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はじめに
ミトコンドリア脳筋症は一般に臨床病理学的に3型に分類される。すなわち,(1)Kearns-Sayre症候群を含む慢性進行性外眼筋麻痺(chronic Progressive externalophthalmoplegia:CPEO);(2)ミオクローヌスてんかんを主症状とするMERRF(myoclonus epilepsy associated with ragged-red fibers);(3)卒中様症状を特徴とするMELAS(mitochondrial myopathy,encephalopathy,lactic acidosis and stoke-like episodes)である。
1988年にHoltらが,25人のミトコンドリア脳筋症患者のうち9人の生検筋に,正常なミトコンドリアDNA(mtDNA)と欠失mtDNAが共存すること(ヘテロプラスミー)を初めて報告した1)。その後の研究から,欠失mtDNAが存在するのは上の3型のうちのKearns-Sayre症候群を含むCPEO患者に限られることが明らかとなった。筆者らは臨床症状と筋病理所見からミトコンドリア脳筋症と確定した75例について,生検筋のmt-DNAをサザンプロット法で検索した結果,CPEO患者の27例に欠失mtDNAが存在し,CPEO患者全体(40名)の68%を占めることが明らかとなった2)。これら日本人での結果は欧米人でのMoraesら(47%)やHoltら(42%)の報告と比較すると高い値を示したが,CPEO患者のみにmtDNAの欠失が認められた事実は,欧米の報告と一致していた1,3)。最近になり,以下に述べるように残る2型,すなわちMERRFとMELASに関してもmtDNA異常が明らかとなり,ミトコンドリア脳筋症の研究に大きな進歩がもたらされた。
Mitochondrial encephalomyopathies are usually divided into three distinct clinical subgroups: (1) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome; (2) myoclonus epilepsy associated with ragged-red fibers (MERRF); and (3) mitochondrial myopathy, encephalopathy, lactic acidosis and stoke-like syndrome (MELAS). Large deletions of human mitochondrial DNA (mt-DNA) give rise to CPEO including Kearns-Sayre syndrome. Recently, mtDNA abnormalities due to point mutations in mitochondrial tRNA genes have been demonstrated in MERRF as well as in MELAS.
1) MERRF: In a sequence analysis of mtDNA from a Japanese patient with MERRF, 33 substitutions were identified. Among them, an A-to-G transition at nucleotide position 8344 in the tRNALys was commonly observed in two other MERRF patients. The mutated position is highly conserved between species during evolution. Therefore, the substitution was presumed to be a causal mutation for MERRF. To investigate whether a point mutation in the tRNA gene results in a deficiency in translation, Attardi and coworkers have developed novel approaches for mitochondria-mediated transformation of mtDNA-less human cells (ρ0 cells). As a result, a severe defect in mitochondrial protein synthesis and marked deficiencies in respiration and cytochrome c oxidase activity were observed in the transformants containing virtually pure mutant mtDNA, as compared to the parent of the ρ0 cells or to transformants containing exclusively wide-type mtDNA.
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