Transfer RNA tRNA Mutations

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. 

Because oxidative phosphorylation capacity declines with age, individuals with identical mtDNA genotypes may express different cliiucal signs if they are of different ages. Individuals under the age of 20 with 80% mutant mtDNAs can be asymptomatic individuals with the same 

Large mtDNA deletions account for most cases of ocular myopathy and Pearson s marrow/pancreas syndrome. Ocular myopathy patients can exhibit a variety of clinical symptoms, from mild chronic progressive external ophthalmoplegia (CPEO) to Kearns-Sayre Syndrome (KSS). These diseases are characterized by an early onset of ophthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and usually cerebellar syndrome and cardiac conduction abnormalities. More than 120 different mtDNA deletions have been identified from patients tissues. Partial duplications of mtDNA have been detected in ocular myopathy and Pearson s syndrome, however, duplications are much rarer than spontaneous deletions in patients with these conditions. Exactly how partial mtDNA duplications arise is unknown. 

Patients with mitochondrial disorders may present at any age and show variation in both the severity and kind of symptoms associated with a single genetic abnormality. For example, the tRNA mutation is predominantly associated with the neurological syndrome MELAS but may also be manifested as CPEO, myopathy, diabetes, and deafness. 

Mitochondriopathies associated with severe limitation of aerobic metabolism in such organs as liver, kidney, heart, and brain are probably incompatible with survival. Milder mitochondrial disorders may become clinically observable when cellular energy demand is not satisfied (e.g.. 

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