MERRF

Myoclonic epilepsy with ragged red fibers (MERRF) Mitochondrial tRNAi>,s... 

Tissue Symptom/sign KSS Pearson MERRF MELAS NARP MILS... 

MERRF (myoclonic epilepsy with ragged red fibers) Is characterized by weakness on exertion, ataxia, and associated deafness and Is due to mutation of the mitochondrial tRNA gene. 

MERRF [22] An encephalomyopathy with myoclonus, ataxia, hearing loss, muscle weakness, and generalized seizures. A missense mutation in the mt tRNAlys gene (A8344G) accounts for 80% of MERRF cases. 

It is well established that mitochondrial function defects are not severe until the proportion of mutant mtDNA reaches a high level, which forms the basis of the concept of the threshold effect. In skeletal muscle, the level of the A3243G mutation is related to the severity of strokelike episodes, epilepsy, and dementia in patients with MELAS syndrome (C6, H14, PI). Similarly, the level of the A8344G mutation is correlated with the degree of cerebellar ataxia and myoclonus in patients with MERRF syndrome (C6). Thus, molecular genetic analysis of mtDNA mutations in muscle biopsies usually provides more definitive diagnosis of... 

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... 

On the other hand, defective respiratory function elicited by the mtDNA mutation contributes to an increase in the production of ROS and free radicals, thereby causing higher oxidative stress and severe oxidative damage in affected cells (P2, W6). Because either enhanced oxidative stress or disruption of calcium homeostasis is an important factor in the triggering of cell death, mitochondrial dysfunction in tissue cells from MELAS and MERRF patients may contribute significantly to the pathogenesis of these diseases. 

C6. Chinnery, R F., Howell, N., Lightowlers, R. N., and Turnbull, D. M., Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 120, 1713-1721 (1997). 

E2. Enriquez, J. A., Chomyn, A., and Attardi, G., MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination. Nat. Genet. 10, 47-55 (1995). 

Borner GY Zeviani M, Tiranti V, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet 9 467-475, 2000. 

Mildly deleterious base substitutions 2. Moderately deleterious nucleotide substitutions 3. Severe nucleotide substitutions Familial deafness, Alzheimer s disease, Parkinson s disease Leber s Hereditary Optic Neuropathy (LHON), Myoclonic Epilepsy and Ragged-Red Fiber disease (MERRF) Leigh s Syndrome dystonia... 

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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