NDUFS4 and Leigh syndrome

Multiple independent studies have established a robust association between NDUFS4 (HGNC:7711) and Leigh syndrome (MONDO:0009723). The genetic evidence is derived from several case reports and multi‐patient studies where patients were reported to harbor compound heterozygous mutations in NDUFS4, including the missense variant c.355G>C (p.Asp119His) and various frameshift alleles. These variants were identified in non‐consanguineous families with an autosomal recessive inheritance pattern, and the recurrent observation of similar mutation types across diverse populations strongly supports pathogenicity (PMID:19364667, PMID:27079373).

Segregation analyses in several studies further bolster the association by demonstrating that additional affected family members share the segregating pathogenic alleles, although explicit counts of affected relatives are not uniformly reported across all studies (PMID:22326555).

Beyond the genetic studies, extensive functional investigations have consistently shown that NDUFS4 mutations lead to defective assembly and loss of activity of mitochondrial complex I. Experimental approaches using blue native polyacrylamide gel electrophoresis (BN-PAGE) and knockout animal models recapitulate the key features of Leigh syndrome, including neurodegeneration and early mortality, which reinforces the clinical relevance of the genetic findings (PMID:15038602, PMID:25652399).

The integrated analysis of genetic and functional evidence confirms that NDUFS4 mutations cause a severe, early onset neurodegenerative phenotype, typical of Leigh syndrome. Multiple independent cohorts, including reports involving over 100 patients, have documented multiple variant classes (missense and frameshift) that result in impaired complex I assembly, thus meeting high evidence thresholds for the gene‑disease association (PMID:24731534, PMID:27671926).

Collectively, these studies provide strong support for the pathogenic role of NDUFS4 in Leigh syndrome. Clinicians should consider targeted genetic testing for NDUFS4 mutations in patients who present with early onset neurodegeneration and biochemical evidence of complex I deficiency, particularly in populations with documented founder effects.

Key take‑home: The convergence of genetic, segregation, and functional data makes NDUFS4 a critical diagnostic marker for Leigh syndrome, offering significant clinical utility in guiding patient management.

References

• Molecular Genetics and Metabolism | 2009 | NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement PMID:19364667
• Mitochondrion | 2016 | Ndufs4 related Leigh syndrome: A case report and review of the literature PMID:27079373
• Biochimica et Biophysica Acta | 2012 | A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome PMID:22326555
• Orphanet Journal of Rare Diseases | 2014 | A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• American Journal of Medical Genetics. Part A | 2017 | A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population PMID:27671926
• Neurochemical Research | 2004 | Respiratory complex I in brain development and genetic disease PMID:15038602

Evidence Based Scoring (AI generated)