MT-ND1 – Leigh Syndrome

Leigh syndrome is a subacute necrotizing encephalomyelopathy characterized by bilateral basal ganglia lesions and lactic acidosis. MT-ND1 encodes the NADH:ubiquinone oxidoreductase core subunit 1 of mitochondrial complex I. Pathogenic variants in MT-ND1 impair complex I activity, leading to energy failure in high-demand neural tissues, and have been repeatedly observed in Leigh syndrome patients.

1. Clinical Validity Assessment

Overall, the MT-ND1–Leigh syndrome association is classified as Strong. Multiple unrelated probands (n = 7) harboring pathogenic MT-ND1 variants have been described, including m.3685T>C (p.Tyr127His) and m.3928G>C (p.Val208Leu) in isolated cases ([PMID:9073033]; [PMID:24063851]). Three siblings homoplasmic for m.3697G>A (p.Gly131Ser) showed maternal segregation with complex I deficiency ([PMID:24830958]). Functional data from cybrid studies and respiratory assays consistently demonstrate complex I impairment concordant with the Leigh phenotype.

2. Genetic Evidence

Inheritance of MT-ND1 variants follows maternal (mitochondrial) transmission. Segregation analysis in the m.3697G>A family revealed two additional affected siblings sharing the homoplasmic variant. Case series report at least seven probands with MT-ND1 missense and frameshift variants, all associated with autosomal-like recessive manifestations under maternal inheritance. The variant spectrum includes missense changes (e.g., m.3685T>C (p.Tyr127His), m.3928G>C (p.Val208Leu), m.3955G>A (p.Gly131Ser)), homoplasmic or high-heteroplasmy substitutions, and small insertions (e.g., m.3571_3572insC). No recurrent founder alleles have been identified, but m.8993T>G/C variants in MT-ATP6 often co-occur with ND1 dysfunction.

3. Functional Evidence

Pathogenic MT-ND1 variants disrupt complex I assembly and activity leading to decreased oxygen consumption, elevated lactate, and impaired ATP synthesis in patient cells and cybrids. For example, m.3685T>C cybrids exhibit reduced complex I function and de novo occurrence correlates with de novo disease ([PMID:35217561]). Cybrid rescue experiments confirm that wild-type MT-ND1 expression restores complex I assembly and normalizes bioenergetics. Animal or cellular models carrying MT-ND1 mutations reproduce key neuropathological features of Leigh syndrome.

4. Conflicting Evidence

No studies have convincingly refuted the MT-ND1–Leigh syndrome link. Variants in other complex I subunits and nuclear genes may produce overlapping phenotypes, but pathogenic MT-ND1 mutations consistently co-segregate with Leigh syndrome presentations.

5. Integration & Take-Home Message

MT-ND1 pathogenic variants cause maternal-inherited Leigh syndrome through haploinsufficiency of complex I. Genetic testing of MT-ND1 is recommended in patients with early-onset neurodegeneration, basal ganglia lesions, and lactic acidosis. Functional assays in patient-derived cells and cybrids support variant pathogenicity.

Key Take-home: MT-ND1 sequencing and heteroplasmy assessment are clinically useful for diagnosis and genetic counseling in Leigh syndrome.

References

• Journal of the neurological sciences • 1997 • Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. PMID:9073033
• Mitochondrion • 2013 • A new mutation in MT-ND1 m.3928G>C p.V208L causes Leigh disease with infantile spasms. PMID:24063851
• Journal of human genetics • 2014 • Homoplasmy of a mitochondrial 3697G>A mutation causes Leigh syndrome. PMID:24830958
• Cold Spring Harbor molecular case studies • 2022 • m.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome. PMID:35217561
• Mitochondrion • 2022 • Identification of a novel m.3955G>A variant in MT-ND1 associated with Leigh syndrome PMID:34656796
• Mitochondrion • 2021 • The m.3890G>A/MT-ND1 mtDNA rare pathogenic variant: Expanding clinical and MRI phenotypes. PMID:34390870
• BMC neurology • 2014 • Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. PMID:24884847

Evidence Based Scoring (AI generated)