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MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring

Lookup NU author(s): Professor Patrick Chinnery, Professor Robert Lightowlers, Emeritus Professor Doug Turnbull


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The majority of pathogenic mitochondrial DNA (mtDNA) mutations are heteroplasmic, with both mutant and wild-type alleles present within the same individual. MtDNA is transmitted only from females to their offspring but a single female can bear offspring who harbour different levels of mutant mtDNA and have a variable phenotype. In single families, this complex genetic and phenotypic variability has confounded the identification of any relationship between the level of mutant mtDNA (mutation load) in the mother and the clinical features of her offspring. To obtain a more accurate description of the inheritance of pathogenic mtDNA mutations, we studied a large number of pedigrees that carried either the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (A3243G MELAS) or the myoclonic epilepsy with ragged-red fibres (A8344G MERRF) mutations. We made two principal observations. First, for both mutations, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Secondly, at any one level of maternal mutation load there was a greater frequency of affected offspring for the A3243G MELAS mutation than for the A8344G MERRF mutation. Although these results should not be used to give absolute risks to a female contemplating pregnancy, they suggest that the outcome of pregnancy is related to the level of mutant mtDNA in the mother and that the risks of having affected offspring may differ between different mtDNA mutations.

Publication metadata

Author(s): Chinnery PF, Howell N, Lightowlers RN, Turnbull DM

Publication type: Article

Publication status: Published

Journal: Brain

Year: 1998

Volume: 121

Issue: 10

Pages: 1889-1894

Print publication date: 01/01/1998

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/121.10.1889

PubMed id: 9798744


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Funder referenceFunder name
Wellcome Trust