冯连元医生的科普号

线粒体脑肌病、乳酸中毒和卒中样发作（缩写为MELAS），它是线粒体性脑肌病中的主要一种， MELAS的病人多在3-11岁之间发病，但大于此年龄的发病的亦有几例报道。系母性遗传【诊断精要】1.脑病表现：生长发育迟缓，头痛及发作性呕吐，癫痫发作、复发性大脑卒中样发作，可引起偏瘫，偏盲或皮质盲。头痛、听力丧失与痴呆也是常见的特征。2肌肉病：运动不耐受，近端对称性无力。临床表现在同一个家族中很难发现超过1个病人具有MELAS的全部症状，母系遗传的亲属常出现单发症状或无症状。 3全身系统性症状：色素视网膜病、心肌病(15%)、身材矮小和糖尿病。其他系统的症状也可以孤立表现。4.血和脑脊液出现乳酸血征以及血肌酸磷酸激酶升高，肌电图显示正常或肌原性肌改变。骨骼肌出现线粒体酶复合体I和IV的活性下降。5.CT可以显示局灶改变，但特别注意这种病变不是以典型的血管走行分布。有些病人显示基底节区钙化。其它常见的病理改变有海绵状变性和局灶性脑软化。MRI检查可以发现大脑皮层出现多发性长T1长T2信号的病灶。部分病人出现基底节钙化，脑萎缩和脑室扩大6.肌活检则显示有蓬毛样红纤维(RRF)及线粒体异常的晶体包含物。基底节钙化，大脑皮层出现假分层坏死和萎缩，表现为皮层神经细胞脱失伴随毛细血管和胶质细胞增生，小脑出现皮层萎缩和葡肯野细胞树突出现肿胀伴随线粒体增加。大脑和小脑白质出现胶质细胞增生。7.主要为3243位点tRNAleu(UUR)突变,占80%

一、线粒体细胞病概述：线粒体细胞病是一类数量正在不断增加的疾病，这类疾病是由于线粒体中各种酶的生化缺陷所引起。在电镜下可见到线粒体常常有结构的异常，通常累及肌肉的线粒体(故最初的名称叫线粒体肌病)。但现在已清楚许多器官的线粒体也可受累(出现临床或亚临床表现)。在光镜下用改良Gomori氏三色染色可在肌肉中见到蓬毛样红纤维(RRF)。线粒体细胞病的各个综合征在病变范围及严重程度上均存在差异。且许多综合征上都有相互重叠现象。这类病通常在儿童及青春期发病，但也可发生于中年。男女发病相等，且可有家族发病史。【诊断精要】临床特征上至少可存在三类变化：⑴进行性眼瘫虽多年但确无复视现象。几乎所有病人总要有眼睑下垂及眼肌无力症状(即Kearns-Sayre综合征)。⑵肢体、面及颈肌无力症状，伴有明显疲劳和活动后更突出的现象(有时可误诊为重症肌无力)。有时因心功能衰竭及代谢性乳酸中毒而出现呼吸困难。⑶伴有脑病特征的线粒体细胞病：部分和原发性全身性癫痫发作。卒中样发作，有CT上的低密度，但其不与动脉区分布相符。头痛伴有呕吐与偏头痛相似。共济失调。痴呆。脑海绵样变性。锥体束征。其它可伴随的特征包括：⑴视网膜色素变性。⑵耳聋。⑶轻度智能障碍。⑷心脏传导阻滞。⑸身材矮小。⑹甲状旁腺功能低下。⑺头颅CT上基底节钙化。实验室检查⑴血清酶学：CK，LDH及SGOT可能升高。⑵血乳酸、丙酮酸升高。⑶肌电图呈肌源性损害，少数可有神经源性损害。⑷肌肉活检在Gomori三色染色上可见蓬毛样红纤维(RRF)，电子显微镜下可见大量异常线粒体。⑸线粒体DNA检测这是金标准，包括点突变、缺失和减失等，其中各种具体线粒体疾病又有所不同。诊断要点诊断上主要根据有：⑴实验室的乳酸增高和/或运动后反应性极度增高。⑵肌活检和肌电图上示肌原性改变。⑶而肌酸激酶水平不一定增高。鉴别诊断主要有癫痫、头痛及其它肌无力的疾病。⑴癫痫，在癫痫患者中有一部分病人系此病所致，可以为大发作性，⑵头痛(页)。⑶重症肌无力。⑷多发性肌炎。⑸进行性肌营养不良。

