肌肉活检未见显著异常的MELAS综合征：3例病理病例分析

目的：探讨肌肉活检未见显著线粒体异常病理改变的MELAS综合征的临床、神经影像及分子病理学特点。方法：3例患者（1男,2女）,发病年龄13-18岁,1例以癫痫首发,2例以头痛呕吐首发。3例均有家族史,符合母系遗传方式。主要临床表现包括：癫痫发作(3/3例),视物下降(3/3例),发作性头痛(2/3例),听力减退 (2/3例),身材矮小（2/3例）,智能减退 (2/3例),精神异常(1/3例)。3例患者均进行肱二头肌活检。应用限制性片段长度多态方法对患者尿液mtDNA A3243G位点突变进行分析。结果：3例患者血清肌酸激酶正常,空腹血乳酸增高。肌电图检查正常。头颅MRI示T2异常高信号,枕叶3例,颞叶2例,顶叶2例,动态检查卒中样病灶呈迁徙样改变者1例。肌活检在3例患者均可见个别SDH深染的肌间小血管,未见破碎红肌纤维和COX阴性肌纤维。3例患者mtDNA基因突变分析发现均存在A3243G点突变。结论：MELAS综合征的临床异质性明显,肌无力症状可以不突出,而且肌肉活检可以没有破碎红肌纤维和COX阴性肌纤维,SDH深染的小血管可能有重要提示价值。     

Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation

We report on a unique patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting optic atrophy, cardiomyopathy, and bilateral striatal necrosis before stoke-like episodes became apparent. Skeletal muscle total mitochondrial DNA analysis identified a heteroplasmic A to G point mutation in the tRNA(Lys) gene at position 8296. Skeletal muscle pathology revealed typical MELAS findings, including ragged-red fibers cytochrome c oxidase positive strongly succinate dehydrogenase-reactive blood vessels. Recent reports describe the 8296 mutation identified in patients with diabetes mellitus or myoclonus epilepsy with ragged-red fibers, not MELAS. We conclude that the 8296 mutation is likely to be pathogenic and that it may be not only a mutation responsible for diabetes mellitus or myoclonus epilepsy with ragged-red fibers but also for MELAS.     

Atypical MELAS associated with mitochondrial tRNA gene A8296G mutation

We report on a unique patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting optic atrophy, cardiomyopathy, and bilateral striatal necrosis before stoke-like episodes became apparent. Skeletal muscle total mitochondrial DNA analysis identified a heteroplasmic A to G point mutation in the tRNA^Lys gene at position 8296. Skeletal muscle pathology revealed typical MELAS findings, including ragged-red fibers cytochrome c oxidase positive strongly succinate dehydrogenase-reactive blood vessels. Recent reports describe the 8296 mutation identified in patients with diabetes mellitus or myoclonus epilepsy with ragged-red fibers, not MELAS. We conclude that the 8296 mutation is likely to be pathogenic and that it may be not only a mutation responsible for diabetes mellitus or myoclonus epilepsy with ragged-red fibers but also for MELAS.     

Mitochondrial 3243 A-->G mutation (MELAS mutation) associated with painful muscle stiffness.

The mitochondrial mutation A-->G at nucleotide position 3243 is associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and other mitochondrial encephalomyopathies. We found this mutation in a 61-year-old patient who developed at the age of 54 a myopathy with painful muscle stiffness as the predominant symptom. Additionally hypacusis, a mild hemisensory syndrome and impaired glucose tolerance were present. Muscle histopathology showed few ragged red fibers. The mutation was detected heteroplasmatically in DNA from muscle and blood. So far painful muscle stiffness has not been a known phenotype of the 3243 mutation.     

mtDNA nt3243 Mutation, External Ophthalmoplegia, and Hypogonadism in an Adolescent Girl

A 14-year-old girl presented with a 3-month history of easy fatigue and exercise intolerance, especially when climbing stairs. She had a mild ptosis and mild limitation of upward gaze. Her puberty was delayed, and she manifested hypogonadotrophic hypogonadism. Serum lactic and pyruvic acids were elevated. Cranial magnetic resonance imaging was normal. Muscle biopsy documented typical ragged-red fibers. A point mutation at nucleotide 3243 in the tRNA^Leu(UUR) (typical mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation) was detected in mitochondrial DNA from both blood and muscle tissues, indicating that our patient was suffering from a mitochondrial myopathy. Hypogonadism may be a manifestation of the MELAS nucleotide 3243 mutation.     

