MT-ND1 – MELAS Syndrome

Mitochondrial NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) encodes a critical component of respiratory chain complex I. Pathogenic variants in MT-ND1 have been implicated in several mitochondrial disorders, including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. MELAS is clinically defined by encephalopathy, stroke-like episodes, lactic acidosis, and mitochondrial myopathy, often with maternal inheritance.

Genetic evidence for MT-ND1 in MELAS includes four unrelated probands harboring distinct MT-ND1 variants. Two novel missense changes, m.3959G>A and m.3995A>G, were each identified in separate individuals with MELAS features and confirmed by decreased complex I enzyme activity and ragged-red fibers in muscle ([PMID:23834081]). A de novo frameshift variant m.3571_3572insC was reported in a classic MELAS case with severe complex I deficiency in muscle and fibroblasts ([PMID:36717040]). Additionally, a heteroplasmic point mutation m.3376G>A (c.3376G>A (p.Arg195Gln)) was found in a patient exhibiting both LHON and MELAS overlap syndrome, with isolated complex I deficiency on biochemical testing ([PMID:15657614]). Together these represent four probands with three distinct MT-ND1 alleles and MELAS-like presentations.

No robust segregation data are available beyond index cases, and familial transmission was only documented for the m.3376G>A variant in maternal relatives. Consequently, the number of affected relatives with confirmed MT-ND1 variants remains zero in published reports.

Variant classes include two missense substitutions (c.3376G>A (p.Arg195Gln), m.3959G>A, m.3995A>G) and one frameshift insertion (m.3571_3572insC). All variants are heteroplasmic, with varying tissue loads, and none represents a recurrent founder allele. Phenotypes overlap core MELAS features: encephalopathy (HP:0001298), stroke-like episodes (HP:0002401), lactic acidosis (HP:0003128), and mitochondrial myopathy (HP:0003737).

Functional assays across multiple studies demonstrate concordant complex I impairment. Missense variants m.3959G>A and m.3995A>G reduce complex I activity and mitochondrial respiratory capacity in patient muscle biopsies. The m.3571_3572insC frameshift causes loss of complex I assembly and diminished oxygen consumption rate in fibroblast clones. The p.Arg195Gln substitution (m.3376G>A) likewise destabilizes complex I, leading to isolated enzyme deficiency in muscle.

No conflicting evidence has been reported that refutes the role of MT-ND1 variants in MELAS. Negative functional studies of other MT-ND1 polymorphisms (e.g., T3394C) in psychiatric cohorts have not been linked to MELAS phenotypes.

Integration of genetic and experimental data supports a moderate clinical validity for MT-ND1–related MELAS. Multiple independent variants show coherent phenotypic overlap and mechanistic concordance with complex I dysfunction. Additional family studies and replication in larger cohorts would further strengthen this association. Key take-home: MT-ND1 sequencing should be considered in patients with MELAS features and negative MT-TL1 testing, as pathogenic MT-ND1 variants result in complex I deficiency amenable to biochemical and genetic confirmation.

References

• Gene • 2023 • De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome PMID:36717040
• Mitochondrial DNA • 2014 • Novel mutations m.3959G>A and m.3995A>G in mitochondrial gene MT-ND1 associated with MELAS PMID:23834081
• European journal of human genetics • 2005 • LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation PMID:15657614

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