Hammans S R, Sweeney M G, Hanna M G, Brockington M, Morgan-Hughes J A, Harding A E
University Department of Clinical Neurology, Institute of Neurology, London, UK.
Brain. 1995 Jun;118 ( Pt 3):721-34. doi: 10.1093/brain/118.3.721.
The mitochondrial tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), usually associated with this mutation, 12 probands had other phenotypes including other encephalopathies, chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy and ragged red fibres (MERRF), myopathy alone and diabetes and deafness. Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with CPEO compared with those with MELAS. The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the tRNALys A-->G(8344) mutation. The proportion of mutant mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with mitochondrial myopathy. The family with this transition had high levels of mutant mtDNA A-->G(3243), with a unique phenotype of predominant skeletal myopathy, suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.
在22名无亲缘关系的患者中发现了线粒体tRNALeu(UUR) A→G(3243)突变。对先证者及其亲属进行了临床评估和线粒体DNA（mtDNA）定量分析。虽然10名先证者具有与线粒体肌病、脑病、乳酸酸中毒和卒中样发作综合征（MELAS）一致的临床特征，该综合征通常与这种突变相关，但12名先证者有其他表型，包括其他脑病、慢性进行性眼外肌麻痹（CPEO）、肌阵挛性癫痫伴破碎红纤维（MERRF）、单纯肌病以及糖尿病和耳聋。与MELAS患者相比，CPEO患者肌肉活检的组织化学分析显示细胞色素氧化酶（COX）阴性纤维比例更高，但强COX反应性纤维更少。有症状的受试者血液中存在的突变型mtDNA比例明显高于无症状受试者，且在两者中均与年龄相关。tRNALys A→G(8344)突变的患者未观察到这种相关性。肌肉中突变型mtDNA A→G(3243)的比例总是高于血液中的比例。观察到血液中突变型mtDNA比例与疾病发病年龄和临床严重程度评分之间存在显著相关性。然而，受累和未受累病例血液中突变型mtDNA的比例有重叠，因此无法将遗传 - 临床相关性用于预后或预测目的。表型的家族内聚集以及突变型mtDNA比例与疾病存在与否之间的不完美关系表明，其他因素可能决定表型。为了进一步研究这种可能性，对23名先证者和6名亲属的tRNALeu(UUR)基因进行了测序。在28名患者中，除了3243突变外，序列正常，但在一个家族的成员中，在3290位点存在纯合的T→C转换，在140名对照或50名其他线粒体肌病患者中未发现这种转换。具有这种转换的家族中突变型mtDNA A→G(3243)水平较高，具有以骨骼肌病为主的独特表型，这表明tRNALeu(UUR)中的这种第二个碱基变化可能影响临床表型。