First fix for mitochondrial diseases Researchers have successfully replaced defective mitochondrial genomes with healthy ones in monkey embryos -- a potential fix for mitochondrial diseasesBy Victoria Stern Researchers have for the first time succeeded in replacing defective mitochondrial genomes with healthy ones in monkey embryos--a technique that could be used to prevent children from inheriting a variety of incurable genetic diseases caused by defective mitochondrial genes, they report online today (August 26) in Nature. A mitochondrion Image: Wikipedia"The general idea of preventing mitochondrial diseases by altering egg cells has been around for quite a while now," David Samuels, a professor of molecular physiology and biophysics at Vanderbilt University School of Medicine, told The Scientist in an email. "The difficulty has been in working out how to actually carry out the procedure without harming the egg cell," added Samuels, who was not involved in the study. Mitochondria, which generate most of the cell's energy supply, contain their own genome, distinct from the cell's nuclear DNA, which is inherited exclusively through the mother. Mutations in mitochondrial DNA can deplete cells of energy and eventually kill them. Mitochondrial genome defects are associated with numerous diseases, including types of diabetes and deafness, a form of blindness called Leber's hereditary optic neuropathy, and metabolic disorders that cause liver failure. Shoukhrat Mitalipov and his colleagues from Oregon National Primate Research Center devised a way to replace that defective DNA by combining in vitro fertilization with cell surgery to generate functional eggs in rhesus monkeys. First, they removed the nucleus from a donor egg cell and replaced it with the nucleus--including nuclear DNA--from the mother's egg cell. They then fertilized the egg with the father's sperm, creating an oocyte which contains the parents' nuclear genes and another female's healthy mitochondrial genes. "Mitalipov's group [was] able to find a time in the egg cell's development when the nuclear DNA and mitochondrial DNA are safely separated, so that they could pull the nuclear DNA out of the egg cell without also pulling out any detectible amount of the mitochondrial DNA," Samuels said. After transplanting 15 manipulated embryos into nine rhesus monkeys, the scientists found that the reconstructed eggs functioned normally, supporting healthy fertilization and embryo development. Three of the nine rhesus macaques became pregnant, the first giving birth to twins by caesarean section on April 24 of this year. "So far, we have produced four infants from this method and they are all healthy," Masahito Tachibana, an author on the study, said in a telephone press briefing. He said that the group hopes to take the approach to clinical trials in a few years. "It is important to stop transmission of these [mitochondrial] mutations," Tachibana said. Samuels pointed out, however, that the technique does nothing to help those who already have inherited pathogenic mitochondrial DNA or who already have a mitochondrial disease. Additionally, researchers do not fully understand the implications of transferring one person's mitochondrial genes into a different nuclear background. "This study was very well done, and the data look very convincing," said M. Flint Beal, a professor of neurology and neuroscience at the Weill Medical College of Cornell University, who was not involved in the research. He added that it provides the first real possibility of preventing mitochondrial diseases. But, he cautioned, "[t]here may be unexpected interactions between the nuclear DNA and mitochondrial DNA."

