Clinical and genetic spectrum of pediatric mitochondrial disorders in china: insights from a 47-case genetically confirmed cohort

Primary mitochondrial disorders (MDs) are genetically and clinically heterogeneous metabolic diseases caused by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations. Pediatric MDs pose diagnostic challenges due to variable onset, multisystem involvement, and complex genotype–phenotype correlations. We retrospectively analyzed 69 children with suspected MDs at Shanghai Children’s Medical Center (2015–2025). Genetic diagnoses were established through targeted next-generation sequencing (NGS) combined with clinical, biochemical, and neuroimaging evaluation. Forty-seven patients were genetically confirmed and classified into mtDNA and nDNA groups for comparison. The diagnostic yield was 68% (47/69). mtDNA mutations accounted for 64% (30/47), with MT-TL1 m.3243 A > G being the most frequent (60%), followed by MT-ATP6 m.8993T > C and MT-ND6 m.14484T > C. nDNA mutations (36%) affected 12 genes, mostly related to complex I. Common phenotypes included MELAS (45%) and Leigh syndrome (LS) (28%). Compared to nDNA cases, mtDNA patients had higher epilepsy (64.5% vs. 43.8%) and stroke-like episodes (58.1% vs. 31.2%), while nDNA cases had earlier onset (1.15 vs. 5.42 years, P < 0.001) and more hypoglycemia. MT-TL1 pedigrees showed maternal inheritance, phenotypic variability, and generational worsening. Mutation load was higher in MT-ATP6-related LS than in MT-TL1-related MELAS (P = 0.008). Serial neuroimaging revealed syndrome-specific progression. All six fatal cases exhibited a “neuroimaging–metabolic–cardiac/respiratory failure” triad. Chinese pediatric MDs show marked genetic and phenotypic heterogeneity. Recognizing genotype–phenotype patterns, longitudinal imaging, and critical risk triads may improve diagnosis, management, and patient selection for future trials.