A novel variant of MIEF2 gene expands the clinical spectrum of combined oxidative phosphorylation deficiency 49

Abstract

Combined oxidative phosphorylation deficiency (COXPD) encompasses a highly heterogeneous group of inherited mitochondrial disorders characterized by a fundamental defect in cellular energy production. Combined oxidative phosphorylation deficiency type 49 (COXPD49) is an ultra-rare subtype caused by mutations in the MIEF2 gene, which encodes the MID49 protein, a critical regulator of mitochondrial dynamics. Only one case of this condition has been previously reported in scientific literature. This manuscript documents the second and third cases of COXPD49, found in two siblings from a non-consanguineous family. This study confirms the pathogenic role of the MIEF2 gene and demonstrates that the clinical spectrum of COXPD49 is more extensive than previously understood, extending beyond isolated muscle involvement to include severe neurological components. The findings underscore the critical importance of genetic testing for the definitive diagnosis of rare diseases with significant clinical diversity.