四、线粒体性神经胃肠脑肌病（MNGIE）常染色体隐性遗传病。发病年龄小于20岁、在5月到43岁。病程平均38岁死亡（18-53岁）。【诊断精要】临床特征：1.进行性眼外肌瘫(眼睑下垂、眼外肌麻痹)、.肢体无力等肌病症状2.周围神经病（周围神经障碍症状，可导致感觉丧失及肌肉无力）。3胃肠病伴慢性难治性腹泻与假性肠梗阻、4.脑病损害(脑白质营养不良)。6.血乳酸中毒、心电图异常及脑脊液出现高蛋白7.肌活检显示在所有三例有RRF，生化分析显示有部分COX缺陷。肌肉mtDNA的Southern分析不能显示大的缺失，其分子的缺陷仍不知。8.头颅MRI检查证实脑白质营养不良改变。9.肌电图出现神经原性或神经原性加肌原性损害。10.肌纤维出现RRF和COX阴性肌纤维，部分病人出现SDH深染的肌纤维以及神经原性肌肉损害。周围神经存在轴索脱失和脱髓鞘。肠道平滑肌细胞和神经节细胞内也存在大量异常线粒体。五、Kearns-Sayre氏综合征Kearns-Sayre氏综合征(简写为KSS)是一种极少见的疾病，属线粒体性脑肌病的范畴，是三种主要线粒体性脑肌病中的一种。几乎所有KSS的病例为散发的。在20岁前发病,有特征性的三联征。【诊断精要】1进行性眼外肌麻痹(PEO)，一般是该疾病的初期症状2.视网膜色素变性及下列之一：3.心脏传导阻滞、小脑性共济失调或脑脊淮高蛋白(>100mg/dl)。4.其它包括精神发育迟缓，听力丧失及内分泌疾患（包括短小身高）。我们的病例尚有夜间视力差及轻度智力减退，发育差，骨龄及心理年龄均小于实际年龄。5.肌活检显示RRF和COX缺乏的纤维。6.一些病人有甲状旁腺功能低下，同时伴有内分泌的异常。7.尸检发现所有病例均有脑海绵状变性，头CT显示基底节钙化，MRI检查表现为脑萎缩和双侧皮层下白质广泛的长T2信号，脑干、苍白球、丘脑和小脑高信号损害。8.mtDNA的大段缺失。也有人介绍有2名患KSS的病人在mtDNA的区域重复。本病预后不佳，治疗可选用辅酶Q，其可使某些心电图异常扭转，但不能使心脏传导阻滞等症扭转至正常。有人用辅酶Q10 对17例病人治疗，每天给辅酶Q10 60-150mg，结果使病人的血及脑脊液中的乳酸和脑脊液的蛋白均有所降低。六、不完全型Kearns-Sayre 综合征(KSS- ，也称PEO) 不完全型Kearns-Sayre 综合征(KSS- ，某些学者也称PEO)，发病年龄：通常为青春期或成年早期【诊断精要】临床特征为正规的KSS诊断所必备的条件缺少一种。不过患KSS- 的病人在稍后可发展为完全型的KSS，这使KSS和KSS- 的鉴别出现困难。与典型的KSS同样，大多数KSS- 病人也有异常的mtDNA缺失，这进一步增强的两个综合征的同一性。故PEO往往是线粒体病的一种症状，但有时则也是一种独立的病症七、慢性进行眼外肌瘫(CPEO)【诊断精要】临床特征：1.病人表现在童年或青春期有双侧对称性眼睑下垂和PEO，通常没有复视。2.近端肢体无力是常见的特征，但不是残弱状态，大多数病人的生活相对正常。实验室检查：1.大约有眼肌(OM)的50%病人的肌肉存在异常的mtDNA缺失，2.有伴mtDNA缺失的病人的肌活检均显示有RRF。而没有缺失的眼肌病的病人只有2/3有这种形态学异常。而有mtDNA缺失的大多数病人的家族史阴性，这是与其它类型OM明显的鉴别特征，如常染色体显性的PEO伴有多重缺失。八、单纯性线粒体肌病线粒体肌病儿童与成人均可发病,可以是一组症状，也可是一个独立的疾病。主要选择性累及骨骼肌,包括肢带肌和躯干肌。【诊断精要】临床特征：1.均表现为四肢肌无力,无眼外肌和其他组织器官受累的证据。2.血清CK水平多不超过正常对照组上限的3倍。可为轻～中度增高。3.EMG检查,大多数正常,少数表现为肌源性损害,神经源性损害。4.肌活检查出RRF、COX缺失纤维和琥珀酸脱氢酶高反应性血管( SSV)。临床诊断和鉴别诊断主要依靠肌活检病理学观察。

MERRF是三种主要线粒体性脑肌病之一，有时MERRF可以和MELAS重叠出现。本病为母性遗传，同一家庭累及成员严重程度可不尽相同。有些成员甚至缺乏典型的RRF的特征。生化研究已显示有复合体Ⅲ，复合体Ⅳ和联合有复合体Ⅰ与复合体Ⅳ的缺陷。【诊断精要】临床特征变化较大。1. 通常在5-12岁之间发生，但也可发生于成年人。2.在完全型，MERRF综合征以进行性肌阵挛、小脑共济失调和肌无力为特征。3.此外但不常见特征包括:⑴全身性癫痫视神经萎缩感觉神经性耳聋痴呆、偏颅性头痛、足畸形、锥体束征和周围感觉神经病。MRI主要表现为大脑和小脑萎缩。肌肉发现RRF和COX阴性肌纤维。4.神经病理学包括神经元的丧失和胶质增生。特别是齿状核和下橄榄核，小脑上脚变性，脊髓后柱和脊髓小脑束变性。视神经、苍白球、红核、黑质小脑皮质和Clark氏柱也受累。5.肌活检显示线粒体病的典型改变，伴有RRF和COX阴性纤维，及超微结构有异常线粒体和副晶包含物。6.主要为mtDNA第8344位点上A突变为G，