MELAS AND MERRF - THE RELATIONSHIP BETWEEN MATERNAL MUTATION LOAD ANDTHE FREQUENCY OF CLINICALLY AFFECTED OFFSPRING

The majority of pathogenic mitochondrial DNA (mtDNA) mutations are het eroplasmic, with both mutant and wildtype alleles present within the s ame individual. MtDNA is transmitted only from females to their offspr ing but a single female can bear offspring who harbour different level s of mutant mtDNA and have a variable phenotype, In single families, t his complex genetic and phenotypic variability has confounded the iden tification of any relationship between the level of mutant mtDNA (muta tion load) in the mother and the clinical features of her offspring. T o obtain a more accurate description of the inheritance of pathogenic mtDNA mutations, we studied a large number of pedigrees that carried e ither the mitochondrial encephalomyopathy with lactic acidosis and str oke-like episodes (A3243G MELAS) or the myoclonic epilepsy with ragged -red fibres (A8344G MERRF) mutations. We made two principal observatio ns. First, for both mutations, higher levels of mutant mtDNA in the mo thers' blood were associated with an increased frequency of affected o ffspring. Secondly, at any one level of maternal mutation load there w as a greater frequency of affected offspring for the A3243G MELAS muta tion than for the A8344G MERRF mutation. Although these results should not be used to give absolute risks to a female contemplating pregnanc y, 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 of fspring may differ between different mtDNA mutations.