松岡 太郎 国立精神, 神経センター神経研究所・微細構造研究部, 研究員
作田 亮一 国立精神, 神経センター神経研究所・微細構造研究部, 研究員
GOTO Yuichi same as above, Researcher, 神経センター神経研究所・微細構造研究部, 研究員 (20225668)
MATSUOKA Taro same as above, Researcher
SAKUTA Ryoichi same as above, Researcher
|Budget Amount *help
¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1993 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1992 : ¥1,400,000 (Direct Cost : ¥1,400,000)
In past two years, we have identified additional 75 patients with mitochondrial encephalomyopathies from mitochondrial (mt) DNA analyzes and pathologic evaluation, including 26 patients with progressive external ophthalmoplegia (CPEO), 43 with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and 6 with myoclonus epilepsy with ragged-red fibers (MERRF). All mitochondrial DNA extracted from muscles and/or blood samples have been kept in our DNA bank system, and are now provided to many researchers all over the world.
We have analyzed the mtDNA mutations of patients with typical MELAS symptoms and found 80% of them had the 3243 mutation. On the other hand, when we examined members of the families of MELAS patients, they had a wide variety of symptoms from asymptomatic through mildly symptomatic patients easily fatigued and having short stature, to typical MELAS patients with stroke-like episodes. Recently we found that the 3243 mutation was occasion
ally seen in patients with familial diabetes mellitus and with idiopathic cardiomypathy.
The heterogeneous clinical phenotypes can been explained by the presence of normal and mutant mitochondrial genomes coexisting in a heteroplasmic state, but differeing in their relative populations from tissue to tissue and from individual to individual even in the same family. When the mutant mtDNA increases over a threshold in a given cell, all mitochondria in the cell lose their function. In an in vitro study we have done, the cultured cells containing the 3243 mutation in over 94% of the total mtDNA lose all mitochondria function, suggesting that the threshold level is about 90% for the 3243 mutation.
We applied a simple method of staining for succinate dehydrogenase (SDH) which was helpful in identifying vasuclar abnormalities in muscle biopsies and provided another approach to the daignosis of MELAS.The wall of the abnormal blood vessels, with increased numbers of mitochondria, had increased SDH activity, and were designated "strongly SDH-reactive blood vessels (SSV)". The SSV were seen in 84% of MELAS, 86% of MERRF and very rarely in CPEO patients. The vessels contained larger populations of mutant mtDNA over 80% by an in situ hybridization study.
メラスの主症状は卆中様発作である。この発作症状の発現には血管の異常が関与していると推定される。我々は血管系の異常は全身に分布していると推定し,生検筋内の小動脈を検索したところ,約90%の生検筋に異常(平滑筋細胞内のミトコンドリアの増加)をみた。In situ hybridizationでは血管壁に変異ミトコンドリアが80-90%と増加していた。