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.     

Cardiac tamponade: a new complication in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

We report the first case of cardiac tamponade in a 14-year-old female patient with an underlying illness of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The patient underwent a subxiphoid pericardiocentesis and pericardiotomy smoothly and was discharged with no sequelae. The coexistence of massive pericardial effusion and MELAS has never been mentioned in any literature. This case report attempts to exemplify the possibility of this connection.     

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.     

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,入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MELAS的较常见的突变,但在线粒体3314～3589之间有276 bp的碱基缺失.结论线粒体DNA 3314～3589位点之间276 bp的碱基缺失可能是能够导致MELAS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.     

Mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome (MELAS): a case report, presentation, and management

Mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome (MELAS) is a progressive neurodegenerative disorder frequently complicated by diabetes mellitus and sensory neuronal hearing loss. This syndrome tends to present initially with stroke-like symptoms. These strokes are nonvascular in nature and are linked to mitochondrial defect such as transient oxidative phosphorylation dysfunction, which in turn results in encephalopathy. The combination of lactic acidosis, multiple nonvascular strokes, encephalopathic psychosis, diabetes, and sensory neuronal hearing loss causes severe dysfunction leading to increased mental disabilities, physical disabilities, and eventually, death.     

超声心动图提示线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征早期心肌受损2例

病例1,男,21岁,无明显诱因出现持续性紧箍样头痛伴发作性口角抽搐1个月;既往神经性耳聋4个月.查体:神志清;双侧眼睑下垂,双侧眼球各方向运动受限;四肢肌力5级,肌张力正常,病理征均(一).实验室检查:血浆乳酸(lactic acid,Lac)24.1 mg/dl,血清肌钙蛋白Ⅰ(cardiac troponin Ⅰ,...     

Familial mitochondrial encephalomyopathy,lactic acidosis,and stroke-like episode syndrome: Three case reports

BACKGROUNDMitochondrial encephalomyopathy (ME) is a multisystem metabolic disease that primarily affects the central nervous system and skeletal muscle. It is caused by mutations in mitochondrial or nuclear DNA, resulting in abnormal mitochondrial structure and function and insufficient ATP synthesis. The most common subtype is mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome. In recent years, reports of MELAS syndrome have increased but familial cases are rare.CASE SUMMARYWe report a case of familial MELAS syndrome. Cases 2 and 3 are sisters and case 1 is their nephew. All are short in stature and showed stroke-like episodes with rapid onset and no obvious symptoms such as paroxysmal headache, aphasia, or blurred vision. After admission, blood lactate levels were significantly higher than normal. The patients underwent magnetic resonance imaging of the head. Cases 1 and 2 were considered to have ME, whereas case 3 was considered to have a space-occupying lesion in the left temporal lobe. Pathological evaluation showed no obvious tumor cells in the brain lesions of case 3. Muscle biopsy or genetic test results were consistent with ME. The patients were diagnosed with MELAS syndrome and their symptoms improved with intravenous infusions of coenzyme Q10, coenzyme A, vitamin B, and vitamin C. At the 6 mo follow-up, there was no recurrence or progression.CONCLUSIONWhen a patient has MELAS syndrome, familial MELAS syndrome should be considered if related family members have similar symptoms.     

Detection of common disease-causing mutations in mitochondrial DNA (mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes MTTL1 3243 A>G and myoclonic epilepsy associated with ragged-red fibers MTTK 8344A>G) by real-time polymerase chain reaction

The 3243A>G mutation in the MTTL1 (tRNA(Leu)) gene and the 8344A>G mutation in the MTTK (tRNA(Lys)) gene are the most common mutations found in mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes and myoclonic epilepsy associated with ragged-red fibers, respectively. These mitochondrial DNA mutations are usually detected by conventional polymerase chain reaction followed by restriction enzyme digestion and gel electrophoresis. We developed a LightCycler real-time polymerase chain reaction assay to detect these two mutations based on fluorescence resonance energy transfer technology and melting curve analysis. Primers and fluorescence-labeled hybridization probes were designed so that the sensor probe spans the mutation site. The observed melting temperatures differed in the mutant and wild-type DNA by 9 degrees C for the MTTL1 gene and 6 degrees C for the MTTK gene. This method correctly identified all 10 samples that were 3243A>G mutation-positive, all 4 samples that were 8344A>G mutation-positive, and all 30 samples that were negative for both mutations, as previously identified by traditional gel-based methods. This LightCycler assay is a rapid and reliable technique for molecular diagnosis of these mitochondrial gene mutations.     

Continuous venovenous hemodiafiltration for life-threatening mitochondrial myopathy with lactic acidosis and rhabdomyolysis

We report here the clinical course of a 31-year-old male who recovered from a fulminant form of mitochondrial myopathy with lactic acidosis. The patient was transferred to our hospital with acute dyspnea and a convulsive seizure. On admission, he was in a state of shock, and presented with severe high-output heart failure, acute renal failure, and rhabdomyolysis. Treatment with continuous venovenous hemodiafiltration (CVVHDF) resulted in an excellent response, with no signs of hemodynamic instability. This case suggests that CVVHDF with serial hemodynamic monitoring may be effective in treating hypotensive patients with a life-threatening mitochondrial disorder.     

