Melas within a family: mitochondrial DNA heteroplasmy and clinical varability

Mitochondrial encephalopathy, lactic acidosis, and stroke like episodes (MELAS) is a multi-system disorder caused by a mutation in the mitochondrial genome. Genetic counseling and prognosis in patients with MELAS, in pattern with other mitochondrial disorders, is challenging due to highly variable presentation of penetrance, organ systems involved, severity of symptoms, and age of onset. One source of variability is the existence of heteroplasmy; this is the co-occurrence of wild-type and mutant DNA within an individual's cells. Heteroplasmy levels can differ both between individuals and between different tissue types in the same individual. This research evaluated whether there was a correlation between mutation load, as measured in urine sediment cells, and clinical manifestations in an extended family with the mtA3243G MELAS mutation. This study examined 23 maternal relatives of a patient diagnosed with MELAS for the presence of clinical symptoms, physical findings and degree of heteroplasmy in urine sediment cells. A significant correlation was found between age and number of MELAS-associated symptoms, as well as age and number of physical findings. In contrast to a number of reported studies, no significant correlation was found between levels of mutation load measured in urine and the number of symptoms or physical findings. This research concluded that urine sediment cell heteroplasmy analysis is not a uniformly effective test to predict clinical phenotype in individuals or small sample sizes that carry the mtA3243G mutation.