The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management

J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):936-8. doi: 10.1136/jnnp-2012-303528. Epub 2013 Jan 25.


Background: Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes.

Methods: We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK.

Results: 10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic.

Conclusion: Following this study we propose guidelines for screening and for the management of confirmed cases.

Keywords: Clinical Neurology; Diabetes Mellitus; Epidemiology; Epilepsy; Mitochondrial Disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cardiomyopathies / epidemiology
  • Cardiomyopathies / etiology
  • Cardiomyopathies / genetics
  • Child
  • Child, Preschool
  • Cohort Studies
  • Diabetes Complications / epidemiology
  • Diabetes Complications / genetics
  • Diabetes Mellitus / epidemiology
  • Diabetes Mellitus / genetics
  • Female
  • Hearing Loss, Sensorineural / epidemiology
  • Hearing Loss, Sensorineural / etiology
  • Humans
  • Infant
  • MELAS Syndrome / epidemiology
  • MELAS Syndrome / genetics
  • Male
  • Middle Aged
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / therapy
  • Mitochondrial Encephalomyopathies / epidemiology
  • Mitochondrial Encephalomyopathies / etiology
  • Mitochondrial Encephalomyopathies / genetics
  • Mutation / genetics*
  • United Kingdom / epidemiology
  • Young Adult

Supplementary concepts

  • Mitochondrial encephalopathy