一种新的线粒体DNA基因突变：线粒体脑肌病伴高乳酸血症和卒中样发作综合征1例基因与残障特征分析

背景：线粒体脑肌病伴高乳酸血症和卒中样发作综合征(MELAS)是线粒体脑肌病中最常见的一种临床类型，多种线粒体基因突变均可导致MELAS。目的：探讨1例MELAS患者的临床表现和线粒体基因突变的关系。设计：临床、病理和基因分析对照研究。地点和对象：实验在解放军济南军区总医院神经内科病房、神经病理实验室和神经分子生物学实验室进行。患者，男，13岁，因发作性头痛、呕吐，肢体抽搐1个月于2001-06-04入院，人院后逐渐出现失明和智能减退。血乳酸和丙酮酸水平升高，临床诊断MELAS。干预：对患者行头颅MRI检查、脑活检病理检查和线粒体基因分析。主要观察指标：临床表现特点、MRI病变特征、脑组织病理改变特点以及线粒体基因突变类型。结果：患者不存在能引起MEIAS的较常见的突变，但在线粒体3314—3589之间有276bD的碱基缺失。结论：线粒体DNA3314—3589位点之间276bp的碱基缺失可能是能够导致MEIAS的一种新的基因突变类型，也是导致患者出现失明、癫痫和痴呆的原因。     

乳酸酸中毒和卒中样发作综合征型线粒体脑肌病误诊分析

目的探讨乳酸酸中毒和卒中样发作综合征(MELAS)型线粒体脑肌病的临床特点及误诊原因。方法回顾性分析MELAS型线粒体脑肌病长期误诊1例的临床资料。结果本例因反应迟钝、发热3 d入院,行颅脑MRI及腰椎穿刺脑脊液等检查多次误诊为病毒性脑炎,先后行抗病毒、糖皮质激素、丙种球蛋白等治疗2年余,症状反复。后经血乳酸升高、乳酸运动试验阳性、肌肉活检病理检查确诊为MELAS型线粒体脑肌病,予相应治疗后病情明显缓解。结论 MELAS型线粒体脑肌病临床表现复杂多样,易误诊为病毒性脑炎。对病情反复发作按病毒性脑炎治疗效果不佳者应高度可疑本病,及时行血乳酸、乳酸运动试验、肌电图及肌肉活检病理检查,以帮助确诊。     

线粒体脑肌病的研究进展

线粒体脑肌病（mitochondrial encephalomyopathy）是指由线粒体基因或细胞核基因发生缺失或点突变导致的线粒体结构和功能异常,引起机体能量代谢障碍,主要累及脑和横纹肌的一类疾病。线粒体脑肌病根据临床和病理特点分为许多类型,如坏死性脑脊髓病（Leigh综合征）、卷发样脑灰质营养不良综合征（Menke病）和进行性皮层灰质萎缩症（Alpers病）、Kearne-Sayre综合征（KSS）、线粒体脑肌病并发乳酸血症和卒中样发作（MELAS）、肌阵挛瘢痫并发不整红边纤维（MERRF）、慢性进行性外眼肌麻痹（CPEO）等。笔者从该病常见类型的病理、临床表现、影像学表现及治疗等方面进行综述。     

MELAS型线粒体脑肌病一个家系的临床-影像和基因学研究

线粒体脑肌病(Mitochondrial encephalomyopathies,ME)是一种罕见遗传病,它是由于线粒体结构或功能异常导致的以横纹肌和脑受累为主的多系统疾病,以ME伴高乳酸血症和卒中样发作最为常见.因其临床表现复杂且缺乏特异性,在临床上常被误诊为脑梗死、脑膜脑炎和癫痫等.本研究通过对一个家系MELAS型ME患者的系统分析,了解线粒体突变类型、临床表现和影像学特点.     

