In contrast to nuclear genes, each consisting of 1 maternal and 1 paternal allele, there are hundreds or thousands of copies of mtDNA in every cell. Thus, when there is a deleterious mutation, both normal and mutated mtDNAs may coexist within a patient's tissues, a condition known as heteroplasmy. The situation in healthy individuals, in whom all mtDNAs are identical, is called homoplasmy. Nondeleterious mutations of mtDNA (neutral polymorphisms) are homoplasmic, whereas pathogenic mutations are usually, but not always, heteroplasmic. A critical number of mutated mtDNAs must be present before tissue dysfunction and clinical signs become apparent (the so-called threshold effect). Tissues with high requirements for oxidative energy metabolism, such as muscle, heart, eye, and brain, have relatively low thresholds and are particularly vulnerable to mtDNA mutations. Relatively low levels of mutated mtDNAs can affect the respiratory capacity of these tissues, and high levels can be devastating. It is therefore not surprising that most mtDNA disorders are encephalomyopathies, affecting primarily brain and muscle.