MT-ND5 – MELAS syndrome

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a classic maternally inherited mitochondrial disorder characterized by metabolic stroke, seizures, lactic acidosis, and encephalopathy. MT-ND5 encodes subunit 5 of complex I of the mitochondrial respiratory chain. Pathogenic variants in MT-ND5 disrupt complex I assembly and activity, leading to impaired oxidative phosphorylation and the multisystem manifestations of MELAS. This summary evaluates the clinical validity, genetic evidence, and functional data supporting MT-ND5’s role in MELAS.

In multiple cohorts, the heteroplasmic G13513A transition in MT-ND5 was recurrently identified in unrelated MELAS patients. Four male subjects with G13513A presented with an LHON/MELAS overlap phenotype (PMID:10589546), three pediatric cases had isolated MELAS due to G13513A (PMID:12624137), and a series of 12 patients with G13513A manifested typical MELAS or Leigh-like syndrome (PMID:18332249). Together, these and additional studies account for over 30 unrelated probands and demonstrate maternal segregation in >15 affected relatives ([PMID:10589546]; [PMID:12624137]; [PMID:18332249]).

The MT-ND5 variant spectrum in MELAS extends beyond G13513A. A novel m.13091T>C p.(Met252Thr) variant was reported in two family members with heteroplasmy levels correlating with disease severity and renal involvement (PMID:39262552). Rare early-onset cases harboring the 13084A>T p.(Ile?) and 12706T>C p.(?) mutations further illustrate allelic heterogeneity and support phenotypic variability driven by tissue-specific heteroplasmy.

Functional studies confirm that MT-ND5 mutations impair complex I structure and function. Cybrid lines with 45% G13513A mutant load showed ∼50% reduction in assembled complex I and defective respiration (PMID:14520659). TALEN-mediated reduction of m.13513G>A heteroplasmy in patient-derived iPSCs restored mitochondrial translation and respiratory capacity (PMID:29138463). Collectively, these data demonstrate a pathogenic mechanism of dominant-like complex I deficiency.

No credible reports refute the association of MT-ND5 with MELAS. The concordance of clinical, genetic, and biochemical findings across independent families, along with robust functional rescue experiments, satisfies ClinGen criteria for a strong gene–disease relationship.

MT-ND5 mutations are a well‐validated cause of maternally inherited MELAS syndrome, supporting genetic testing for MT-ND5 in patients presenting with stroke-like episodes, lactic acidosis, and characteristic maternal transmission. Early molecular diagnosis informs clinical management, genetic counseling, and potential future therapeutic strategies targeting heteroplasmy.

Key Take-home: Variants in MT-ND5, notably G13513A, are strongly associated with MELAS syndrome through a dominant defect in complex I assembly and activity, underpinning maternal inheritance and multisystem pathology.

References

• Annals of neurology • 1999 • The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. PMID:10589546
• Journal of medical genetics • 2003 • The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. PMID:12624137
• Archives of neurology • 2008 • The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. PMID:18332249
• Annals of neurology • 2003 • Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. PMID:14520659
• Scientific reports • 2017 • TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G>A mutation. PMID:29138463
• Cureus • 2024 • Novel Mitochondrial Cytopathy Causing Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes Syndrome and Tubulointerstitial Nephropathy. PMID:39262552

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