Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.

Many patients with inherited mitochondrial encephalopathies have one of two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A8344G. Individuals who harbour these mutations carry both mutant and wild-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondrial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the level of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studied the relationship between the incidence of specific clinical features and the level of mutant mtDNA in blood (for A3243G, n = 73; for A8344G, n = 25) and/or skeletal muscle (for A3234G, n = 111; for A8344G, n = 55). Within this study group, the frequency of key clinical features was significantly different for individuals harbouring the A3243G and A8344G mutations. For both mutations, there was a correlation between the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtDNA in blood. Therefore, measurement of the level of the A3243G and A8344G mutations in muscle will allow the identification of individuals who are at risk of developing specific complications, thus improving the prognostic advice that can be given to patients and family members who carry these mutations.

Gene dosage effect in one family with myoclonic epilepsy and ragged-red fibers (MERRF).

OBJECTIVES: We analyzed the percentage of mitochondrial DNA (mtDNA) heteroplasmy in blood samples of 13 individuals belonging to a three family generation of myoclonic epilepsy with ragged-red fibers (MERRF) and compared the 5 affected patients and the 8 unaffected relatives. MATERIAL AND METHODS: DNA was extracted from blood and muscle of the proband and from blood of 12 maternal relatives. A PCR restriction analysis method was used to detect the mutation. RESULTS: The proband had the complete MERRF phenotype. The phenotype in three other individuals in the maternal lineage was consistent with the MERRF syndrome. The remaining were asymptomatic. The np 8344 mutation was observed in muscle and blood of the proband, and in blood from every one of 12 maternal relatives, ranging from 44% to 83% of mutated genomes. Symptomatic individuals had higher levels (P < 0.001) of mutated mtDNA than asymptomatic maternal relatives. However, high proportions of mutant genomes (up to 63%) were found in asymptomatic relatives. CONCLUSIONS: Although there seems to be a gene dosage effect in MERRF, we found no absolute relationship between the relative proportion of mutant genomes in blood and clinical severity. Factors other than gene dosage in blood may account for the differences in clinical phenotype.

Myoclonus epilepsy with ragged-red fibers: a clinical and electrophysiologic follow-up study on two sibling cases.

We performed a 5-year clinical and electrophysiologic follow-up study on two sibling cases with myoclonus epilepsy with ragged-red fibers. Both had myoclonus, intention tremor, slight muscle weakness, slight mental disturbance, hearing impairment, and optic atrophy. Neither had epileptic attacks or truncal or gait ataxia. Biochemical activity of cytochrome c oxidase was at the lower limit of the normal range of values, and an adenine to guanine transition mutation at nucleotide 8344 in the transfer RNA specific for lysine of mitochondrial DNA was detected in both cases. The electroencephalograms showed slowing of basic patterns, diffuse spike-and-wave complexes, occipital dominant wave-and-spike phantoms, 6- and 14-Hz positive spikes, and photosensitivity. No definite deterioration of basic patterns was seen, and diffuse spike-and-wave complexes and photosensitivity gradually disappeared during the slowly progressive clinical course. P2 latencies of pattern-reversal visual evoked potentials throughout the clinical course and III through V interpeak latencies of auditory brainstem responses at follow-up were prolonged without giant sensory evoked potentials in both cases.