线粒脑肌病伴高乳酸血症和卒中样发作患者的临床、病理和线粒体DNA突变分析

Mitochondrial Encephalomyopathies with Lactic Acidosis and Stroke Like Episodes——Clinical, Pathological and Mitochondrial DNA Analysis

目的能量代谢障碍是青年期卒中的重要病因之一，该研究总结线粒体脑肌病伴高乳酸血症和卒中样发作（mitochondrial encephalomyopathy with lactic acidosis and stroke-like episode，MELAS）患者的临床、病理特征，分析线粒体DNA突变，望能有助于提高对该病的认识、改进青年卒中的诊治。 方法回顾分析15例临床特征和骨骼肌病理符合MELAS的患者。分析线粒体脱氧核糖核酸（mitochondrial DNA，mtDNA）突变，多聚酶链反应（polymerase chain reaction，PCB）后直接测序分析mtDNA热点突变，并对未发现热点突变的患者进行全mtDNA序列分析。 结果15例患者的临床表现以头痛和卒中样发作、癫痫发作为主要表现，病灶以皮层尤其枕叶、顶叶为多，磁共振成像（magnetic resonance imaging，MBI）有一定特征，生化检查发现血乳酸、乳酸／丙酮酸比值升高，肌酶轻度升高，病理上以破碎红纤维（ragged-red fibers，BBF）和细胞色素C氧化酶（cytochrome C oxidase，COX）／琥珀酸脱氢酶（Succinate dehydrogenase，SDH）蓝染纤维为主要特征，电镜下显示线粒体增多，线粒体内包涵体。11例由亮氨酸转运核糖核酸（mitochondrial tRNA for leucine，MTTL1，tBNA1）基因突变导致，细胞色素C氧化酶亚单位3（Cytochrome c oxidase subunit Ⅲ，C05）基因9469C／T突变，线粒体ATP合成酶亚单位8（Subunit 8 of mitochondrial ATP synthase，ATP8）基因8489A／G突变和细胞色素C氧化酶亚单位1（Cytochrome c oxidase subunit 1，COI or MTC01）基因6255T／0突变各1例，1例患者无任何mtDNA突变。结论MELAS是青年期卒中重要原因之一，肌肉活检是临床诊断的主要手段，mtDNA突变分析尤其是热点突变（MTTL1＊3245G和MTTL1＊5271C）分析对于确诊有重要价值。

Objective Mitochondrial disorder is one of the important factors in young stroke patients. To understand the clinical, pathological and molecular genetics features of Mitochondrial encephalomyopathies with lactic acidosis and stroke like episodes（MELAS）. Methods Fifteen young stroke patients who were accordant with MELAS by biopsied skeletal muscle pathologies were analysed and related reports were reviewed. The clinical presentations, the findings of their biochemistry tests, the neuroimagings and the pathology of biopsied muscles were summarized. The hotspot mutations of mtDNA have been analyzed after PCR. For the patients without hotspot mutations, the sequential analyses of the entire mtDNA have been performed. Results All the patients have headache, stroke like episodes or seizures with the lesions in the cortex, especially in occipital and parietal lobes. The results of the MRI reveal some common features. Their biochemistry tests show the increase of blood lactic acid and the ratio of lactic acid to pyruvic acid and a slight increase of creatase. The biopsied muscles show the RRF and COX/SDH blue-dyed fibers with the observation of the accumulation of mitochondria and intramitochondrial inclusions by electric microscopy. Mitochondrial DNA analysis revealed that eleven patients were caused by mutations in leucine tRNA1 gene, while CO3＊9469C/T, ATPS＊8489A/G, CO1＊6253T/C was supposed as the causative mutation of three patients, alternatively. But there was not any mtDNA mutation identified in a patient. Conclusion MELAS is one of important diseases among young stroke patients which can be diagnosed by pathological study ofbiopsied muscles. The leucine tRNA1 gene is the most frequent causative gene.