ABSTRACT Background Pathogenic variants of IBA57 (OMIM ID: 615330) are usually associated with multiple mitochondrial dysfunction syndrome (MMDS) and hereditary spastic paraplegia type 74 (SPG74). Here, we present a novel compound heterozygous IBA57 mutation in a boy with severe global developmental delay, optic atrophy, spastic paraplegia, and focal epileptic seizures. Methods The clinical data of a child diagnosed with MMDS were retrospectively collected. Video electroencephalogram (VEEG), cranial magnetic resonance imaging (MRI), and family whole‐exome sequencing (WES) were performed. Suspected mutation sites were further confirmed using Sanger sequencing. The activities of mitochondrial respiratory chain complexes I–IV were determined in peripheral blood mononuclear cells. The phylogenetic conservation of the affected residues was assessed by multiple sequence alignment of IBA57 gene orthologs. Furthermore, we conducted a review of the relevant literature. Results Whole‐exome sequencing identified compound heterozygous variants in the IBA57 gene: c. 395₄00dup (p. V132Q133dup) and c. 832delC (p. R278Afs*23), inherited from his phenotypically normal father and mother, respectively. Biochemical assays demonstrated selective reduction of complexes I and II activities, with normal complexes III and IV, consistent with impaired 4Fe–4S cluster maturation. Phylogenetic alignment revealed strict conservation of residues V132–Q133 and R278 across vertebrates. These variants had not been previously reported in domestic or international databases. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the former was classified as a variant of uncertain significance (PM4 + PM2), while the latter was classified as likely pathogenic (PVS1 + PM2). Conclusion Diseases associated with IBA57 gene variants are autosomal recessive disorders with a broad clinical phenotypic spectrum. Early genetic testing and family screening are beneficial for the diagnosis, treatment, and prognosis of the disease.
Xu et al. (Thu,) studied this question.