Clinical and modifier gene profiles in reversible infantile respiratory chain deficiency: three Chinese cases report and literature review.

BACKGROUND: Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy caused by homoplasmic MT‑TE m.14674T>C/G variants, characterized by severe infantile onset followed by spontaneous recovery. Nuclear modifiers are thought to modulate its incomplete penetrance, but evidence for digenic inheritance remains limited. We aim to analyze the clinical, genetic, and prognostic features of RIRCD, explore the roles of nuclear modifiers and digenic inheritance. CASE DESCRIPTION: We report three Chinese RIRCD patients carrying the homoplasmic m.14674T>C variant. All presented with recurrent respiratory infections and feeding difficulties, with gradual developmental recovery after 1 year of age. Notably, we report a case of a homoplasmic m.14674T>C variant (maternal) and a pathogenic EARS2 heterozygous variant (paternal), indicating digenic inheritance of EARS2. Additionally, we report another case of a homoplasmic m.14674T>C variant and a maternally inherited CLCN4 variant associated with language delay and autistic features after recovery from RIRCD, suggesting the presence of additional modifiers or comorbidities. Among 52 published cases and our 3 new cases, 92.16% of cases had onset within 3 months, 85.55% had neuromuscular symptoms, 70.91% required nasogastric feeding, and 43.63% needed mechanical ventilation. Elevated lactate and creatine kinase levels, ragged-red fibers, and mitochondrial ultrastructural abnormalities in muscle biopsies were common pre-recovery. Respiratory chain deficiencies included isolated complex IV and combined I + IV defects. Prognosis was favorable (32.00% full recovery, 58.00% mild residual myopathy). Twenty-four cases (43.64%) had nuclear modifiers, including EARS2 (n=9) and TRMU (n=6). CONCLUSIONS: RIRCD is a rare mitochondrial myopathy caused by mitochondrial DNA (mtDNA) variants with penetrance regulated by nuclear modifiers. Digenic inheritance contributes to phenotypic heterogeneity, supporting precise diagnosis and future therapy.