EVALUATION OF MITOCHONDRIAL ENCEPHALOMYOPATHY WITH LACTIC ACIDOSIS AND STROKE-LIKE EPISODES WITH MAGNETIC RESONANCE IMAGING AND PROTON MAGNETIC RESONANCE SPECTROSCOPY

Objective To study the characteristics of spectra on proton magnetic resonance spectroscopy （^1H-MRS） and its value in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes （MELAS）. Methods Seven clinically diagnosed patients with MELAS underwent magnetic resonance imaging （MRI） and ^1H-MRS examinations. The ^1H-MRS techniques, characteristics of the spectra, and its correlation with the laboratory tests were analyzed. Reaults Cerebral abnormalities were revealed in all 7 patients on conventional MR images, and most abnormal signals were observed in bilateral occipital, parietal, and temporal lobes. We found 4 cases with basal ganglia involvement, 2 cases with mild frontal lobe lesions, and 1 case with involvement of lateral cerebral peduncles and thalami. Additionally, 1 patient was involved with left insular lobe. Spectra from prominent lesions in brain parenchyma showed lactate doublet peak in 6 patients, 3 of whom were also noted lactate peak in ventricular cerehrospinal fluid （CSF）. Conclusion ^1H-MRS may provide more direct information about the metabolism changes, which aids to affirm the diagnosis, and may replace the conventional invasive method of quantifying lactate in CSF.

Mucosal necrosis of the small intestine in myopathy,encephalopathy,lactic acidosis,and stroke-like episodes syndrome

This report presents a case of massive mucosal necrosis of the small intestine in a patient with mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),which particularly affects the brain,nervous system and muscles.A 45-year-old Japanese female,with an established diagnosis of MELAS,presented with vomiting.Computed tomography showed portomesenteric venous gas and pneumatosis intestinalis.She underwent a resection of the small intestine.A microscopic study showed necrosis of the mucosa and vacuolar degeneration of smooth muscle cells in the arterial wall.Immunohistochemistry showed anti-mitochondrial antibody to be highly expressed in the crypts adjacent the necrotic mucosa.The microscopic and immunohistochemical findings suggested the presence of a large number of abnormal mitochondria in MELAS to be closely linked to mucosal necrosis of the small intestine.

Progress in Diagnosing Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes

Objective： Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes （MELAS） is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. M ELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well. Data Sources： The data used in this review came fi-om published peer review articles from October 1984 to October 2014, which were obtained fiom PubMed. The search term is ＂MELAS＂, Study Selection： lnfornmtion selected from those reported studies is mainly based on the progress on clinical tkatures, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS. Results： MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging （MRI） can provide directional information on this disease. Muscle biopsy has meaningflil value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the lnutation in.3243A〉G of the mitochondrial transfer RNA （Leu （UU R）） gene （MT-TLI）. Conclusions： MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MR1, muscle biopsy, and genetics.

Clinical,pathological and genetic study of a kindred of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

The first description of a syndrome including stroke-like episodes, lactic acidaemia, and ragged red fibres, was reported by Shapira et al in 1975. 1 Pavlakis et al 2 described further cases, introduced the acronym MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and suggested that this represented a distinct mitochondrial disease phenotype. In 1990, Goto et al 3 identified A3243G mutation in the transfer RNA (tRNA) leucine (UUR) gene in some patients with MELAS. Although this mutation has now been established to be the commonest mtDNA defect it is often misdiagnosed. Here we report a kindred of MELAS including a mother and a son. Clinical, pathological and genetic studies are proceeding.

White matter connection's damage,not cortical activation, leading to language dysfunction of mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes

Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) is a metabolic disorder characterized by hyperlactic acidemia and stroke-like symptoms.

characteristics of intestinal pseudo-obstruction in patients with mitochondrial diseases

