Neurological manifestations in adult patients with the m.3243A>G variant in mitochondrial DNA.

abstractBackground: The m.3243A>G variant in mitochondrial DNA (mtDNA) is the most common cause of the MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome usually commencing in childhood or adolescence. In adults, the variant presents with versatile and mostly neurological phenotypes, but MELAS may not be common. Objective: To examine the frequency of phenotypes in adults with m.3243A>G in a population-based cohort and in a meta-analysis of reported case series. Methods: We clinically examined 51 adult patients with m.3243A>G to determine the frequency of phenotypes and to analyse the contribution of variant heteroplasmy, age, sex and mtDNA haplogroup to the phenotypes. The frequencies of neurological features were also assessed in a meta-analysis on 25 published case series reporting 1314 patients. Results: Sensorineural hearing impairment (HI), cognitive impairment and myopathy were the most common manifestations, whereas stroke-like episodes were infrequent. Variant heteroplasmy and age were only modest predictors of the phenotypes, although heteroplasmy correlated significantly with disability and Kaplan-Meier analysis showed progression of phenotypes with age. Male sex predicted more severe disability, whereas haplogroup UK was associated with no significant disability. Meta-analysis revealed substantial heterogeneity of phenotype frequencies and preferential inclusion of the MELAS phenotype. Discussion: In adult patients with m.3243A>G sensorineural HI, cognitive impairment and myopathy are common manifestations with lifetime prevalences approaching unity. Stroke-like episodes are rare. Variant heteroplasmy, age, sex and mtDNA haplogroup contribute to the severity of the disease. Meta-analysis provided a solid estimate of the various neurological symptoms in adults with m.3243A>G.