NDUFA10 and Leigh syndrome

This summary details the association between NDUFA10 (HGNC:7684) and Leigh syndrome (MONDO:0009723). Leigh syndrome is an early‑onset progressive neurodegenerative disorder characterized by bilateral symmetric lesions in the basal ganglia, brainstem, and other central nervous system structures, with mitochondrial dysfunction as its common pathological basis (PMID:28247337). The clinical heterogeneity of this syndrome has been extensively documented in both single‐patient case reports and multi‑center studies (PMID:24731534).

Genetic evidence supporting the involvement of NDUFA10 comes from reports describing pathogenic coding variants. In one case report, a patient with Leigh syndrome was found to harbor a homozygous mutation, c.1A>G (p.Met1Val), which disrupts the initiation codon leading to impaired protein synthesis (PMID:28247337). Additional multi‑patient studies report compound heterozygous mutations in NDUFA10, further emphasizing the role of coding variants in the disease (PMID:21150889).

The inheritance pattern in these families is consistent with autosomal recessive transmission. Although explicit segregation details beyond the proband have not been exhaustively reported, the recurrence of NDUFA10 variants in unrelated cases strongly supports a recessive mode of inheritance. This genetic architecture is in line with other mitochondrial disorders where biallelic mutations lead to a consistent clinical phenotype.

Beyond the identification of the mutation itself, extensive variant analysis has revealed a spectrum of sequence alterations in NDUFA10. The reported variant, c.1A>G (p.Met1Val), exemplifies a complete coding change affecting protein translation. The use of standardized HGVS nomenclature and three‑letter amino acid codes ensures clarity in reporting (PMID:21150889). This variant, along with other alleles identified in different studies, constitutes a compelling body of genetic evidence supporting the association.

Functional and experimental studies further corroborate the pathogenicity of NDUFA10 mutations. In vitro assessments and animal model studies have demonstrated that mutations in NDUFA10 lead to a reduction of complex I assembly and activity, impairing mitochondrial oxidative phosphorylation (PMID:18442173, PMID:21150889). These findings are consistent with the biochemical phenotype observed in Leigh syndrome patients and provide strong experimental confirmation of the genetic data.

In summary, integration of clinical, genetic, and functional evidence establishes a strong association between NDUFA10 mutations and Leigh syndrome. The convergence of data across multiple independent studies supports the diagnostic utility of screening NDUFA10 in patients presenting with clinical features of Leigh syndrome. Key take‑home: Assessment of NDUFA10 variants is critical for confirming a diagnosis of Leigh syndrome and may guide prognostic evaluation and patient management.

References

• JIMD reports • 2017 • Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation PMID:28247337
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• European journal of human genetics : EJHG • 2011 • NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease PMID:21150889
• Proteomics • 2008 • Mass spectrometric characterization of mitochondrial complex I NDUFA10 variants PMID:18442173

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