Mitochondrial DNA Mutations: An Overview of Clinical and Molecular Aspects

Mutations that arise in mitochondrial DNA (mtDNA) may be sporadic, maternally inherited, or Mendelian in character and include mtDNA rearrangements such as deletions, inversions or duplications, point mutations, or copy number depletion. Primary mtDNA mutations occur sporadically or exhibit maternal inheritance and arise due in large part to the high mutation rate of mtDNA. mtDNA mutations may also occur because of defects in the biogenesis or maintenance of mtDNA, reflecting the contribution of nuclear-encoded genes to these processes, and in this case exhibit Mendelian inheritance. Whether maternally inherited, sporadic, or Mendelian, mtDNA mutations can exhibit a complex and broad spectrum of disease manifestations due to the central role mitochondria play in a variety of cellular functions. In addition, because there exist hundreds to thousands of copies of mtDNA in each cell, the proportion of mutant mtDNA molecules can have a profound effect on the cellular and clinical phenotype. This chapter reviews the classification of mtDNA mutations and the clinical features that determine the diagnosis of a primary mtDNA disorder.