AIM: To reveal the frequency, characteristics and prognosis of chronic intestinal pseudo-obstruction (CIP) in mitochondrial disease patients. METHODS: Between January 2000 and December 2010, 31 patients (13 males and 18 females) were di-agnosed with mitochondrial diseases at our hospital. We conducted a retrospective review of the patients' sex, subclass of mitochondrial disease, age at onset of mitochondrial disease, frequency of CIP and the age at its onset, and the duration of survival. The age at onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined. RESULTS: Twenty patients were sub-classified with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), 8 with chronic progressive external ophthalmoplegia (CPEO), and 3 with myoclonus epilepsy associated with ragged-red fibers (MERRF). Nine patients were diagnosed with CIP, 8 of the 20 (40.0%) patients with MELAS, 0 of the 8 (0.0%) patients with CPEO, and 1 of the 3 (33.3%) patients with MERRF. The median age (range) at the diagnosis and the median age at onset of mitochondrial disease were 40 (17-69) and 25 (12-63) years in patients with CIP, and 49 (17-81) and 40 (11-71) years in patients without CIP. During the survey period, 5 patients (4 patients with MELAS and 1 with CPEO) died. The cause of death was cardiomyopathy in 2 patients with MELAS, cerebral infarction in 1 patient with MELAS, epilepsy and aspiration pneumonia in 1 patient with MELAS, and multiple metastases from gastric cancer and aspiration pneumonia in 1 patient with CPEO. CONCLUSION: Patients with CIP tend to have disorders that are suspected to be related to mitochondrial diseases at younger ages than are patients without CIP.

线粒体脑肌病伴高乳酸血症和卒中样发作的诊断与治疗策略

线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)是线粒体病最常见的临床亚型。MELAS的临床表现包括卒中样发作、头痛、癫痫、肌无力等,同时还可伴有多系统受累的表现,从而呈现出高度异质性。诊断需结合详细准确的病史、家族史,以及病理、生化和基因检测的结果。治疗需要多学科综合管理,包括药物治疗和营养运动干预。本文总结了MELAS的诊断和治疗方法,旨在帮助临床医生更全面地理解MELAS,从而做到早期诊断并规范化治疗以改善患者长期预后。

1例线粒体基因A3243G突变的线粒体脑肌病伴高乳酸血症和卒中样发作、Leigh叠加综合征患者的诊疗分析

线粒体脑肌病是较为少见的线粒体结构和(或)功能异常所导致的以脑和肌肉受累为主的多系统疾病,病因为遗传基因的缺陷。目前,临床针对线粒体脑肌病尚无根治方法,主要通过对症治疗纠正患者缺陷,缓解患者临床症状。该文分析1例线粒体基因A3243G突变的线粒体脑肌病伴高乳酸血症和卒中样发作、Leigh叠加综合征患者的诊疗,为临床提供参考。

线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征的临床、影像学特征及线粒体基因A3243G位点点突变异质性分析(附1家系报告)

目的探讨线粒体脑肌病伴高乳酸血症和脑卒中样发作(MELAS)综合征的临床、影像学特征及线粒体基因突变异质性。方法通过对1例以头痛及卒中样发作起病的MELAS患者及其家系成员的临床诊治,结合病史、实验室检查、影像学检查、病理学检查及基因学检查及已有的文献报道,分析其家系患者临床表型是否与致病基因异质性相关。结果先证者存在典型的MELAS临床症状,其生化指标、肌肉活检和影像学资料均符合MELAS诊断标准,但血液标本线粒体基因一代测序结果显示突变比例未高于其突变阈值。因先证者小女儿发病,取其尿液标本行基因检测,测序结果提示先证者小女儿线粒体基因组存在chrM:3243A>G(tRNA Leu1)突变,尿液标本突变负荷为97%。随后对先证者的血液及尿液行二代深度测序,结果显示血液及尿液突变负荷分别为5.0%、51%。结论MELAS综合征患者临床表现复杂多样,拟诊MELAS的患者应行基因检测。当线粒体病患者血液中突变率较低,或对于突变较低的仅有单一症状和无症状的患者,需要取材多种组织行基因检测,避免漏诊的发生。

线粒体DNA A3243G点突变的临床异质性表现

目的探讨线粒体DNAA3243G点突变的临床表现特点。方法以25例临床怀疑为线粒体病,经血或肌肉线粒体DNA检查证实有A3243G点突变的线粒体脑肌病患者为研究对象,分析其临床表现、脑影像学特点、血乳酸水平和肌肉病理检查结果。结果基因检测证实25例患者均存在比例不同的线粒体DNAA3243G点突变,但临床表型有很大不同,其中19例为线粒体脑肌病伴乳酸血症和卒中样发作(MELAS),2例为无法分类的线粒体脑病,2例为松软儿,1例为Kearns-Sayer综合征(KSS),1例为线粒体胃肠肌病。大部分患者脑影像学检查可见病灶,肌肉活检可见蓬毛样红纤维改变,所有患者均有血乳酸水平增高。结论线粒体DNAA3243G点突变的临床表现和脑影像学均呈高度的异质性。对表现为多系统受累的患者,如果同时合并高乳酸血症,就应考虑线粒体病的可能,应进行线粒体DNA突变的检查以明确诊断。