线粒体脑肌病伴高乳酸血症和卒中样发作误诊为脑梗死

目的探讨线粒体脑肌病伴高乳酸血症和卒中样发作的诊断要点、误诊原因及防范措施。方法对我院近期收治的误诊为脑梗死的线粒体脑肌病伴高乳酸血症和卒中样发作1例的临床资料进行回顾性分析。结果患者因双眼突发视力减退1 d入院,经查体及头颅MRI等相关检查考虑脑梗死,予相应治疗,视力稍好转。后患者行头颅数字减影血管造影及磁共振波谱检查排除脑梗死,最终经基因检查确诊线粒体脑肌病(MELAS综合征)。予改善代谢及脑供血等治疗3个月,患者病情明显好转,头颅MRI检查示病灶消失。结论临床表现与急性脑梗死相似、头颅MRI检查提示脑梗死及接诊医生知识面狭窄是导致本例误诊的主要原因。加强学习、拓宽知识面、了解并掌握线粒体脑肌病相关知识,可防止或减少其误诊。     

成人MELAS型线粒体脑肌病误诊一例分析

目的 分析MELAS型线粒体脑肌病的临床特点及误诊原因.方法 回顾性分析1例MELAS型线粒体脑肌病的临床资料.结果 患者出现发作性抽搐,言语异常、视力下降,于当地医院误诊为脑梗死,转入首都医科大学宣武医院误诊为病毒性脑炎,后经磁共振波谱分析、及左侧肱二头肌活检诊断为MELAS型线粒体脑肌病.给予B族维生素、辅酶Q10治疗,病情缓解.结论 对于青年患者出现进行性加重的智力、听力、视力下降及肌无力癫痫发作等症状,应考虑MELAS型线粒体脑肌病的可能,进一步结合血乳酸测定、肌肉活检病理及基因检查,以及早确诊.     

伴有胃肠道表现的线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征4例

线粒体脑肌病(mitochondrial encephalopathy)是一组因线粒体DNA(mitochondrial DNA.mtDNA)发生点突变或缺失,引起线粒体结构和功能异常而导致的,以脑和肌肉受累为主的多系统疾病.线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征(mitochondrial encephalomyopathy with lacticacidosis and stroke-like episodes MELAS)作为线粒体脑肌病中最为常见的一种类型,已证实与多种mtDNA点突变有关,其中A3243G点突变最为常见.     

一例线粒体脑肌病伴高乳酸血症和卒中样发作患者的护理

<正>线粒体脑肌病伴高乳酸血症和卒中样发作(Mitochondrial encephalomyopathy with lactic acidemia and stroke-like episodes,MELAS)是最常见的一类表现为综合征的线粒体疾病,是由于线粒体DNA及核DNA基因突变,导致的蛋白合成障碍引起的多器官、多组织的进行性变性疾病,具有高度的临床变异性和遗传异质性[1]。临床表现为卒中样发作、癫痫、乳酸     

线粒体脑肌病伴高乳酸血症和卒中样发作综合征一例报告

<正>线粒体脑肌病伴高乳酸血症和卒中样发作综合征(Mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episode,MELAS)为最常见的线粒体脑肌病,是线粒体DNA(mitochondrial DNA,mtDNA)及核DNA基因突变导致蛋白合成障碍引起的多器官、多组织的进行性变性疾病,临床表现为卒中样发作、脑病、肌病、乳酸性酸中毒及耳、眼、心、肾、胃肠道、内分泌等多系统损害[1-3]。本病累及器官广泛,神经系统症状多样,症状复杂,常易误诊、漏诊。本文报道1例如下。     

脑炎样发作的线粒体脑肌病2例误诊分析

线粒体脑肌病合并乳酸血症与中风样发作(mitochondrial encephalomyopathy,lactic acidosis,and stroke-like,MELAS)是由于线粒体结构和功能异常引起的多系统损害的临床综合征.临床上MELAS并非少见,但由于临床表现复杂且缺乏特异性,早期影像学表现不典型,很容易被误诊为癫痫、脑炎或脑梗死,经多次就诊以后才被明确诊断,有些患者被误诊长达数年乃至终生.     

Assessing the relative incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance

OBJECTIVE: To determine whether patients with migraine without aura with maternal "inheritance" are affected by a monosymptomatic form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR) gene. BACKGROUND: The association between migraine and abnormal mitochondrial function has been suggested on clinical, biochemical, and neuroradiological grounds. Migraine attacks with vomiting and cerebral infarctions, most often in the posterior cerebral regions, which are reminiscent of complicated migraine, are typical features of MELAS. The observation that migrainous patients have affected mothers more often than affected fathers suggests a possible role for maternally transmitted genetic factors. METHODS: We studied 25 patients with migraine with aura whose mothers were also affected. A sensitive polymerase chain reaction restriction fragment length polymorphism analysis was used to detect mutated genomes. CONCLUSIONS: We failed to detect the MELAS mutation, but migraine may still be associated with point mutations of mtDNA other than A3243G or with as-yet-unidentified nuclear DNA factors related to mitochondrial function.     

