Disease-Associated mtDNA Mutations

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

Point Mutations in rRNA/tRNA Genes of mtDNA Associated with Mitochondrial Diseases 2 

A number of distinctive syndromes have been shown to be associated with specific point mutations of mtDNA (Table 1) (M15, S4, S14). Several point mutations have been reported to occur at tRNA genes in the mitochondrial genome. For example, the A8344G mutation is present in patients with MERRF syndrome (S9), whereas the A3243G mutation of mtDNA was first identified in a subgroup of patients with MELAS syndrome (G4). MERRF syndrome was the first 

Point Mutations in Protein-Coding Genes of mtDNA 

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TABLE 42-1 Clinical features of mitochondrial diseases associated with mtDNA mutations... 

LHON is a disorder caused by OXPHOS deficiency. Although more than 27 mutations have been associated with this disease, mtDNA mutations G3460A, G11778A, and... 

The bioenergetic defects resulting from mtDNA mutations may be a common cause of degenerative diseases (Table 14-7). Defects in nuclear-cytoplasmic interaction are generally the resultant of autosomal dominant mutations complex disease states result from depletion of mtDNAs from tissues. Mitochondrial DNA mutations are associated with a broad spectrum of chronic degenerative diseases with a variety of clinical presentations. Identical mutations are associated with very different phenotypes and the same phenotype can be associated with different mutations. 

Leber hereditary optic neuroretinopathy [18] A rapid bilateral central vision loss due to optic nerve death. The disease has been associated with several missense mutations in the mtDNA that can act autonomously or in association with each other to cause the disease. 

Although point mutations and large-scale deletions of mtDNA have been established to be closely associated with mitochondrial diseases (C9, LI, L7, Ml5, S4),... 

At this point, if the results have suggested a specific mitochondrial disorder (e.g., MELAS), then mtDNA isolated from blood cells can be tested for any known mutations associated with the suspected disorder. Unfortunately, many disease-causing mutations are not detectable in mtDNA isolated from blood cells (because of the rapid turnover in these cells, defective mitochondria are often lost). Therefore, inconclusive results may warrant further testing. 

Cellular oxygen utilization decreases as a function of age and the ATP generating capacity of the cell is a function of age. The attenuation of ATP synthesis is associated with an age-related increase in somatic mtDNA damage in postmitotic tissue. The normal decline in ATP generating capability may facilitate disease occurrence when it is associated with an inherited oxidative phosphorylation mutation. 

Fourteen mtDNA tRNA mutations have been associated with maternally inherited disease. Such mutations are typically associated with severe mitochondrial myopathies, characterized by ragged red skeletal muscle fibers upon Gomori trichrome staining and the accumulation of structurally abnormal mitochondria in muscle. Mutations in tRNAs exemplify the threshold effect whereby (due to replicative segragation) individuals may not exhibit clinical signs until the proportion of mutant mtDNA exceeds 80-90%. Myoclonic epilepsy and ragged red fiber (MERRF) disease, mitochondrial encephalomyo-pathy tactic acidosis (MELAS), as well as maternally inherited myopathy and cardiomyopathy (MMC) are well-characterized mitochondrial diseases. 

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