CPEO and carnitine deficiency overlapping in MELAS syndrome

Mitochondrial myopathy, encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the mitochondrial encephalomyopathies that has distinct clinical features including stroke-like episodes with migraine-like headache, nausea, vomiting, encephalopathy and lactic acidosis. We report a 27-year-old woman who presented with partial seizure, stroke-like episodes including hemiparesis, hemianopia and hemihypethesia, sensorineural hearing loss, migraine-like headache, and lactic acidosis. Brain computed tomographic scan showed encephalomalacia in the right parieto-occipital area and recent hypodensity in the left temporoparieto-occipital area with cortical atrophy. Muscle biopsy revealed ragged-red fibers and paracrystaline inclusions in the mitochondria. Genetic study revealed an A to G point mutation at nucleotide position (np) 3243 of mitochondrial DNA. External ophthalmoplegia and ptosis were also found during two exaggerated episodes in this patient. Therefore, the overlapping syndrome of chronic progressive external ophthalmoplegia in the MELAS syndrome is considered in this case. Furthermore, we also found carnitine deficiency in this patient and she was responsive well to steroid therapy. Muscle biopsy also revealed excessive lipid droplets deposits. Therefore, the carnitine defiency may occur in MELAS syndrome with the A to G point mutation at np 3243. We recommend the steroid or carnitine supplement therapy be applied to the MELAS syndrome with carnitine deficiency.     

Acute hearing loss in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)

The mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare congenital disorder of mitochondrial DNA. Patients with this syndrome may present acute onset of sensorineural hearing loss, which is genetic in origin. An impression of the MELAS syndrome is favored because hearing loss is part of the syndrome for some patients with epilepsy. We report a 20-year-old man who suffered from acute onset of bilateral hearing loss with epilepsy and two stroke-like events which recovered without any sequela. Epilepsy with complex partial seizures was controlled by antiepileptic drugs. Brain magnetic resonance images showed high signal lesions in bilateral temporal lobes. Serum levels of pyruvate and lactate were elevated. Muscle biopsy showed ragged-red fibers and molecular genetic study showed a point mutation of the mitochondrial A3243G gene. Mitochondrial disease with the MELAS syndrome was diagnosed and then he was treated with Co-enzyme Q10 and carnitine. The symptoms recovered gradually.     

Deep white matter pathologic features in watershed regions: a novel pattern of central nervous system involvement in MELAS

BACKGROUND: Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome typically manifests in adults younger than 40 years with encephalopathy, stroke-like episodes, and lactic acidosis. Magnetic resonance imaging (MRI) abnormalities typically involve the cortical gray and the adjacent subcortical white matter. OBJECTIVE: To describe a 58-year-old woman diagnosed with MELAS who was initially seen with acute myopathy, cardiac ischemia, psychosis, and MRI changes in a watershed distribution. RESULTS: Initial MRI of the brain showed the characteristic parieto-occipital gray matter lesions involving the adjacent white matter. Follow-up MRI revealed striking deep white matter involvement in a watershed distribution. A cerebral angiogram and thorough hypercoagulable workup results were normal. Electromyography showed acute denervation and myopathy. A muscle biopsy specimen revealed ragged red and cytochrome-c oxidase-negative fibers. Mitochondrial DNA analysis revealed an A3243G mutation. CONCLUSIONS: Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes should be considered in older patients with myopathy, cardiomyopathy, encephalopathy, and unaccountable MRI findings. Watershed pathologic features are a rare pattern of cerebral involvement in MELAS.     