Design and use of a peptide nucleic acid for detection of the heteroplasmic low-frequency mitochondrial encephalomyopathy,lactic acidosis,and stroke-like episodes (MELAS) mutation in human mitochondrial DNA

BACKGROUND: Most pathogenic human mitochondrial DNA (mtDNA) mutations are heteroplasmic (i.e., mutant and wild-type mtDNA coexist in the same individual) and are difficult to detect when their concentration is a small proportion of that of wild-type mtDNA molecules. We describe a simple methodology to detect low proportions of the single base pair heteroplasmic mutation, A3243G, that has been associated with the disease mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in total DNA extracted from blood. METHODS: Three peptide nucleic acids (PNAs) were designed to bind to the wild-type mtDNA in the region of nucleotide position 3243, thus blocking PCR amplification of the wild-type mtDNA while permitting the mutant DNA to become the dominant product and readily discernable. DNA was obtained from both apparently healthy and MELAS individuals. Optimum PCR temperatures were based on the measured ultraviolet thermal stability of the DNA/PNA duplexes. The presence or absence of the mutation was determined by sequencing. RESULTS: In the absence of PNAs, the heteroplasmic mutation was either difficult to detect or undetectable by PCR and sequencing. Only PNA 3 successfully inhibited amplification of the wild-type mtDNA while allowing the mutant mtDNA to amplify. In the presence of PNA 3, we were able to detect the heteroplasmic mutation when its concentration was as low as 0.1% of the concentration of the wild-type sequence. CONCLUSION: This methodology permits easy detection of low concentrations of the MELAS A3243G mutation in blood by standard PCR and sequencing methods.     

MELAS型线粒体脑肌病的MRI诊断

目的 探讨MELAS型线粒体脑肌病的MRI的表现特点.方法 回顾分析10例经病理证实的MELAS型线粒体脑肌病患者的临床及MRI检查资料.结果 10例患者均为多脑叶发病,5例双侧颞、枕、顶叶皮层及皮层下可见大片状长T1长T2信号影,具有一定对称性,3例右侧额叶、颞叶、枕叶大片状长T1长T2信号影,2例左侧颞叶、枕叶大片状长T1长T2信号影,病变不按血管支配区分布.FLAIR序列呈高信号,急性期病变于DW1序列呈高信号,有3例累及脑深部核团,累及豆状核2例,累及豆状核和尾状核1例,累及小脑2例,累及脑干1例,并有不同程度脑萎缩4例.增强扫描少有强化.结论 MELAS型线粒体脑肌病的MRI表现有一定特征性,但最终诊断需结合临床表现和实验室检查.     

High-sensitivity detection of the A3243G mutation of mitochondrial DNA by a combination of allele-specific PCR and peptide nucleic acid-directed PCR clamping

BACKGROUND: The A3243G mutation of mitochondrial DNA (mtDNA) is involved in many common diseases, including diabetes mellitus and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). For detection of this mutation, allele-specific PCR is highly sensitive but requires strict control of PCR conditions; it thus is not adequate for a routine clinical test. We aimed to develop a routinely available PCR method for quantitative detection of low-level heteroplasmy of the A3243G mutation. METHODS: Quantitative allele-specific PCR for the A3243G mutation was performed in the presence of peptide nucleic acid (PNA), in which PNA is complementary to the wild-type mtDNA, with one primer having a 3' end matched to nucleotide position 3243 of the mutant. RESULTS: With our method, amplification of wild-type mtDNA was suppressed 7000-fold compared with amplification of the mutant mtDNA under a broad range of conditions: DNA, 5-100 ng; annealing temperature, 61-66 degrees C; and PNA, 1.5-3.5 micromol/L. Hence, 0.1% heteroplasmy of the A3243G mutation can be reliably quantified by this method. Blood samples form 40 healthy volunteers showed <0.06% heteroplasmy, suggesting that 0.1% is diagnostically significant. CONCLUSIONS: PNA maintains the specificity of allele-specific PCR over a wide range of conditions, which is important for routine clinical testing.     

Headache and mitochondrial disorders

We report on 2 patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS). These 2, and 9 other, reported patients share the following features: ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Lactic acidemia is a common finding. We believe that MELAS represents a distinctive syndrome and that it can be differentiated from 2 other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns–Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome. Existing information suggests that MELAS is transmitted by maternal inheritance. The ragged red fibers suggest an abnormality of the electron transport system, but the precise biochemical disorders in these 3 clinical syndromes remain to be elucidated.     

