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Background <p>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.</p> Methods <p>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.</p> Results <p>The diagnostic yield was 68% (47/69). mtDNA mutations accounted for 64% (30/47), with <i>MT-TL1</i> m.3243&#xa0;A &gt; G being the most frequent (60%), followed by <i>MT-ATP6</i> m.8993T &gt; C and <i>MT-ND6</i> m.14484T &gt; 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, <i>P</i> &lt; 0.001) and more hypoglycemia. <i>MT-TL1</i> pedigrees showed maternal inheritance, phenotypic variability, and generational worsening. Mutation load was higher in <i>MT-ATP6</i>-related LS than in <i>MT-TL1</i>-related MELAS (<i>P</i> = 0.008). Serial neuroimaging revealed syndrome-specific progression. All six fatal cases exhibited a “neuroimaging–metabolic–cardiac/respiratory failure” triad.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Fan Yang,
  • Ruen Yao,
  • Guoying Chang,
  • Jiayue Hu,
  • Biyun Feng,
  • Libo Wang,
  • Feihan Hu,
  • Yiguo Huang,
  • Shuo Wu,
  • Tingting Yu,
  • Yu Ding,
  • Xiumin Wang

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.