Mitochondrial diseases, caused by mutations in either the nuclear or mitochondrial genomes (mtDNA), are the most common form of inherited neurometabolic disorders. They are remarkably heterogeneous, both in their clinical presentation and genetic etiology, presenting challenges for diagnosis, clinical management and elucidation of molecular mechanism. The multifaceted nature of these diseases, compounded by the unique characteristics of mitochondrial genetics, cement their space in the field of complex disease. In this review we examine the m.3243A>G variant, one of the most prevalent mitochondrial DNA mutations, using it as an exemplar to demonstrate the challenges presented by these complex disorders. Disease caused by m.3243A>G is one of the most phenotypically diverse of all mitochondrial diseases; we outline known causes of this heterogeneity including mtDNA heteroplasmy, mtDNA copy number and nuclear genetic factors. We consider the impact that this has in the clinic, discussing the personalized management of common manifestations attributed to this pathogenic mtDNA variant, including hearing impairment, diabetes mellitus, myopathy, cardiac disease, stroke-like episodes and gastrointestinal disturbances. Future research into this complex disorder must account for this heterogeneity, benefitting from the use of large patient cohorts to build upon current clinical expertise. Through multi-disciplinary collaboration, the complexities of this mitochondrial disease can be addressed with the variety of diagnostic, prognostic, and treatment approaches that are moulded to best fit the needs of each individual patient.
Keywords: Complex disease; Heterogeneity; MELAS; Mitochondrial disease; Precision medicine; m.3243A>G.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.