乳酸丙酮酸最小运动量试验在线粒体肌病临床检查中的应用

目的研究乳酸丙酮酸最小运动量试验(theminimum exercise test of lactic acid and pyruvic acid,METLP)在线粒体肌病诊断中的作用。方法选择我院神经生化实验室2005年1月至2008年11月进行METLP检查并且有病理结果证实的患者共67例,根据病理诊断,线粒体病组患者36例,非肌病组20例,对METLP的结果分析。结果非肌病组和线粒体病组的运动后即刻的乳酸和丙酮酸浓度均明显升高,但是休息10min后又逐渐恢复接近初始水平。而二者在运动同一阶段血液内乳酸和丙酮酸浓度比较,线粒体病组浓度明显高于非肌病组,差异有统计学意义(P0.05)。在线粒体病评判的各项指标中,L2/P1是敏感性最高的一项指标。然而,METLP对线粒体肌病的诊断也出现了一定的误诊和漏诊情况,漏诊率为7.46%,误诊率为4.48%。结论METLP在对线粒体肌病的初步筛选起到一定作用,其各项分析指标中,L2/P1是最重要的的一项。     

线粒体肌病临床病理学特征及简易乳酸运动试验筛查价值

目的总结线粒体肌病(MM)的临床病理学特点,探讨简易乳酸运动试验在线粒体肌病筛查中的价值。方法分析经临床和病理学明确诊断的15例线粒体肌病患者临床病理学特点。15例线粒体肌病患者、11例其他肌肉疾病(OM)患者和21例正常对照者行简易乳酸运动试验,于运动前、运动后即刻和运动后10 min检测血清乳酸水平。结果线粒体肌病患者主要表现为发作性加重的肌肉酸痛无力,8例组织病理学显示破碎红纤维比例5%。简易乳酸运动试验显示:MM组运动前、运动后即刻和运动后10 min血清乳酸为(3.57±1.88)、(10.98±4.84)和(7.87±4.38)mmol/L,OM组为(1.89±0.98)、(6.05±4.07)和(4.13±3.14)mmol/L,对照组为(1.91±0.53)、(3.37±1.22)和(2.52±0.89)mmol/L。MM组运动前(P=0.000,0.001)、运动后即刻(P=0.000,0.001)和运动后10 min(P=0.000,0.003)血清乳酸水平均高于对照组和OM组,OM组仅运动后即刻血清乳酸水平高于对照组(P=0.042);3组运动后即刻(P=0.000,0.000,0.003)和运动后10 min(P=0.000,0.000,0.013)血清乳酸水平均高于运动前,运动后即刻亦高于运动后10 min(P=0.000,0.000,0.003)。3组血清乳酸水平升高趋势尤以MM组最显著,对照组最低平。结论简易乳酸运动试验简单易行,可以作为基层医院对线粒体肌病的初筛试验。     

有氧前臂运动试验在线粒体肌病及脑肌病筛选中的应用

目的 探讨血氧分析和乳酸测定在有氧前臂运动试验中的应用,及其对于线粒体肌病及脑肌病的筛选诊断意义.方法 对42例确诊的线粒体肌病及脑肌病(MM)、40名健康人(HC)和40例其他肌病患者(PC)进行有氧前臂运动试验,受试者以40%最大收缩力、1 s间隔做反复等长收缩前臂运动4 min,在运动前、运动中及运动后行血氧分析和乳酸测定.结果 运动中,MM组、HC组和PC组静脉PO2(mm Hg,1 mm Hg=0.133 kPa)分别从41.2±12.6降至39.5±16.2,50.5±14.4降至30.8±13.1,50.1±7.9降至44.3±35.5,HC组下降幅度明显高于其他2组(F=6.34,P＜0.01);3组静脉SO2分别从70.5%±15.8%降至64.4%±15.2%,82.4%±10.0%降至47.2%±11.7%,84.6%±6.3%降至51.1%±9.3%,MM组下降幅度明显低于其他2组(F=91.95,P＜0.01).运动后,静脉PO2、SO2 3组间差异无统计学意义.3组运动中血乳酸(mmol/L)分别由2.7±3.2升至5.1±3.8,1.1±0.5升至3.1±1.9,1.3±0.8升至3.5±1.8.运动后,3组血乳酸分别为3.8±3.5、1.8±1.0、2.3±1.4,MM组高于其余2组(F=8.50,P＜0.01).结论 线粒体肌病及脑肌病患者运动时氧摄取能力比健康人及其他肌病患者下降.有氧前臂运动试验运用血氧分析和乳酸测定的方法,是一种行之有效的线粒体肌病及脑肌病筛查试验,对于线粒体肌病及脑肌病的辅助诊断有意义,其敏感性及特异性较高.     