An autopsy case of mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes (MELAS) with a point mutation of mitochondrial DNA

A 14-year-old boy with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is reported. He had suffered blepharoptosis and cataracts prior to the stroke-like episodes, and was thus reported in 1984 as having Kearns-Shy (Sayre) syndrome. After his death, an A-to-G mutation of the mitochondrial DNA (mtDNA) at bp 3243 was identified in cardiac muscle and the liver. Neuropathologically, multiple old and recent necrotic foci were observed in the gray and white matter of the cerebrum and cerebellum. These lesions were occasionally observed in areas outside of the distribution of major blood vessels of the brain. In the recent necrotic foci, neural loss and sponginess were observed while some neurons were preserved intact. The latter finding has not been described in MELAS and suggests that metabolic degeneration had occurred in the neurons of this patient. This is the first report of a confirmed 3243 mutation of the mtDNA in an autopsied MELAS case.     

A novel tRNA(Val) mitochondrial DNA mutation causing MELAS

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common mitochondrial disease due to mitochondrial DNA (mtDNA) mutations. At least 15 distinct mtDNA mutations have been associated with MELAS, and about 80% of the cases are caused by the A3243G tRNA(Leu(UUR)) gene mutation. We report here a novel tRNA(Val) mutation in a 37-year-old woman with manifestations of MELAS, and compare her clinicopathological phenotype with other rare cases associated tRNA(Val) mutations.     

Heterogeneous phenotypic manifestations of maternally inherited deafness associated with the mitochondrial A3243G mutation. Case report

The A3243G mutation is one of the most frequent mutations of mitochondrial DNA. The phenotypic expression of the A3243G mutation is variable and causes a wide range of syndromic and non-syndromic clinical disorders. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is the most frequent syndromic manifestation of the A3243G mutation. Stroke-like episodes seem to be the dominant feature of MELAS. We have investigated the case of a family with A3243G mutation, in which a dominant symptom in three generations was the maternally inherited hearing loss with absence of stroke-like episodes. Besides deafness, we found also other clinical features such as myopathy, neuropathy, migraine, ataxia, short stature, diabetes mellitus, and cardiomyopathy.     

Clinical and genetic features in two families with MELAS and the T3271C mutation in mitochondrial DNA

The majority of patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) have the A3243G point mutation. The much rarer T3271C mutation has been reported predominantly in Japanese subjects. Our objective was to better define the clinical phenotype and mutation load in patients with MELAS and the T3271C mutation in mitochondrial DNA. We present clinical and molecular genetic data in two pedigrees with the T3271C mutation. The age at onset was 8 years in one proband and 14 years in the other. Both patients had migrainelike headache, seizures, and strokelike episodes. Mutation loads were quantified in multiple tissues from the patients and from family members by polymerase chain reaction-restriction fragment length polymorphism analysis. The symptoms in both probands were typical of MELAS, and, contrary to previous reports, onset was early. Hearing loss was less common than in typical MELAS, and ragged red fibers were absent. The proportion of mutant genomes was consistently and markedly greater in DNA from urinary sediment than from blood. In the mother of one proband, mutant genomes were detected only in DNA from hair follicles and cheek mucosa The phenotype of patients with the T3271C mutation might not be as distinct as that of the A3243G mutation, as previously described. Our data also suggest that urine is a better source of DNA than blood for diagnosis and that multiple tissues should be studied in maternal relatives, especially when the mutation cannot be detected in blood.     

线粒体脑肌病伴有高乳酸血症和卒中样发作综合征的临床及基因突变分析

目的 探讨线粒体脑肌病伴有高乳酸血症和卒中样发作综合征(MELAS)的临床及基因突变特征. 方法 对1例MELAS患者的临床表现、影像学、肌肉病理特点进行分析,并用PCR-RFLP结合基因测序方法进行线粒体基因突变分析. 结果 患者主要临床表现为发作性头痛和呕吐、反复卒中样发作、癫痫、运动不耐受、身材矮小、神经性耳聋、乳酸水平升高等.脑CT见双侧基底节多个钙化灶,MRI见枕叶异常信号,1H-MRS见T2WI异常信号区域有明显的乳酸峰,在T2正常信号区域也有小的乳酸峰.光镜及电镜肌肉病理检查未见明显的线粒体异常,基因检测显示mtDNA A3243G杂合突变. 结论 MELAS的诊断必须结合临床表现、影像学、病理学和基因突变检测等结果进行综合分析,病理学检查阴性不能否定MELAS的诊断,诊断MELAS应常规进行mtDNA突变分析.     

