The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?

J Neurol. 2014 Mar;261(3):504-10. doi: 10.1007/s00415-013-7225-3. Epub 2013 Dec 29.


The m.3243A>G "MELAS" (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study ("Nation-wide Italian Collaborative Network of Mitochondrial Diseases"). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. "MIDD" (maternally-inherited diabetes and deafness) and "PEO" (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The "MELAS" acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • DNA, Mitochondrial / genetics
  • Databases, Genetic
  • Female
  • Genotype*
  • Heterozygote
  • Humans
  • Infant
  • Italy
  • MELAS Syndrome / genetics
  • MELAS Syndrome / physiopathology*
  • Male
  • Middle Aged
  • Mitochondrial Encephalomyopathies / classification
  • Mitochondrial Encephalomyopathies / genetics
  • Mitochondrial Encephalomyopathies / physiopathology*
  • Mutation / genetics
  • Phenotype*
  • Retrospective Studies
  • Sex Factors
  • Young Adult


  • DNA, Mitochondrial