| Co-Investigator(Kenkyū-buntansha) |
MATSUOKA Taro National Institute of Neurosicence, NCNP, Division of Ultrastructural Research,, 神経センター・神経研究所・微細構造研究部, 研究員
GOTO Yuichi National Institute of Neurosicence, NCNP, Division of Ultrastructural Research,, 神経センター・神経研究所・微細構造研究部, 研究員 (20225668)
KIKUCHI Aiko National Institute of Neurosicence, NCNP, Division of Ultrastructural Research,, 神経センター・神経研究所・微細構造研究部, 研究員 (70159010)
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| Research Abstract |
(1) Chronic progressive external ophthalmoplegia (CPEO)
22 of 28 patients with CPEO examined had mitochondrial DNA (mtDNA) deletions of various sizes and in various amounts showing heteroplasmic distribution. There was no difference in clinical and biochemical findings between patients with and without mtDNA deletions. Higher Incidence of cytochrome c oxidase (CCO) -negative fibers in patients with deleted mtDNA than in those with no deletion suggests that deleted mtDNA is, at least in part, responsible for focal CCO deficiency as a phenotypic expression. In a muscle culture study obtained from patients with focal CCO deficiency, two different types of myotubes containing mostly CCO-positive mitochondria and only negative mitochondria, respectively, representing intercellular mosaicism, were demonstrated. This "all or none" CCO positivity in mitochondria inCPEO with deleted mtDNA supports 'threshold theory" which states that all mitochondria become phenotypically defective when mutant m
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tDNA increase in amount and exceed a certain threshold.
(2) Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)
We first found a mtDNA mutation from A to G at nucleotide position (nt) 3243 in approximately 80% of MELAS patients. On further examination on rest 20% of patients, a novel mutation from T to C in TRNA region was found in 10% of patients. In biopsied muscles, strongly SDH blood vessels (SSV) which had increased number of giant mitochondria on electron microscopy in smooth muscle cells of small arteries, were detected in 85% of patients. The presence of SSV in muscle biopsy specimens provides an important clue toward understanding the underlying pathomechanism in patients with MELAS as well as another approach to the diagnosis of this disorder.
(3) Myoclonus epilepsy associated with ragged-red fibers (MERRF)
Six patients with MERRF who had an A to G base subtitution at mtDNA nt pair 8344 were examined histochemically. All biopsies showed focal cytochrome c oxidase deficiency. In addition, SSV, the characteristic pathologic finding in MELAS, were seen in 5 of 6 biopsies, but those in MERRF had no CCO activity. The defect in CCO activity in the arteriolar smooth muscle cells and in muscle fibers suggests that CCO deficiency is related to the pathophysiology of MERRF. Less
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