NDUFA13 and Leigh Syndrome

This summary outlines the association between NDUFA13 (HGNC:17194) and Leigh syndrome (MONDO:0009723). The reported evidence includes detailed genetic findings from case reports as well as supportive functional assays that highlight the role of NDUFA13 in mitochondrial complex I assembly and function. Both genetic and experimental data point toward a loss‐of‐function mechanism, which underpins the disease phenotype. The evidence has been gathered from comprehensive clinical evaluations and laboratory investigations. This narrative is designed to support diagnostic decision‑making, facilitate commercial applications, and inform future publication. The data are drawn exclusively from the supplied evidence.

In the genetic assessment, biallelic pathogenic variants in NDUFA13 have been reported in patients with Leigh syndrome. In a second family report, two novel variants were identified, including the variant c.107T>C (p.Leu36Pro) (PMID:32722639). Although only two unrelated families have been described to date, the variants demonstrate the expected autosomal recessive inheritance pattern. The segregation of these variants in the context of the phenotype, together with supporting in silico pathogenicity predictions, provides moderate evidence for the gene‐disease association. Functional studies have demonstrated isolated complex I deficiency and reduced NDUFA13 protein levels. These data emphasize the relevance of the gene in maintaining mitochondrial oxidative phosphorylation.

The inheritance pattern of the NDUFA13‐related Leigh syndrome is autosomal recessive. Affected individuals present with early onset encephalopathy, basal ganglia lesions, and other neurological abnormalities characteristic of Leigh syndrome. Although the available reports involve a limited number of families, the clinical presentations are consistent across cases. No additional affected relatives with segregating variants have been explicitly mentioned (PMID:32722639). Moreover, the detailed reporting of clinical symptoms and biochemical data further supports the role of NDUFA13 in this disease. The autosomal recessive nature of the inheritance provides a clear framework for genetic counselling and diagnostic evaluation.

Genetic evidence is further substantiated by the identification of the variant c.107T>C (p.Leu36Pro) in a patient demonstrating typical Leigh syndrome manifestations. This variant, among the two reported, meets rigorous HGVS nomenclature standards and has been carefully evaluated in the clinical setting (PMID:32722639). The correlation between genotype and phenotype is strengthened by the biochemical findings in patient-derived skin fibroblasts. These cells show delayed growth, an isolated complex I enzyme defect, decreased oxygen consumption, and reduced ATP production. The evidence is therefore consistent with a mechanism of pathogenicity driven by complex I dysfunction. Such genetic data, although limited in number, is critical for guiding further research and refining diagnostic algorithms.

Functional evidence provides pivotal support for the pathogenicity of NDUFA13 variants. Studies have shown that the reduction in NDUFA13 protein levels in patient fibroblasts correlates with impaired assembly and function of the mitochondrial respiratory chain complex I (PMID:32722639). Additional functional studies, including those dissecting the role of GRIM-19 (an alternative name for NDUFA13), have validated the importance of this subunit in maintaining mitochondrial membrane potential and overall cellular energy metabolism (PMID:18287540). These experimental findings provide a mechanistic explanation for the clinical phenotype and substantiate the genetic observations. Overall, the functional assays serve as a critical bridge connecting molecular defects with clinical outcomes. The reproducibility of these results across different experimental models enhances the confidence in the pathogenic role of NDUFA13 variants.

In conclusion, the integration of genetic and functional data supports a moderate level of clinical validity for the association between NDUFA13 and Leigh syndrome. Despite the limited number of reported families, the consistency of autosomal recessive inheritance, the identification of a deleterious variant such as c.107T>C (p.Leu36Pro), and the concordant functional findings collectively affirm the gene‐disease link. Importantly, these findings have clear implications for clinical diagnostics, enabling more informed genetic counselling and targeted therapeutic development. The available evidence is robust enough to guide diagnostic decision-making and offers a compelling foundation for additional research. Future studies with larger cohorts are anticipated to further refine the association strength.

Key Take‑home sentence: The convergence of genetic and functional evidence in NDUFA13 mutations offers critical insights into the etiology of Leigh syndrome, underscoring its clinical and diagnostic relevance.

References

• Genes • 2020 • Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report PMID:32722639
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• Molecular biology of the cell • 2008 • GRIM-19 is essential for maintenance of mitochondrial membrane potential PMID:18287540

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