线粒体脑肌病伴乳酸血症和卒中样发作综合征的临床特征及遗传学研究

目的探讨线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）综合征临床与分子遗传学特征,寻找MELAS线粒体DNA（mtDNA）A3243G点突变比例与临床特征的关联性。方法对2001年1月至2008年1月在首都医科大学附属北京儿童医院神经内科住院和门诊临床疑似线粒体脑肌病的患儿,行外周血白细胞mtDNA A3243G点突变筛查、血乳酸检测和神经影像学等检查。A3243G点突变阳性病例中选取符合MELAS临床疑似诊断标准的患儿（突变阳性组）,对其家系进行调查,采集家族成员血进行mtDNA A3243G点突变筛查;A3243G点突变阴性病例中选取符合MELAS临床疑似诊断标准的患儿行肌肉病理活检和肌肉A3243G点突变筛查（突变阴性组）。分析比较两组的临床资料及MELAS遗传学特征。结果研究期间共有272例疑似线粒体脑肌病的患儿进行了外周血白细胞A3243G点突变的筛查。A3243G点突变的20例阳性标本中,突变均为异胞质性（heteroplasmy）,18例符合MELAS的临床疑似诊断标准。血细胞中突变型mtDNA的比例为9.0%-50.0%,其中4例同时在肌肉组织检测到相同突变,突变比例为42.4%-64.8%。临床症状以惊厥、乏力、智力进行性倒退、发热、呕吐、视力障碍和失语为主,身材矮小和体毛增多为主要体征,13例合并癫,血乳酸均升高,头颅CT/MRI显示双侧对称性苍白球钙化和脑梗死信号。A3243G点突变筛查阴性标本中有4例临床符合MELAS临床疑似诊断标准,肌肉病理可见破碎红边纤维,肌肉A3243G点突变筛查阴性。14个家庭中的37名家庭成员采集了外周血进行mtDNA A3243G点突变筛查,突变阳性组中患儿母亲5名检测到A3243G点突变,突变比例分别为3.0%,5.0%,11.8%,21.3%和26.9%,同胞兄弟4名检测到A3243G突变,突变比例分别为19.3%、33.3%,37.5%和41.5%,均无临床症状,其他成员未检测到突变。本研究A3243G点突变比例与发病年龄和就诊年龄呈负相关趋势,与病程未见相关性。结论MELAS综合征的临床表现复杂多样,线粒体A3243G点突变是我国儿童MELAS最常见的突变,母系遗传为主。突变比例与年龄有相关趋势,与病程未见相关,血A3243G突变检查不能代替肌肉病理诊断。

6例线粒体脑肌病伴高乳酸血症和卒中样发作的临床分析

目的分析线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)的临床特征,为早期诊断和及时治疗提供依据。方法对6例确诊为MELAS患者的临床表现,影像学、病理及遗传学特征进行回顾性分析。结果肌无力、卒中样发作、抽搐、视物模糊、血乳酸增高是该组患者的主要临床表现。6例患者CT或MRI检查显示与血管分布不一致的病灶,肌肉活检组织的电镜观察发现线粒体增多、形态不规则,病理均见破碎红纤维(RRF)。2例基因检测发现A3243G点突变,典型病例患者磁共振波谱(MRS)可见升高和倒置的乳酸峰。结论 MELAS临床表现多样,确诊有赖于肌肉活检或基因检测,影像学检查(尤其是MRS)对于MELAS的早期诊断和鉴别诊断有一定的价值。

线粒体脑肌病伴高乳酸血症和脑卒中样发作的临床、影像学及病理学特点(附1例报告)