The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS

We report on 4 male patients with clinical, radiological, and muscle biopsy findings typical of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype. Skeletal muscle mitochondrial DNA (mtDNA) analysis showed that all patients harbored a heteroplasmic G13513A mutation in the ND5 subunit gene. One of these cases (Patient 1) presented with symptoms characteristic of Leber's hereditary optic neuropathy (LHON) 2 years before the first stroke-like episode. Quantitative analysis in several postmortem tissue sections showed that the relative proportions of mutant mtDNA were generally lower than those reported with other pathogenic mtDNA mutations. Single-fiber polymerase chain reaction studies demonstrated significantly higher amounts of mutant mtDNA in ragged red fibers (RRFs) compared with non-RRFs. This study indicates that the G13513A transition is likely to be pathogenic, that it can cause an LHON/MELAS overlap syndrome, and that it may be a more frequent cause of MELAS than previously recognized.     

MELAS syndrome with mitochondrial tRNA(Leu(UUR)) gene mutation in a Chinese family.

The clinical features of a patient in a Chinese family with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) are reported. The study revealed that hearing and visual impairments and miscarriages may be early clinical presentations in MELAS. A heteroplasmic A to G transition in the tRNA(Leu(UUR)) gene was noted at the nucleotide pair 3243 in the mitochondrial DNA of muscle, blood, and hair follicles of the proband and his maternal relatives. Quantitative analysis of the mutated mitochondrial DNA revealed variable proportions in different tissues and subjects of maternal lineage in the family. Muscle tissue contained a higher proportion of the mutant mitochondria than other tissues examined. The function of the reproductive system of the proband seems to be impaired. In one clinically healthy sibling, the 3243rd point mutation was found in sperm mitochondrial DNA, although sperm motility was not affected. It seems that biochemical defects in mitochondrial respiration and oxidative phosphorylation are tissue specific expressions of the 3243rd point mutation in the mitochondrial DNA of the affected target tissues.     

Overlapping syndrome of MERRF and MELAS: molecular and neuroradiological studies

We describe a 42-year-old woman with overlapping syndrome of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonus epilepsy and ragged-red fibers). Clinically, she had episodic headache, stroke-like episode with left hemiparesis and lactic acidosis commonly found in MELAS syndrome. However, myoclonus seizure, and ataxia with dyssynergic gait characteristic of MERRF were also noted. Computed tomographic scans showed a right temporo-parietal hypodense lesion. The lesion disappeared 20 months later, even magnetic resonance images also failed to reveal this abnormality. A molecular analysis of mitochondrial DNA was conducted by using restriction endonucleases Apa I and Nae I. A transition from A to G was found at the nucleotide position 3243, but not found at the 8344th nucleotide pair. In this report, we document the fluctuating CT changes and emphasize the importance of molecular analysis in patients with overlapping syndrome of mitochondrial encephalomyopathies.     

The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?

The m.3243A>G “MELAS” (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study (“Nation-wide Italian Collaborative Network of Mitochondrial Diseases”). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. “MIDD” (maternally-inherited diabetes and deafness) and “PEO” (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The “MELAS” acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.     

线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征一家系临床特征及线粒体基因A3243G位点点突变异质性水平

目的 调查1个疑似患有母系遗传性线粒体脑肌病伴高乳酸血症和脑卒中样发作(MELAS)综合征家系的临床表现、生物化学检测数据和影像学资料,并探索其与血细胞线粒体基因突变异质性水平的关联性.方法 收集先证者和11位其母系家系成员的一般情况、抽搐及脑卒中样发作等病史,检测家系成员的血常规和运动前后血浆乳酸水平等生化指标,并做头颅磁共振检查.用聚合酶链反应(PCR)-限制性内切酶片段长度多态和DNA测序法检测其成员是否存在线粒体基因组A3243G点突变,并用荧光实时定量PCR定量该突变的水平.结果 该家系部分成员存在抽搐、脑卒中样发作和高乳酸血症等MELAS综合征典型症状,以及身材矮小、运动不耐受和发热、偏头痛等非典型症状.发作期头颅磁共振成像符合MELAS综合征的典型特点,且普遍存在小脑萎缩.母系亲属均存在线粒体基因的A3243G位点点突变,突变异质性水平越高,症状越典型且严重.结论 该调查家系确诊母系遗传性MELAS综合征,其致病基因为线粒体A3243G点突变.外周血血细胞线粒体基因突变异质性水平与亲缘关系、抽搐早现性和血乳酸值等临床表型存在相关性.     

