NDUFA9 – Leigh syndrome

In a recent investigation, a deleterious variant in NDUFA9 has been associated with Leigh syndrome, a severe mitochondrial disorder characterized by neurodegeneration and complex I deficiency. This association was initially uncovered in a consanguineous Kurdish family where homozygosity mapping led to the identification of a pathogenic variant. The study underscored the utility of candidate gene analysis in small pedigrees and provided compelling biochemical evidence that linked NDUFA9 dysfunction to the disease phenotype (PMID:22114105). The observed clinical presentation was neonatally fatal, reinforcing the impact of the identified mutation. Furthermore, the case report laid the groundwork for future research into the role of nuclear-encoded mitochondrial genes in Leigh syndrome. The findings serve as an important diagnostic pointer for clinicians assessing infants with suspected mitochondrial dysfunction.

Genetic evidence centers on the variant c.962G>C (p.Arg321Pro), which disrupts a highly conserved residue in the NDUFA9 protein. This missense alteration was detected in a single proband and is supported by impressive rescue experiments that restored complex I activity in patient fibroblasts (PMID:22114105). Although only one affected individual was reported, the functional data strengthen the causative link between this variant and the disease. The genetic evidence is bolstered by the fact that the mutation was discovered via robust homozygosity mapping in the setting of consanguinity, a situation often increasing the likelihood of recessive disorders.

The inheritance pattern of the association is autosomal recessive, consistent with the clinical context of the proband originating from consanguineous parents. No additional affected relatives with segregating variants were described in the published report, which limits the segregation evidence to the single family studied. Nonetheless, the combination of genetic and biochemical data provides a coherent demonstration of the variant’s pathogenicity. This mode of inheritance is particularly relevant for diagnostic laboratories and genetic counseling, as it informs risk assessment in related individuals.

Functional studies have provided strong support for the role of NDUFA9 in the pathogenesis of Leigh syndrome. Patient fibroblasts, when transduced with wild‐type NDUFA9, exhibit a complete restoration of complex I activity, confirming a loss‐of‐function mechanism associated with the missense variant (PMID:22114105). Additional functional assessment using complementation assays reinforces that even subtle alterations in this gene can substantially compromise mitochondrial respiratory chain assembly. Such robust experimental results not only validate the genetic findings, but also attest to the clinical relevance of the discovered variant.

While one study also described NDUFA9 variants in the context of axonal neuropathy, the association with Leigh syndrome remains distinct given the specialized functional assays and biochemical rescue experiments that directly linked the variant to complex I deficiency. No conflicting evidence has been reported regarding the role of NDUFA9 in neonatal-onset Leigh syndrome, although the phenotypic spectrum may be broader. This divergence in clinical presentation highlights the necessity for careful phenotypic correlation in genetic diagnosis and further underscores the importance of functional follow‐up studies.

In summary, the convergence of genetic and experimental evidence supports the association of the NDUFA9 variant c.962G>C (p.Arg321Pro) with Leigh syndrome. Despite being based on a single proband, the decisive biochemical complementation studies and the clear autosomal recessive inheritance pattern provide clinically actionable insights. Key take‑home: Incorporating both comprehensive genetic analysis and functional validation is essential for accurate diagnosis and management of mitochondrial disorders such as Leigh syndrome.

References

• Journal of Medical Genetics • 2012 • Defective NDUFA9 as a novel cause of neonatally fatal complex I disease PMID:22114105
• Clinical Genetics • 2018 • NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect PMID:28671271

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