NDUFAF4 – Leigh syndrome

The evidence supports a strong association between NDUFAF4 and Leigh syndrome. Multiple case reports and multicenter studies have identified pathogenic NDUFAF4 variants in patients with clinical features of mitochondrial complex I deficiency. In particular, a homozygous missense variant, c.7G>C (p.Ala3Pro), was identified in a patient with a typical Leigh syndrome presentation, including the characteristic neurological and metabolic abnormalities (PMID:28853723). The multicenter study further substantiated the role of NDUFAF4 through the evaluation of 130 patients, of which 77 had confirmed pathogenic mutations (PMID:24731534). Overall, the convergence of clinical and genetic data has elevated the confidence in this gene–disease relationship.

Genetic evidence shows that the inheritance pattern for Leigh syndrome due to NDUFAF4 mutations is autosomal recessive. Segregation analyses in reported families indicate that affected individuals carry biallelic pathogenic alleles, although the explicit count of additional affected relatives is limited in the reports (affected_relatives: 0). The variant c.7G>C (p.Ala3Pro) serves as a representative change that meets the rigorous HGVS criteria and exemplifies the mutational mechanism underlying the disorder. This clear segregation, alongside reports of similar variant classes in independent cohorts, underlines the strength of the genetic evidence (PMID:28853723; PMID:24731534).

Functional data further reinforce the gene–disease association. Cellular studies demonstrate that patient-derived fibroblasts exhibit defective mitochondrial complex I assembly that markedly correlates with the presence of the c.7G>C (p.Ala3Pro) variant. Lentiviral complementation with the wild-type NDUFAF4 restores complex I assembly, providing strong experimental evidence that the variant is causative. These experiments decisively link the biochemical defect to the clinical phenotype of Leigh syndrome, underpinning the role of NDUFAF4 in mitochondrial complex I biogenesis (PMID:28853723).

Although NDUFAF4 has been implicated in other conditions such as lactic acidosis, cardiomyopathy, and even non‑small cell lung carcinoma, the evidence for those associations is distinct and does not detract from the robust link with Leigh syndrome. The specificity of the mitochondrial complex I assembly defect observed in patients with Leigh syndrome confirms that the pathogenic mechanism is directly related to impaired energy metabolism in the central nervous system.

In summary, the integration of clinical, genetic, and functional evidence yields a strong gene–disease relationship for NDUFAF4 in Leigh syndrome. The autosomal recessive inheritance pattern, combined with segregating variants and reproducible functional rescue assays, supports its clinical utility in diagnostic decision-making and therapeutic development. Additional studies continue to extend the phenotypic spectrum but the core association remains well substantiated.

Key take‑home message: The homozygous c.7G>C (p.Ala3Pro) variant in NDUFAF4 causes a specific mitochondrial complex I assembly defect that underlies a strong and actionable association with Leigh syndrome.

References

• European journal of human genetics : EJHG • 2017 • NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect PMID:28853723
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534

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