Brain, Vol 121, Issue 10 1889-1894, Copyright © 1998 by Oxford University Press
PF Chinnery, N Howell, RN Lightowlers and DM Turnbull
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.
ARTICLES
MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring
Department of Neurology, The University of Newcastle-upon-Tyne, UK.
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