Brain, Vol. 115, No. 2, 343-365, 1992
© 1992 Oxford University Press
research-article |
A MOLECULAR GENETIC STUDY OF FOCAL HISTOCHEMICAL DEFECTS IN MITOCHONDRIAL ENCEPHALOMYOPATHIES
University Department of Clinical Neurology, Institute of Neurology London, UK
Correspondence to:
Correspondence to. Professor A E. Harding, University Department of Clinical Neurology, Institute of Neurology, London WCIN 3BG, UK
Using in situ hybridization and histochemistry we have studied muscle biopsy samples from eight patients with mitochondnal encephalomyopathies and known defects of mitochondrial DNA (mtDNA). In four patients with heteroplasmic mtDNA deletions there were focal accumulations of delected mtDNA and its transcripts within ragged red fibres (RRF). In one of these, a probe designed specifically to detect deleted mtDNA identified abundant deleted mtDNA and its fusion transcript in RRF and lesser accumulations in non-ragged red cytochrome oxidase (COX) deficient fibres. A further patient with a delection involving the heavy strand promoter region showed accumulation of deleted mtDNA and light strand transcripts in RRF, but concomitant depletion of all heavy strand transcripts. In all patients with deletions, normal mtDNA was rare or absent in normal fibres. Within RRF, COX activity was more profoundly impaired in patients with deletions involving COX subunits.
In two patients heteroplasmic for the base pair (bp) 3243 mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS), RRF contained a great excess of mtDNA and transcripts of all species. Some RRF showed excess COX activity. Non-ragged red COX deficient fibres showed equal increases of ribosomal RNA (rRNA) and messenger RNA, suggesting that focal biochemical defects were not associated with a quantitative defect of transcription termination at the 3' end of the 16S rRNA which might be prediected A patient heteroplasmic for the bp 8344 mutation (associated with myoclonic epilepsy and ragged red fibres: MERRF) showed subnormal COX activity within RRF, although the tissue distribution of mtDNA and its transcripts was similar to that seen with the bp 3243 mutation Within mitochondrial encephalomyopathies, the relationships between the distribution and expression of abnormal mtDNA and the focal biochemical consequences are complex and heterogeneous.
Received October 3, 1991. Revised December 30, 1991. Accepted January 12, 1992.
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