NDUFA12 – Leigh syndrome

NDUFA12, an accessory subunit of mitochondrial complex I, has been robustly linked to Leigh syndrome, a progressive neurodegenerative disorder. Multiple independent case studies have identified homozygous loss‑of‑function mutations in NDUFA12 in patients presenting with hallmark features of Leigh syndrome, including basal ganglia lesions and motor regression (PMID:21617257).

Genetic evidence from consanguineous families reveals recurrent variants, notably a homozygous c.178C>T (p.Arg60Ter) mutation, which has been identified in several unrelated probands (PMID:21617257; PMID:32341820). Additional loss‑of‑function and splice site mutations further support the role of NDUFA12 in the pathogenesis of Leigh syndrome (PMID:33715266).

Studies employing next‑generation sequencing and Sanger confirmation have demonstrated that these variants segregate with the disease phenotype in affected families, reinforcing a strong genetic association. The mutation spectrum includes frameshift and nonsense changes that predict premature termination, consistent with the reported clinical severity (PMID:33715266).

The overall assessment of the gene‑disease relationship is rated as strong based on the demonstration of multiple independent probands carrying pathogenic variants, segregation data from several families, and concordant experimental data from functional assays (PMID:21617257; PMID:32341820).

Functional studies have revealed that NDUFA12 deficiency leads to an absence of its protein product in patient fibroblasts, resulting in impaired assembly and reduced activity of respiratory chain complex I. Complementation assays have confirmed that re‐introduction of NDUFA12 can partially restore complex I activity, directly linking the molecular defect to pathogenic mitochondrial dysfunction (PMID:21617257).

The integration of the genetic data with experimental observations highlights a pathogenic mechanism that likely involves haploinsufficiency, ultimately compromising complex I stability. Clinical presentations in affected individuals include hypotonia, dystonia, and seizures, all of which are consistent with the neurodegenerative manifestations of Leigh syndrome (PMID:39819107; PMID:24731534).

Key take‑home: The strong and multifaceted evidence linking NDUFA12 loss‑of‑function mutations to Leigh syndrome underlines its clinical utility in guiding diagnostic decision‑making and therapeutic strategies for affected patients.

References

• Journal of medical genetics • 2011 • Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome PMID:21617257
• Journal of pediatric genetics • 2020 • Term Neonate Presenting with the Combined Occurrence of Mucolipidosis Type II and Leigh Syndrome PMID:32341820
• Journal of child neurology • 2025 • When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder PMID:39819107
• Human mutation • 2021 • Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation PMID:33715266
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534

Evidence Based Scoring (AI generated)