Mitochondrial disorders pose a major diagnostic challenge to clinicians given their significant phenotypic and genetic diversity. This dilemma is underpinned by the dual genomic expression of mitochondrial proteins, which are encoded by both nuclear and mitochondrial genetic material. Mitochondrial DNA (mtDNA)–related disease is further complicated by polyploidy, with hundreds to thousands of mtDNA molecules per cell. Consequently, patients with mtDNA mutations frequently harbor 2 discrete mtDNA populations (so-called mutant and wild type) at variable ratios, a biological phenomenon termed heteroplasmy. The proportion of mutant to wild-type mtDNA and tissue distribution often varies considerably among patients harboring identical mtDNA mutations. Furthermore, the biochemical threshold necessary for a disease to manifest can fluctuate depending on the mtDNA mutation and the energy requirements of the target organ. For instance, skeletal muscle, brain, heart, and neural tissue are all critically dependent on adenosine triphosphate produced by mitochondria and therefore have a low threshold to cellular bioenergetic failure as a consequence of mitochondrial dysfunction. Overall, these factors, in addition to numerous environmental and epigenetic modulators, coalesce to determine the severity and phenotypic spectrum of the disease.
Pitceathly RDS. Mitochondrial Extrapyramidal SyndromesUsing Age and Phenomenology to Guide Genetic Testing. JAMA Neurol. 2016;73(6):630-632. doi:10.1001/jamaneurol.2016.0756