Muscle phenotype and mutation load in 51 persons with the 3243A>G mitochondrial DNA mutation.

BACKGROUND Mitochondrial disorders are generally not associated with a clear phenotype-genotype relationship, which complicates the understanding of the disease and genetic counseling. OBJECTIVE To investigate the relationship between the muscle and blood mitochondrial DNA mutation load and phenotype. DESIGN Survey. SETTING The Neuromuscular Research Unit, Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS Fifty-one persons with the 3243A>G point mutation of mitochondrial DNA, and 20 healthy control subjects. METHODS We recorded the maximal oxygen uptake (Vo(2)max), maximal workload, resting and peak-exercise plasma lactate levels, muscle and blood mutation load, muscle morphology, and presence of diabetes mellitus and hearing impairment in all subjects. RESULTS Muscle mutation load (mean +/- SE, 50% +/- 5%; range, 2%-95%) correlated with Vo(2)max and resting plasma lactate level (P<.001; R>/=0.64). All persons except 5 with a muscle mutation load above 50% had abnormal Vo(2)max and morphology on muscle biopsy findings. Persons with hearing impairment and diabetes mellitus had a muscle mutation load above 65%. The mutation load in blood (mean +/- SE, 18% +/- 3%; range, 0%-61%) did not correlate with Vo(2)max, resting plasma lactate levels, or presence of hearing impairment or diabetes mellitus. CONCLUSIONS This study demonstrates a close relationship between the muscle mutation load and phenotype in persons carrying the 3243A>G mutation. The lack of correlation between the mutation load in blood and symptoms from other tissues emphasizes the importance of assessing phenotype-genotype correlations in the same tissue in mitochondrial disease. The results indicate that the threshold of muscle mutation load at which oxidative impairment occurs can be as low as 50%, which is as much as 40% lower than that suggested by in vitro studies.