OXPHOS complex deficiency in congenital myopathy: A systematic review

Congenital myopathies are inherited neuromuscular disorders characterized by early-onset muscle weakness and distinct histopathological features. Although mitochondrial involvement in congenital myopathy is well recognized in its pathophysiology, oxidative phosphorylation (OXPHOS) complex dysfunction, which is associated with primary mitochondrial diseases (MD), is not. This systematic review aimed to evaluate the prevalence and characteristics of reported OXPHOS complex dysfunction in genetically confirmed congenital myopathy cases.

A systematic literature search was conducted in PubMed, Scopus and Web of Science. The search strategy was developed according to PRISMA guidelines. Two independent reviewers screened the studies for inclusion. Eligible studies reported genetically confirmed congenital myopathy cases or disease models and included diagnostic OXPHOS complex analyses via enzyme kinetic assays and/or protein/RNA expression.

Of 5841 studies screened, 23 publications (2009-2025) met the inclusion criteria, comprising 45 congenital myopathy cases. OXPHOS complex dysfunction was reported in 78% of these cases, including all human cases where OXPHOS enzymology was performed. Nine congenital myopathy-associated genes were involved in the cases, with RYR1 being the most frequent. No definitive genotype-phenotype relationship was established between specific genes and affected complexes.

OXPHOS complex dysfunction in congenital myopathy appears to be more prevalent than previously recognized, challenging the traditional view that associates such dysfunction exclusively with MD. This emerging evidence suggests that mitochondrial involvement in congenital myopathy is not incidental but may represent a meaningful aspect of its pathophysiology. The potential dysregulation of OXPHOS in congenital myopathy has implications for refining diagnostic frameworks for both congenital myopathy and MD.