目的探讨线粒体脑肌病伴高乳酸血症和脑卒中样发作(MELAS)的临床、影像学及病理特点。方法回顾性分析1例MELAS患者的临床资料。结果本例患者临床表现为以卒中样发作为主,有时伴癫发作、精神症状等,每次均为急性起病,经过治疗症状可有不同程度的缓解。头颅MR I提示以皮质受损为主,病灶起自右侧颞叶,每次发病的病损部位按顺时针方向发展,新的病灶总是累及从未发病的部位。其肱二头肌活检,病理结果示出现破碎红纤维。结论MELAS患者临床表现多样,影像学改变明显,且对诊断帮助较大,但确诊仍需肌肉活检。

线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征的临床、影像学及病理学特点

目的探讨线粒体脑肌病伴高乳酸血症和脑卒中样发作(MELAS)综合征的临床、影像及病理学特点。方法回顾性分析7例MELAS综合征患者的临床资料。结果本组患者中,男1例,女6例,平均年龄21.3岁;均为卒中样起病伴癫痫发作,其中视力减退6例,运动后乏力5例,认知功能障碍2例,精神异常1例。头颅MRI检查示顶、枕叶和(或)颞叶T1WI/T2WI长或稍长信号及Flair高信号病灶,呈脑回样改变,均未见强化。4例患者肌肉活检发现有肌纤维变性,横纹消失或断裂,肌膜下出现不规则的不整红边纤维(RRF)。2例行基因检测发现有mtDNA A3243G位点突变。结论 MELAS综合征好发于青少年,以卒中样起病伴癫痫发作,可有视听力减退以及认知功能障碍等;影像学特征为病变主要累及双侧大脑半球后部皮质,呈脑回样改变;肌肉活检发现RRF。

Detection of A3243G point mutation in mitochondrial DNA from 10 cases of MELAS

Objective To search for A3243G point mutations in mitochondrial DNA (mtDNA) from 10 cases of mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS) Methods Using PCR restriction analysis, we investigated A3243G point mutations in mtDNA of muscle and/or blood cells from 10 patients and their 8 maternal relatives We also quantitated the A3243G mtDNA in samples harboring the mutation Results A3243G point mutations were identified in all muscle and/or blood samples from 10 MELAS patients The proportion of mutant mtDNA was 10 8%-47 8% in blood (7 cases), and 39 4%-67 7% in muscle (5 cases) This ratio was invariably higher in muscle than in blood from two patients whose blood and muscle samples were both available Younger patients usually carried higher proportions of A3243G mutant mtDNA in blood Eight maternal relatives from 6 families were also examined Maternal transmission of the disease could be identified in one family No A3243G point mutations were found in mothers' blood from 3 families and siblings' blood from 2 families Conclusions All 10 MELAS patients were found to have the mtDNA A3243G mutation in their muscle and/or blood The A3243G mutation seems to be sporadic in 5 of the families examined, suggesting the mechanism of de novo mutation for the pathogenesis of their MELAS syndrome

线粒体脑肌病伴高乳酸血症和卒中样发作的临床及中枢神经影像学特点

目的探讨线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)的临床与神经影像学特点,分析其诊断及鉴别诊断价值。方法回顾性分析经肌肉活检证实的28例MELAS患者的临床表现及其计算机断层扫描(CT)、磁共振成像(MRI)、磁共振血管成像(MRA)和质子磁共振光谱分析(MRS)的中枢神经影像学特点。结果临床主要表现为头痛、抽搐、卒中样发作、视力及听力障碍、运动不耐受和智力下降。CT表现为基底节区的钙化和卒中区低密度灶,MRI表现为双侧或单侧大脑皮质和皮质下的长T1、长T2信号影,与血管分区不符,可有波动性,伴有脑室扩大和脑萎缩。枕颞叶最常累及,其次为额顶叶,另外其它部位也见受累,以小脑多见。MRS可见病变区域乳酸峰值明显升高,天冬氨酸峰值降低,中心较外周显著。结论根据上述临床和影像学特点,可对MELAS综合征进行早期诊断和鉴别诊断,肌活检可进一步确诊。

