Leucocytes Mutation load Declines with Age in Carriers of the m.3243A>G Mutation. A 10-year Prospective Cohort

Carriers of the mitochondrial mutation m.3243A>G presents highly variable phenotypes including mitochondrial encephalomyopaty, lactoacidosis and stroke-like episodes (MELAS). We conducted a follow-up study to evaluate changes in leucocyte heteroplasmy and the clinical phenotypes in m.3243A>G carriers. Leucocyte heteroplasmy was determined by next generation sequencing covered by 100.000 X reads in 32 individuals with a median follow-up of 10.2 years. Ten-year clinical follow-up is reported on 46 individuals. The annual leucocyte mutation level declined by -0.7 (± 0.4) percentage points/year (p<0.0001), and correlated with the level of the initial sample (ρ =-0.92, p<0.0001). Eleven of 46 m.3243A>G carriers died, and clinical symptoms progressed. This longitudinal study demonstrates the decline in leucocyte m.3243A>G heteroplasmy associates with the level of the initial sample. Further, there was a high mortality among carriers.