MOLECULAR PATHOLOGY OF MELAS AND MERRF - THE RELATIONSHIP BETWEEN MUTATION LOAD AND CLINICAL PHENOTYPES

Many patients with inherited mitochondrial encephalopathies have one o f two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A83 44G. Individuals who harbour these mutations carry both mutant and wil d-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondr ial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the le vel of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studi ed the relationship between the incidence of specific clinical feature s and the level of mutant mtDNA in blood (for A3243G, n = 73; for A834 4G, n = 25) and/or skeletal muscle (for A3234G, n = III; for A8344G, n = 55). Within this study group, the frequency of key clinical feature s was significantly different for individuals harbouring the A3243G an d A8344G mutations. For both mutations, there was a correlation betwee n the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtD NA in blood. Therefore, measurement of the level of the A3243G and A83 44G mutations in muscle will allow the identification of individuals w ho are at risk of developing specific complications, thus improving th e prognostic advice that can be given to patients and family members w ho carry these mutations.