L2 could induce autosomal dominant hereditary spinocerebellar ataxia type 28 (SCA28), while homozygous mutations in AFG3L2 may lead to autosomal recessive spastic ataxia 5 (SPAX5). Methods: A retrospective analysis was performed on a child with suspected SPAX5, including clinical presentation and neuroradiological findings. In addition, peripheral blood was collected from the child and parents for genomic DNA extraction. Whole exome sequencing and Sanger validation were performed on three members of the family to identify possible causative genes. To further analyze the effect of splicing mutations on mRNA integrity in vivo, the AFG3L2 gene cDNA from peripheral blood cells of the affected child was also sequenced and evaluated for possible effects of pathogenic mutations on protein function. Results: The child had a severe clinical presentation with developmental delay, recurrent seizures, microcephaly, and increased blood lactate at the age of 5+ months. The imaging was suggestive of ventricular dilatation and hydrocephalus signs, and the child died prematurely at 5 years of age. Whole exome sequencing and Sanger sequencing showed that the child carried a compound heterozygous mutation in the AFG3L2 gene, a nonsense mutation c.1834G>T (p.E612*) in the AFG3L2 gene, resulting in loss of gene function. The other was the AFG3L2 splice mutation c.2176–6T>A, with aberrant splicing confirmed by the mRNA analysis of the peripheral blood in the proband. Conclusion: Our study provides a novel basis for expanding the mutation spectrum of spastic ataxia 5 (SPAX5), neuroradiology, and genetics.Keywords: AFG3L2, SPAX5, early-onset epilepsy, mutation