Mitochondrial disorders

History, background and terminology Mitochondria, first described as “sarcosomes”in 1857, are essential intracellular organelles whose main functions involve cellular respiration through the oxidative phosphorylation pathway, fatty acid oxidation, the Krebs cycle, pyruvate oxidation, and amino acid metabolism. Primary mitochondrial diseases impede the oxidative phosphorylation pathway, compromising mitochondrial function and cellular respiration. This disproportionately affects tissues that are more dependent on aerobic respiration, and therefore has marked effects on the central nervous system and skeletal muscle. Mitochondrial dysfunction was originally implicated in human disease as early as 1959, and mitochondrial movement disorders have been described at an increasing rate over the past three decades.The genetics of mitochondrial diseases is complex. The majority of mitochondrial proteins are encoded by mitochondrial DNA (mtDNA), discovered in the 1960s. The remainder of the mitochondrial respiration machinery is encoded by nuclear DNA. Therefore, mitochondrial diseases may arise as a consequence of mutations in either mtDNA or nuclear DNA. Clinical diagnosis is complicated by individual mtDNA mutations producing multiple phenotypes, and by specific clinical features being attributable to several different mutations. To date, hundreds of mtDNA mutations have been linked to clinical syndromes, and characterization of the genotype–phenotype relationship is a highly active ongoing area of research. A unique feature of mitochondrial genetics is heteroplasmy, defined as the presence of the wild-type mtDNA and at least one other population of mutated mtDNA. Heteroplasmy, and the proportion of mutant mtDNA present, impacts upon the expression and clinical phenotype, further complicating clinical presentations.