Carboplatin: a new cause of severe type B lactic acidosis secondary to mitochondrial DNA damage

In adults, type B lactic acidosis is rare and generally associated with a toxin, particularly metformin or antiretroviral nucleosides analogues. We report a case of lactic acidosis caused by carboplatin in a 50-year-old woman suffering from primary peritoneal carcinoma. She was admitted for severe lactic acidosis (pH 6.77, lactate 19 mmol/L) associated with multiple organ failure (PaO?/FiO? 96, creatinine 231 μmol/L, aspartate aminotransferase > 25,000 UI, factor V 13%) occurring during the sixth carboplatin cycle. In the absence of sepsis, internal bleeding, alcohol poisoning, or other causes of lactic acidosis, the hypothesis of mitochondrial DNA (mtDNA) damage secondary to carboplatin and subsequent mitochondrial dysfunction leading to increase in glycolysis and lactic acidosis was suspected. L-Carnitine therapy associated with aggressive intensive care support led to a progressive improvement (pH 7.29, bicarbonate 24 mmol/L, lactate 7.8 mmol/L), but life support was withdrawn on day 7 because of peritoneal relapse. A respiratory chain dysfunction of enzyme activities encoded by mtDNA and multiple mtDNA deletions were found in muscle and liver tissue. It is generally accepted that carboplatin toxicity results in bone marrow suppression, renal dysfunction, or neurotoxicity and that platinating agents have no direct mitochondrial effect. However, although very unusual, emergency physicians must be aware that carboplatin can cause mitochondrial toxicity and trigger lactic acidosis.     

Biguanide-induced and - associated lactic acidosis: serum and tissue biguanide levels in hyperlactaemia and lactic acidosis (author's transl)]

An investigation was carried out on 30 diabetic patients in an attempt to clarify the relationship between serum biguanide levels and raised lactate. No consistent relationship was demonstrable between the serum biguanide level, administered dosage and time of administration. There was also no correlation between biguanide and lactate increase. It is not justifiable to quote a specific serum level of biguanides in defining lactic acidosis. A causal association between biguanide medication and lactic acidosis seems to be possible only by determination of serum and tissue levels. Determination of biguanide levels was carried out in the serum and tissue of a patient who had died as a result of lactic acidosis after phenformin administration. While the serum levels were only slightly higher than the therapeutic range, both liver and kidney tissue showed highly toxic levels. Furthermore, the amount of biguanides in the body was calculated in another patient successfully treated for lactic acidosis after buformin therapy. A differentiation should be made between biguanide-induced and biguanide-associated lactic acidosis. In both forms serum levels can be within relatively low ranges. In the former condition, the biguanides alone are responsible for the development of lactic acidosis by blocking the respiratory chain. In the latter condition they aggravate an already existing pathological condition, and can, therefore, represent a lethal factor.     

Phenformin and lactic acidosis: a case report and review

Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Unfortunately, this medication is still available from foreign sources. Another biguanide, metformin, was reintroduced to the United States market for the treatment of diabetes. Biguanide-induced lactic acidosis should be included in the differential diagnosis of elevated anion gap metabolic acidosis. We present a case of phenformin-induced lactic acidosis in which we were consulted at the local poison control center. We also review its pathophysiology, presentation, and treatment. A review of the actions of phenformin illustrates the mechanism of pathology that may also occur with metformin. Risk factors for the development of lactic acidosis include renal deficiency, hepatic disease, cardiac disease, and drug interaction such as cimetidine.     

Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis.

We report the case of an infant with hypoglycemia, progressive lactic acidosis, an increased serum lactate/pyruvate ratio, and elevated plasma alanine, who had a moderate to profound decrease in the ability of mitochondria from four organs to oxidize pyruvate, malate plus glutamate, citrate, and other NAD+-linked respiratory substrates. The capacity to oxidize the flavin adenine dinucleotide-linked substrate, succinate, was normal. The most pronounced deficiency was in skeletal muscle, the least in kidney mitochondria. Enzymatic assays on isolated mitochondria ruled out defects in complexes II, III, and IV of the respiratory chain. Further studies showed that the defect was localized in the inner membrane mitochondrial NADH-ubiquinone oxidoreductase (complex I). When ferricyanide was used as an artificial electron acceptor, complex I activity was normal, indicating that electrons from NADH could reduce the flavin mononucleotide cofactor. However, electron paramagnetic resonance spectroscopy performed on liver submitochondrial particles showed an almost total loss of the iron-sulfur clusters characteristic of complex I, whereas normal signals were noted for other mitochondrial iron-sulfur clusters. This infant is presented as the first reported case of congenital lactic acidosis caused by a deficiency of the iron-sulfur clusters of complex I of the mitochondrial electron transport chain.     

以癫痫发作为主要临床表现的线粒体脑肌病患者的临床及MRI特点分析

目的探讨总结以癫痫发作为主要临床表现的线粒体脑肌病的临床及脑部MRI表现特点,以提高对其认识及诊断正确率。方法回顾性分析7例临床确诊的以癫痫发作为主要临床表现的线粒体脑肌病患者的临床表现、简易乳酸运动试验、脑部MRI表现特点,进行分析总结。结果7例患者中男性3例,女性4例,年龄最大者39岁,最小者13岁,7例均有长期反复发作四肢抽搐病史,伴视物模糊1例,肢体乏力1例;7例患者行简易乳酸运动试验,6例患者高于正常参考值;7例患者脑部MRI均显示为大脑半球受累,6例为双侧大脑半球,其中颞、顶、枕叶较额叶多见,3例皮层受累为主,4例皮层及皮层下白质受累,1例累及双侧基底节区及右侧小脑半球,出现软化灶及脑萎缩;6例患者行多体素磁共振波谱成像检查,5例局部病变区可见乳酸峰;5例扩散加权成像提示病变区轻度扩散受限;2例患者行增强扫描,病变区皮层呈脑回样强化。结论以癫痫发作为主要临床表现的线粒体脑肌病的临床及脑部MRI特点多不典型,易于与其他疾病相混淆,诊断较困难,综合分析病史、简易乳酸运动试验、脑部MRI表现特点,有助于提高对疾病的认识和诊断的正确率。