COMPARISON OF THE RELATIVE LEVELS OF THE 3243 (A-]G) MTDNA MUTATION IN HETEROPLASMIC ADULT AND FETAL TISSUES

In this report, levels of the 3243 A to G mtDNA mutation associated wi th the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome were measured in different heteroplasmic tis sues of subjects in a kindred including adults with variable clinical phenotypes and a fetus. The relative proportions of mutant mtDNA varie d widely (0.03 to 0.67) between identical tissues of the six different subjects and between different tissues of the same subjects. In the o ne adult for whom sufficient data were available there was an apparent correlation between the distribution of mutant mtDNA and clinical pre sentation. A woman without neurological symptoms who died prematurely with a cardiomyopathy and lactic acidosis had higher proportions of mu tant in heart (0.49, SD 0.02), skeletal muscle (0.56, SD 0.01), and li ver (0.55, SD 0.12) than in other tissues studied (for example, kidney , 0.03, SD 0.01). A strikingly different result was found in a 24 week old fetus in whom there was little variation in heteroplasmy in diffe rent tissues (average proportion of mutant mtDNA in six tissues, 0.53, SD 0.02). These observations add cardiomyopathy to the growing list o f presenting features of the 3243 mtDNA mutation. The unique results f rom the fetus suggest also that selection pressures acting on either w ild type or 3243 mutant mtDNA (rather than variation from replicative segregation of the heteroplasmic mtDNA) may be responsible primarily f or the variable levels of 3243 mutant mtDNA in different heteroplasmic tissues of adults.