MT-ND4 – Leigh syndrome

Leigh syndrome is a subacute necrotizing encephalomyelopathy characterized by psychomotor regression, lactic acidosis, and bilateral basal ganglia lesions. The mitochondrial gene MT-ND4 encodes the ND4 subunit of respiratory chain complex I, and pathogenic variants disrupt complex I function, leading to the characteristic neuropathology of Leigh syndrome. MT-ND4 mutations have been reported in multiple unrelated probands with Leigh syndrome, establishing a consistent genotype–phenotype correlation.

Genetic evidence for the MT-ND4–Leigh syndrome association includes seven unrelated cases across five studies. A novel homoplasmic T11984C (p.Tyr160His) variant was identified in a female infant with basal ganglionic lesions (PMID:17022785). A heteroplasmic C11777C>A (p.Arg340Ser) change was detected in one patient and confirmed in two additional unrelated individuals with classic Leigh pathology (PMID:20502985; PMID:16120329). The common LHON mutation G11778G>A (p.Arg340His) has also been associated with Leigh syndrome in two pediatric cases presenting acute neurologic decline (PMID:24062162; PMID:23864591). Finally, targeted sequencing revealed a novel m.11240C>T (p.Leu374Phe) variant in a patient whose cybrids showed reduced ATP‐linked respiration (PMID:27761019). Maternal inheritance and recurrence in independent matrilines support pathogenicity.

The variant spectrum includes both homoplasmic and heteroplasmic missense changes affecting conserved transmembrane regions of ND4. C11777C>A and G11778G>A affect the same Arg340 residue, underscoring a mutational hotspot. T11984C and m.11240C>T map to distinct helices of the proton‐pumping channel. Heteroplasmy levels correlate with age of onset and severity, and no benign population occurrence has been reported.

Functional assays demonstrate that p.Arg340Ser cybrids exhibit markedly decreased complex I activity compared with controls, consistent with severe energy deficiency in neuronal tissues (PMID:16120329). Similarly, m.11240C>T mutant cybrids show diminished ATP‐linked mitochondrial respiration, while complex I assembly remains intact, indicating a proton‐translocation defect (PMID:27761019).

Mechanistically, ND4 variants disrupt electron transfer and proton pumping, compromising ATP synthesis and leading to neurodegeneration in Leigh syndrome. Concordant genetic and biochemical data across multiple variants and assays provide a robust framework for clinical validity.

Key take-home: Pathogenic MT-ND4 variants are a significant cause of mitochondrial complex I–related Leigh syndrome and should be included in diagnostic gene panels to inform genetic counseling and guide therapeutic research.

References

• Acta neurologica Scandinavica • 2006 • Novel mitochondrial mutation in the ND4 gene associated with Leigh syndrome. PMID:17022785
• Mitochondrion • 2003 • A novel mtDNA C11777A mutation in Leigh syndrome. PMID:16120329
• Neuromolecular medicine • 2010 • Mitochondrial DNA 11777C>A mutation associated Leigh syndrome: case report with a review of the previously described pedigrees. PMID:20502985
• Journal of child neurology • 2014 • Uncommon Leber "plus" disease associated with mitochondrial mutation m.11778G>A in a premature child. PMID:23864591
• Neuromolecular medicine • 2014 • Novel mitochondrial C15620A variant may modulate the phenotype of mitochondrial G11778A mutation in a Chinese family with Leigh syndrome. PMID:24062162
• Journal of human genetics • 2017 • Novel mutation of ND4 gene identified by targeted next-generation sequencing in patient with Leigh syndrome. PMID:27761019

Evidence Based Scoring (AI generated)