Phenotypic Heterogeneity of the Mitochondrial DNA Variant m.13513 G > A

Abstract

The mitochondrial DNA (mtDNA) variant m.13513G > A is increasingly recognized as a cause of syndromic and nonsyndromic mitochondrial disorders (MIDs). This minireview aims a summarizing and discussing recent and previous findings about the phenotypic heterogeneity of this variant. A systematic literature review using the databases PubMed and Google Scholar by application of specific search terms was performed. As per the end of July 2021, at least 50 patients carrying the mtDNA variant m.13513G > A have been reported. Age ranged between 0 and 63 years, and of these patients, 28 were male and 22 were female. The phenotype was highly variable. The most common phenotypes were Leigh syndrome (LS; n = 25), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS; n = 11), Leigh-like syndrome (n = 4), MELAS/LS (n = 3), progressive external ophthalmoplegia (n = 3), MELAS/Leber's hereditary optic neuropathy (LHON; n = 1), and LHON (n = 1). More rarely are nonsyndromic phenotypes. Heteroplasmy rates were highly variable ranging from 0 to 86% depending on the investigated tissue. The outcome was reported in only a few cases but was worse in patients with LS compared with those with MELAS. The variant m.13513G > A is responsible for syndromic or nonsyndromic MIDs. Syndromic MIDs in which this variant should be particularly considered include LS, MELAS, and LHON and their overlaps. Patients with suspected MID and maternal inheritance should undergo sequencing of the entire mtDNA not to miss rare mtDNA variants.

Keywords

mtDNA - Leigh's syndrome - MELAS - heteroplasmy - m.13513G > A

Author's Contribution

Study design, literature search, discussion, first draft, critical comments, and final approval were done by J.F., the author himself.

Ethical Approval

The statement was in accordance if ethical guidelines. The study was approved by the Institutional Review Board.

Informed Consent

Informed consent was obtained.

Publication History

Received: 11 September 2021

Accepted: 24 November 2021

Article published online:
27 April 2023

• References

• 1 Rahman S. Mitochondrial disease in children. J Intern Med 2020; 287 (06) 609-633
• 2 Van Karnebeek CD, Waters PJ, Sargent MA. et al. Expanding the clinical phenotype of the mitochondrial m.13513G>A mutation with the first report of a fatal neonatal presentation. Dev Med Child Neurol 2011; 53 (06) 565-568
• 3 Santorelli FM, Tanji K, Kulikova R. et al. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun 1997; 238 (02) 326-328
• 4 Wei Y, Huang Y, Yang Y, Qian M. MELAS/LS overlap syndrome associated with mitochondrial DNA mutations: clinical, genetic, and radiological studies. Front Neurol 2021; 12: 648740
• 5 Yahata N, Matsumoto Y, Omi M, Yamamoto N, Hata R. TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G>A mutation. Sci Rep 2017; 7 (01) 15557
• 6 Liang JM, Xin CJ, Wang GL, Wu XM. Case report: m.13513 G>A mutation in a Chinese patient with both Leigh syndrome and Wolff-Parkinson-White syndrome. Front Pediatr 2021; 9: 700898
• 7 Vázquez-Justes D, Carreño-Gago L, García-Arumi E. et al. Mitochondrial m.13513G>A point mutation in ND5 in a 16-year-old man with Leber hereditary optic neuropathy detected by next-generation sequencing. J Pediatr Genet 2019; 8 (04) 231-234
• 8 Jimenez-Legido M, Bernardino-Cuesta B, Lopez-Marin L. et al. Two new cases of Leigh syndrome caused by mutation m.13513G> A in the MTND5 gene [in Spanish]. Rev Neurol 2019; 68 (07) 312-314
• 9 Hsieh YT, Yang MT, Peng YJ, Hsu WC. Central retinal vein occlusion as the initial manifestation of LHON/MELAS overlap syndrome with mitochondrial DNA G13513A mutation–case report and literature review. Ophthalmic Genet 2011; 32 (01) 31-38
• 10 Wang Z, Qi XK, Yao S. et al. Phenotypic patterns of MELAS/LS overlap syndrome associated with m.13513G>A mutation, and neuropathological findings in one autopsy case. Neuropathology 2010; 30 (06) 606-614
• 11 Wang SB, Weng WC, Lee NC, Hwu WL, Fan PC, Lee WT. Mutation of mitochondrial DNA G13513A presenting with Leigh syndrome, Wolff-Parkinson-White syndrome and cardiomyopathy. Pediatr Neonatol 2008; 49 (04) 145-149
• 12 Ruiter EM, Siers MH, van den Elzen C. et al. The mitochondrial 13513G > A mutation is most frequent in Leigh syndrome combined with reduced complex I activity, optic atrophy and/or Wolff-Parkinson-White. Eur J Hum Genet 2007; 15 (02) 155-161
• 13 Shanske S, Coku J, Lu J. et al. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. Arch Neurol 2008; 65 (03) 368-372
• 14 Dickerson BC, Holtzman D, Grant PE, Tian D. Case records of the Massachusetts General Hospital. Case 36-2005. A 61-year-old woman with seizure, disturbed gait, and altered mental status. N Engl J Med 2005; 353 (21) 2271-2280
• 15 Sudo A, Honzawa S, Nonaka I, Goto YI. Leigh syndrome caused by mitochondrial DNA G13513A mutation: frequency and clinical features in Japan. J Hum Genet 2004; 49 (02) 92-96
• 16 Chol M, Lebon S, Bénit P. et al. 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. J Med Genet 2003; 40 (03) 188-191
• 17 Kirby DM, Boneh A, Chow CW. et al. Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. Ann Neurol 2003; 54 (04) 473-478
• 18 Petruzzella V, Di Giacinto G, Scacco S. et al. Atypical Leigh syndrome associated with the D393N mutation in the mitochondrial ND5 subunit. Neurology 2003; 61 (07) 1017-1018
• 19 Corona P, Antozzi C, Carrara F. et al. A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol 2001; 49 (01) 106-110
• 20 Pénisson-Besnier I, Reynier P, Asfar P. et al. Recurrent brain hematomas in MELAS associated with an ND5 gene mitochondrial mutation. Neurology 2000; 55 (02) 317-318
• 21 Pulkes T, Eunson L, Patterson V. et al. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann Neurol 1999; 46 (06) 916-919 Erratum in: Ann Neurol 2000 Jun;47(6):841