线粒体基因G13513A突变导致的线粒体脑肌病六例临床表型分析

目的 报告6例mtDNA G13513A点突变引起的线粒体脑肌病患者的临床、影像学特点,总结mtDNA G13513A突变所致的线粒体病的临床表型.方法 对35例mtDNA常见突变(包括大片段缺失及A3243G、T3271C、A8344G、T8993G/C点突变)检查为阴性的线粒体脑肌病患者,用线粒体DNA全长测序和(或)聚合酶链反应-限制性片段长度多态法检测mtDNA G13513A点突变,分析阳性患者的临床特点,复习文献报道的mtDNA G13513A所致线粒体病的病例.结果 35例患者中有6例存在mtDNA G13513A突变.该6例患者均出现偏盲、轻偏瘫或偏身感觉障碍等卒中样发作表现,其中3例成人发病者以卒中样发作为主要症状,伴随癫痫、头痛、身材矮小、神经性耳聋等,头颅MRI显示以顶-枕-颢叶受累为主的大片病灶,符合成人型线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)的临床和影像学特点;3例青少年发病者除卒中样发作外,还有构音障碍、共济失调、眼外肌瘫痪等脑干受累的症状,MRI检查可见枕-颞叶大脑皮质非对称性病灶,以及双侧基底节和脑干的对称性病灶,符合青少年型MELAS-Leigh叠加综合征的临床和影像学特点.肌肉病理检查在5例患者发现不整红边纤维.经复习文献,发现mtDNA G13513A突变患者还存在婴幼儿型Leigh或Leigh样综合征表型.结论 mtDNA G13513A点突变是线粒体脑肌病较常见的致病性突变,主要导致Leigh综合征、MELAS-Leigh叠加综合征或MELAS综合征,其临床表型具有年龄依赖性.

Abstract：

Objective To report 6 Chinese patients with mitochondrial encephalomyopathy caused by mitochondrial DNA(mtDNA)G13513A mutation and discuss the mitochondrial phenotype associated with this mutation based on the data of our patient series as well as the reports by others.Methods Direct sequencing of polymerase chain reaction(PCR)products or PCR-RFLP analysis Was performed to screen mtDNA G13513A mutation in 35 cases with mitoehondrial encephalomyopathy.who carried no mtDNA common mutations(1arge 8eale deletion,A3243G,T3271 C,A8344G,or T8993G/C).The clinical features,MRI changes were retrospectively collected and analyzed.Published studies of all patients with mtDNA G13513A mutation were also reviewed.Results Six patients were identified carrying mtDNA G13513A mutation.All patients presented stroke-like episodes with hemianopsia.hemiparesis or hemiparesthesia.Three adult patients presented clinical and radiological features of adult-onset mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),including stroke-like episodes,epilepsy,headache,short stature,sensorineural deafness,multifocal lesions on parietal,occipital and temporal lobes on cranial MRI scans.Three iuvenile.onset patients presented the clinical and brain MRI features of MELAS-Leigh syndrome(LS)overlap syndrome.In addition to the stroke-like episodes,they also showed brain stem lesions with dysarthria,ataxia,and ophthalmopJegia. Brain MRI revealed asymmetrical lesions in the cortex of the oecipital and temporal lobes,as well as symmetrical lesions in the bilateral basal ganglia and brainstem.Muslce biopsy showed ragged redfibem in 5 patients.The infant-onset LS or Leigh-like syndrome with mtDNA G135 13A was described in the English literature.Conclusions mtDNA G13513A mutation is a common pathogenic mutmion for mitochondrial encephalomyopathy,which can result in Leigh syndrome,MELAS-LS overlap syndrome and adult MELAS.The onset of various phenotypes is relatively age-dependent.