Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF phenotype.

BACKGROUND

A 26-year-old man presented at onset with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and later with a phenotype for MELAS and myoclonic epilepsy and ragged red fiber disease (MELAS/MERRF).

OBJECTIVE

To identify the possible defects in the mitochondrial genome in blood and muscle samples of the patient.

DESIGN

Case study of a patient clinically exhibiting strokelike episodes and then epilepsy with myoclonic features, ataxia, and dementia.

SETTING

Research unit of a university hospital.

MAIN OUTCOME MEASURES: Electromyographic, morphologic, and biochemical studies of muscle and molecular analysis of blood and muscle to investigate mitochondrial DNA (mtDNA) size and quantity.

RESULTS

Morphologically, we found abnormal mitochondrial proliferation with several cytochrome-c oxidase (COX)-negative fibers in muscle biopsy specimens; the analysis of serial sections showed a decreased immunoreactivity for the mtDNA-encoded subunits COXII and, partially, COXI. Biochemically, we found a partial and isolated COX deficiency. The complete mtDNA sequence analysis identified 3 sequence changes, 2 of which were reported polymorphisms. The remaining change, a G12147A transition in the transfer RNA(His) gene, appeared to be the likely pathogenic mutation.

CONCLUSIONS

Our data propose that the G12147A change, the first mutation in the transfer RNA(His) gene associated with an overlapped MELAS/MERFF phenotype, is the cause of the encephalomyopathy in this patient interfering with the overall mitochondrial protein synthesis.