Proteomic and metabolomic advances uncover biomarkers of mitochondrial disease pathophysiology and severity

Advancing proteomic and metabolomic technologies that integrate curated omic databases have crossed a threshold to enable their clinical utility. In this issue of the JCI, Sharma et al. exploit emerging technologies to evaluate whether biomarkers identified in the mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome could refine disease characterization, uncover pathways to monitor therapeutic efficacy, and/or delineate disease-modifying targets. The authors analyzed blood and urine samples from patients with this genetic mitochondrial disease and elucidated proteins and metabolites related to NADH-reductive stress. These circulating biomarkers have intriguing clinical potential that implicate disease pathophysiology and may prove important biomarkers for the future management of MELAS.     

伴小脑萎缩的线粒体脑肌病MELAS一例

线粒体脑肌病伴高乳酸血症和卒中样发作（MELAS）是一种少见的遗传性疾病,可累及机体多系统。该病主要临床表现为头痛、癫痫、耳聋、皮质盲及认知功能下降等。MELAS呈卒中样发作,临床易误诊为脑梗死及脑炎,目前尚缺乏特效治疗方法。该文报道1例33岁女性MELAS 患者,其以突发头痛、视物不清为首发症状,伴有不完全感觉性失语、听力下降、不能耐受疲劳,急诊颅脑CT显示双侧小脑半球萎缩,入院后经外周血基因检查明确MELAS诊断,予辅酶Q10胶囊、艾地苯醌及维生素E治疗。患者病情好转后出院,随访3个月病情稳定。该病例提示临床医师应提高对MELAS的认识,注意鉴别诊断,避免漏诊或误诊。     

Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS): a mitochondrial disorder presents as fibromyalgia

This case report describes a patient who presented with symptoms and signs of longstanding fibromyalgia. Routine laboratory tests revealed an elevated anion gap. Evaluation of the elevated anion gap demonstrated elevated lactate and pyruvate levels and a lactate-to-pyruvate ratio greater than 20:1. A muscle biopsy was performed, exhibiting red ragged fibers, pathognomonic for a mitochondrial disorder. The patient was diagnosed with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS). This is the first report describing fibromyalgia as the initial presentation of MELAS. This article outlines the diagnostic process that can assist the physician in distinguishing mitochondrial disorders from other muscular diseases, particularly fibromyalgia.     

Acute blindness

A 15-year-old man presenting with cortical blindness as the initial symptom of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is reported. He showed fluctuating consciousness and severe occipital headache with nausea and vomiting. T2 and diffusion-weighted magnetic resonance imaging showed high signal intensity in the occipital lobes. Electroencephalography showed diffuse sharp waves with focal epileptic discharges over the posterior region. The nature of stroke-like episodes and seizure mechanisms is unexplained in MELAS. Consequently, the possible mechanisms of the cortical blindness in this case are discussed.     

Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms

Study objectives: Muscle is one of the most commonly affected organs in mitochondrial disorders, and the symptoms are often exercise related. The cardiopulmonary exercise test with the determination of lactic acid formation could give supplementary information about the exercise‐induced metabolic stress and compensatory mechanisms used in these disorders. The aim of this study was to evaluate the exercise capacity and lactate kinetics related to exercise in subjects with two genetically characterized mitochondrial disorders (multiple mitochondrial DNA deletions with PEO, MELAS) compared with lactate kinetics in subjects with metabolic myopathy (McArdle's disease) and in the healthy controls. Design: The subjects were consecutive, co‐operative patients of Department of Neurology of Helsinki University Hospital. Molecular genetic analyses were used for group classification of the mitochondrial myopathy. Study subjects: The study groups consisted of 11 patients with multiple deletions (PEO) and five patients with a point mutation in the mitochondrial DNA (MELAS), four patients with a muscle phosphorylase enzyme deficiency (McArdle's disease) and 13 healthy controls. The clinical disease of the patients was relatively mild. Measurements and results: A graded exercise test with ventilatory gas analyses and venous blood lactic acid analyses was performed. The main finding was the prolonged accumulation of blood lactate after the exercise in the PEO and MELAS groups compared with the controls. An overcompensation in ventilation was found in the MELAS and PEO group. Conclusions: The blood lactate accumulation after exercise occurs in patients with multiple mitochondrial DNA deletions or MELAS even in patients with only mild exercise intolerance. Cardiopulmonary exercise can be used in the diagnostic process of patients with mitochondrial myopathies.