线粒体肌病与线粒体脑肌病的临床分析

目的探讨神经肌肉系统线粒体病的发病机制、临床与病理特征及诊断。方法对7例确诊为线粒体病患者的临床表现、病理检查、实验室与影像学资料进行了回顾性分析。结果该组患者诊断为线粒体肌病3例,线粒体脑肌病4例;其中2例患者血乳酸水平升高;7例患者肌电图均有异常发现,肌肉活检均有特征性的改变;4例线粒体脑肌病患者头部影像学均有异常改变。结论线粒体病主要累及肌肉及中枢神经系统,诊断要求多种手段结合,以临床和病理表现为主,近年来基因方面的研究及影像学诊断发展迅速,目前对本病主要采取对症治疗。     

线粒体脑肌病:六例报告并文献复习

共6例经临床与肌肉组织活检明确诊断的线粒体脑肌病患者,临床主要表现为卒中样发作、癫、眼肌受累、视物模糊或皮质盲、精神症状、智力减退等,可伴有运动不耐受;血清乳酸水平不同程度升高;MRI以多发性皮质和皮质下异常信号为主,且病灶未处于血管分布区。肱二头肌肌肉组织活检可见典型破碎红纤维。线粒体脑肌病临床表现复杂,血清乳酸水平升高、影像学改变、肌肉组织活检为确诊之重要依据。     

脂肪累积性肌肉病线粒体形态计量分析

目的:通过对脂肪累积性肌肉病(LSM)的肌肉标本进行线粒体形态计量分析,探讨LSM的发病机制及与线粒体肌病的关系。方法:肌活检证实的LSM30例,按照有无破碎红纤维(RRF)又分为RRF(一)的LSM-1组及RRF(+)的LSM-2组。线粒体肌病15例。正常对照15例。分别测量线粒体的平均周长、截面积、面数密度、比表面积,应用SPSS软件进行单因素方差分析及Q检验。结果:LSM-1组的线粒体各项指标与正常对照组比较无显著性差异(P>0.05)。LSM-1组与线粒体肌病组的差异有非常显著意义(P<0.01)。LSM-2组的线粒体的各项指标与正常对照组的差异有显著意义(P<0.05)。LSM-1组与LSM-2组的线粒体的各项指标的差异有显著意义(P<0.05)。结论:LSM是一病理诊断,其可由多种原因导致发病。LSM-1组可能为原发脂肪代谢异常导致。LSM-2组可能为继发于线粒体功能异常的脂肪代谢障碍,为线粒体肌病的一型。     

抗线粒体抗体在线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征患者肌纤维中的免疫组织化学表达

目的 探讨抗线粒体抗体(anti-mitochondrial antibody,AMA)在线粒体腩肌病伴高乳酸血症和脑卒巾样发作(MELAS)综合征患者肌肉组织中的免疫组织化学表达特点及其诊断价值.方法 收集经临床、病理以及基因检测确诊的MELAS综合征患者10例,以2名肌肉病理正常者和3例肌肉活体组织检查发现坏死肌纤维的非线粒体病患者作为对照组,对所有15例肌肉冰冻组织标本行AMA免疫组织化学染色.结果 普通光镜下观察发现MELAS患者骨骼肌AMA免疫组织化学染色可见大量不整棕褐色肌纤维(ragged brown fibers,RBF),其形态类似MGT染色下的不整红边纤维(ragged red fibers,RRF).而对照组未发现RBF.结论 AMA免疫组织化学下的RBF是线粒体异常增生的特异性表现,同MGT染色下的RRF类似,可以作为诊断线粒体病异常线粒体的病理学指标.     

