Clinical and Modifier Gene Profiles in Reversible Infantile Respiratory Chain Deficiency: Three Chinese Cases and Literature Review

Abstract Background Reversible infantile respiratory chain deficiency (RIRCD) associated with homoplasmic MT-TE m.14674T > C/G variants is characterized by severe infantile crisis followed by spontaneous recovery. Nuclear genetic modifiers may influence its phenotypic penetrance. Methods We analyzed the clinical profiles, genetic profiles, and prognosis of three patients with RIRCD and 55 published cases. Results Among the 55 cases, almost cases developed symptoms within the first 6 months. Neuromuscular symptoms were reported in 85.5%, with nasogastric feeding required in 70.9%, and mechanical ventilation in 43.6%. Pre-recovery biomarkers showed elevated lactate and creatine kinase levels. Muscle biopsies revealed ragged-red fibers, vacuolar changes, and mitochondrial ultrastructural abnormalities in most cases. Respiratory chain deficiencies included isolated complex IV and combined I + IV defects. The prognosis of RIRCD was favorable. In total, 32.0% of patients were healthy, and 58.0% had mild residual myopathy. Genetically, 96.4% harbored the homoplasmic m.14674T > C variant. Whole-exome sequencing identified nuclear modifier genes in 24 cases, including EARS2 (n = 9) and TRMU (n = 7). We reported a case of a homoplasmic m.14674T > C variant (maternal) and a pathogenic EARS2 heterozygous variant (paternal), indicating digenic inheritance of EARS2. Additionally, we reported another case of a homoplasmic m.14674T > C variant and a maternally inherited CLCN4 variant associated with RIRCD post-recovery language delay and autistic features, suggesting the presence of additional modifiers or comorbidities. Conclusion RIRCD is a rare, reversible mitochondrial myopathy, driven by homoplasmic MT-TE m.14674T > C/G variants but influenced by nuclear modifiers (e.g. EARS2) for penetrance. Understanding these modifier genes and digenic inheritance offers insights into phenotypic heterogeneity and may guide future therapy.