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In the case of heteroplasmy, a certain selleck compound amount of wild-type mtDNA can compensate for the mutant mtDNA in a cell or tissue. If the effects of the mutant mtDNA exceed a certain threshold, however, the wild-type mtDNA can no longer compensate. This critical threshold level is often tissue-specific; metabolically active tissues, particularly the RGCs, which constitute the optic nerve and the cells of the retinal pigment epithelium, have a lower threshold than less metabolically active tissues.52 In addition, post-mitotic cells like neurons accumulate more mutant mtDNA copies over time, which eventually exceed the critical threshold and account for the age-dependent expression of many mitochondrial diseases.44 Over 200 point mutations in mtDNA account for mitochondrial diseases. Most point mutations that cause disease are heteroplasmic. However, there are several exceptions, including the common mutations in LHON, which are usually homoplasmic. Deletions and duplications in mtDNA can also lead to mitochondrial diseases including mitochondrial myopathies, which are often sporadic.15,45,53 Genetics and incomplete penetrance of LHON Ninety percent of all cases of LHON are due to one of three point mutations in mtDNA, which are located at nucleotide positions 3460, 11778, and 14484.5 The most common point mutation is 11778, which accounts for 70% of all cases.5 The 14484 and 3460 mutations account for ~14% and ~13%, respectively.20,50 An exception is among those of French Canadian descent, in which the 14484 mutation accounts for about 90% of cases within that population due to a founder effect.54 Other relatively rare mutations have also been discovered but occur in single families.20,21 All of the mutations occur in genes encoding subunits for complex I in the respiratory chain, particularly in those encoding the ND1 and ND6 subunits.55,56 LHON is notable for incomplete penetrance, meaning that not all mutation carriers will develop vision loss. While the mechanisms involved have not been fully elucidated, it appears that complex genetic and environmental factors play a role. Like several other mitochondrial disorders, heteroplasmy is thought to influence the penetrance of LHON. For instance, it has been observed that offspring born to mothers with less than 80% mutated mtDNA present in their blood are less likely to be symptomatic than offspring born to homoplasmic mothers.57 Even more variability is present because tissue-specific segregation of mutant mtDNA is stochastic during embryogenesis. Considering that 80%�C90% of all LHON individuals carry homoplasmic mutations, heteroplasmy alone does not explain the incomplete penetrance of LHON.8,14 Another risk factor for vision loss is the set of inherited genes that commonly segregate with the pathogenic mtDNA mutation.