NDUFAF5 – Leigh syndrome

NDUFAF5 is strongly associated with Leigh syndrome, a severe neurodegenerative disorder characterized by progressive developmental regression, seizures, and respiratory failure. Multiple independent studies have reported biallelic mutations in this gene in patients with early‐onset mitochondrial dysfunction. In families with consanguineous relationships as well as in compound heterozygous cases, the pattern of inheritance has consistently been autosomal recessive (PMID:19542079). The collective evidence from case reports and multi‐patient studies underscores the clinical relevance of NDUFAF5 and its role in mitochondrial complex I assembly defects. Several independent reports have assessed both the clinical and molecular characteristics, confirming that disruption of NDUFAF5 function results in a phenotype diagnostic for Leigh syndrome. These observations support the integration of genetic testing of NDUFAF5 into the diagnostic workup for patients presenting with hallmark symptoms of Leigh syndrome.

Detailed genetic analyses have identified a diverse variant spectrum in NDUFAF5, including missense, frameshift, and splicing mutations. Notably, the variant c.611C>T (p.Ala204Val) has been reported among compound heterozygous cases and is consistent with pathogenicity. Segregation studies in multiple families have shown that affected individuals consistently harbor biallelic mutations, while unaffected carriers are heterozygous (PMID:34964562). This genetic evidence, supported by recurrence in ethnically diverse populations and the use of in silico prediction tools, has reinforced the causative role of NDUFAF5 variants in Leigh syndrome. In addition, detailed molecular evaluation confirms the autosomal recessive mode of inheritance common to these cases.

Functional studies provide compelling evidence for the pathogenic mechanism underlying NDUFAF5-associated Leigh syndrome. Experimental assays, including patient-derived fibroblast analyses, have demonstrated that mutations in NDUFAF5 impair the assembly and stability of mitochondrial complex I, leading to decreased oxidative phosphorylation capacity. These in vitro findings are supported by in vivo animal models that recapitulate key aspects of the human phenotype, such as altered energy metabolism and neurodegeneration (PMID:30473481). The abnormal complex I assembly observed in functional studies aligns with the clinical presentation characterized by lactic acidosis and neurodegenerative symptoms. This experimental concordance establishes a direct mechanistic link between the genetic variants and the Leigh syndrome phenotype.

While the heterogeneity observed in variant effects and clinical presentation suggests that additional modifying factors may influence phenotypic severity, there is no significant conflicting evidence to refute the association between NDUFAF5 and Leigh syndrome. The aggregate data from genetic and functional studies has led to a consensus that NDUFAF5 mutations result in mitochondrial complex I deficiency. The clinical features, ranging from early infant death to later onset dystonia, underscore the variable expressivity but do not detract from the central role of NDUFAF5 in disease causation. This reinforces the importance of considering NDUFAF5 analysis in patients with suspected mitochondrial disorders.

Collectively, the genetic and functional evidence for NDUFAF5 underscores a strong gene-disease association with Leigh syndrome. The consistent autosomal recessive inheritance pattern, robust segregation data, and concordant experimental results support its use as a diagnostic marker in clinical settings. This integration of molecular and functional data not only aids in accurate diagnosis but also provides avenues for potential therapeutic interventions in mitochondrial disorders. Clinicians should incorporate NDUFAF5 testing as part of a comprehensive evaluation for patients exhibiting early signs of mitochondrial dysfunction.

Key Take‑home: NDUFAF5 variants represent a clinically actionable marker in Leigh syndrome, where integrated genetic and functional assessments enable precise diagnosis and inform management strategies.

References

• Journal of Medical Genetics • 2010 • Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome PMID:19542079
• Molecular Genetics & Genomic Medicine • 2022 • A Leigh syndrome caused by compound heterozygous mutations on NDUFAF5 induce early infant death: A case report PMID:34964562
• Molecular Genetics and Metabolism • 2019 • Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes PMID:30473481

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