多重连接探针扩增技术检测常见线粒体疾病

目的探讨多重连接探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)用于常见线粒体疾病基因检测的可行性。方法收集2010年5月至2012年8月北京协和医院281例可疑线粒体异常病例,包括神经科存在神经系统损伤的患者233例及眼科疑诊Leber遗传性视神经病变的患者48例,运用MLPA法对常见线粒体疾病突变位点进行检测,并使用线粒体基因序列测定方法进行验证。结果 281例标本中共38例检测到线粒体基因突变,总检出率为13.5%。眼科48例标本中,3460G>A、11778G>A和14484T>C3种突变共检测到19例,检出率为39.6%;神经科233例标本中,3243A>G、8344A>G、8993T>G和大片段缺失共检测到19例,检出率为8.2%。除1例大片段缺失暂无PCR测序验证外,其余MLPA结果均经序列测定验证为相符。结论 MLPA法是一种可行的快速、准确、简便的基因诊断方法,可作为筛查常见线粒体疾病的检测工具,为临床诊断和治疗提供依据。

线粒体脑肌病伴高乳酸血症及卒中样发作患者头痛的临床特征

目的探讨线粒体脑肌病伴高乳酸血症及卒中样发作(MELAS)患者头痛的临床特征。方法收集46例伴头痛的MELAS综合征患者(头痛组)及14例无头痛患者(非头痛组)的临床资料进行分析。结果与非头痛组比较,头痛组癫痫发作率及恶心、呕吐率显著升高(均P<0.05),肢体无力、偏盲、失语、听力减退、认知障碍、共济失调、眼外肌麻痹、发热、发育异常以及腹泻、便秘比率的差异无统计学意义(均P>0.05)。头痛组患者血乳酸异常率显著高于非头痛组(P=0.013);肌肉病理活检、基因检测以及EEG异常率在两组间差异无统计学意义(均P>0.05)。头痛组枕叶及2处病灶比率显著高于非头痛组(均P<0.05)。结论MELAS头痛患者以偏头痛样头痛为主,更容易发生癫痫发作,血乳酸水平更高。受累病灶多在枕叶。

线粒体脑肌病伴高乳酸血症和卒中样发作综合征的临床、影像及病理学特征

目的:探讨线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征(MELAS)的临床、影像及病理学特点。方法:通过4例MELAS综合征病例结合文献回顾性分析MELAS的临床、影像学及病理学特征。结果:以癫痫发作起病1例,头痛起病2例,发热伴意识障碍起病1例;头颅MRI检查示顶、枕叶和(或)颞叶T1WI/T2WI长或稍长信号及FLAIR高信号病灶,呈脑回样改变,均未见强化。3例肌肉活检发现有肌纤维变性,横纹消失或断裂,肌膜下出现不规则的不整红边纤维(RRF);其中1例行基因检测发现有线粒体DNA A3243G位点突变,另有1例曾多次住院未行肌肉活检。结论:MELAS主要表现为卒中样起病伴癫痫发作,可有视听力减退以及认知功能障碍等;影像学特征为病变主要累及双侧大脑半球后部皮质,呈脑回样改变;肌肉活检发现RRF;基因检测可发现线粒体DNA A3243G位点突变。

线粒体基因T13094C突变致伴颈髓病变的线粒体脑肌病伴高乳酸血症和卒中样发作/Leigh叠加综合征的临床、影像、病理及基因突变特点(附1例报告)

目的探讨线粒体基因T13094C突变致伴有颈髓病变的线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)/Leigh叠加综合征的临床、影像、病理及基因突变特点。方法回顾性分析1例伴颈髓病变的MELAS/Leigh叠加综合征患者的临床资料。结果患者为14岁女性,以双下肢麻木、抽搐起病,症状反复发作并进展,逐渐出现呕吐、眼球运动障碍、共济失调、乳酸酸中毒、易激惹、呼吸衰竭、昏迷等,于发病后20个月时死于癫痫持续状态。影像学表现为双侧大脑半球、C_(2-6)段颈髓、丘脑、双侧小脑半球、中脑、脑桥、延髓等处不断变化的新病灶。肌肉病理学检查示Gomori染色可见破碎红纤维,琥珀酸脱氢酶染色可见周边深染的肌纤维,电镜示明显的线粒体数量和形态异常。血和肌肉线粒体基因测序示T13094C杂合突变。结论线粒体基因T13094G突变致MELAS/Leigh综合征出现颈髓病变为线粒体病所罕见;持续进展乃至死亡的病程不同于A3243G突变患者。