线粒体脑肌病的临床、病理及影像学特点

目的探讨线粒体脑肌病(ME)的临床、病理及影像学特点。方法回顾性分析20例ME患者的临床资料。结果本组中,慢性进行性眼外肌麻痹(CPEO)7例;肌阵挛性癫痫伴破碎红纤维(MERRF)6例;线粒体脑肌病伴乳酸中毒以及卒中样发作(MELAS)5例;Leigh综合征(LS)2例。临床表现为眼睑下垂7例(35%),肢体无力12例(60%),癫痫10例(50%),卒中样发作5例(25%)和精神智能障碍9例(45%)。8例患者血肌酸激酶升高;7例患者行血乳酸水平检查,均不同程度增高。EMG显示肌源性损害8例,神经源性损害4例,周围神经损害2例,正常6例。头颅MRI表现为脑萎缩、脑白质变性和不符合血管分布的卒中样改变。骨骼肌病理可见破碎红纤维(RRF)和SDH染色肌间小血管强染(SSV);细胞色素C氧化酶(COX)酶活性减低或缺失。电镜下线粒体结构和/或数量异常。结论 ME临床表现复杂多样,多有骨骼肌和脑受累。RRF和SSV是ME主要病理表现。     

单纯血清肌酶升高患者肌活检病理分析

目的 通过分析单纯血清肌酶升高患者的肌肉病理诊断,了解单纯血清肌酶升高患者的病因.方法 采用归纳分析法分析了24例单纯血清肌酶升高患者的人口学资料、血清肌酶水平、肌电图及病理特点.结果 男性16例,女性8例,年龄3岁～54岁,平均年龄(32.56±15.93)岁.血清CK波动于577.40～17720.00 U/L之间,平均(8081.83±6065.50)U/L,LDH波动于150.20～ 1643.80 U/L之间,平均(415.30±324.90) U/L.20例患者肌电图检查提示,15例为肌源性损害,3例正常,1例可疑肌源性损害,1例仅表现为运动单位时限偏短.肌肉病理提示2例为正常(8.33％)、5例(20.83％)为非特异性散在肌萎缩以及17例为肌病(70.83％),肌病包括肌营养不良13例(54.17％),炎性肌病组3例(12.50％)和Danon病1例(4.17％).结论 无症状性单纯血清肌酶升高患者的病因较多,肌肉酶组织化学和免疫组织化学可以协助多数患者的病因诊断.     

MELAS综合征八例

目的探讨MELAS综合征(线粒体脑肌病伴乳酸血症和卒中样发作)的临床特征,为早期诊断和治疗提供参考。方法对8例确诊的MELAS综合征患者的临床表现、肌活检病理及影像学资料进行回顾性分析。结果头痛、抽搐、运动耐受差、智能障碍、脑卒中样发作、血乳酸水平升高为本组患者的主要临床表现。8例患者脑内病灶均表现为T1WI低信号、T2WI高信号,病变主要累及额、颞、顶、枕叶皮层、皮层下及基底节,伴有不同程度的脑萎缩,病灶多发且与血管分布区不一致。8例患者行肌肉活检可见破碎红纤维(RRF)、异常线粒体增多。结论 MELAS综合征临床表现复杂多样,确诊依赖于临床特征分析和肌肉活检。磁共振成像在线粒体脑肌病的诊断、鉴别诊断方面具有一定的价值。     

EEG and evoked potential findings in mitochondrial myopathies

Electroencephalograms (EEGs) and evoked potentials (EPs) were studied in 43 patients with mitochondrial myopathies. Abnormalities were found most frequently in patients who presented predominantly or exclusively with central nervous system (CNS) dysfunction (abnormal EEGs in 18 of 21 patients, abnormal EPs in 9 of 11 patients). However, of patients presenting with ocular myopathy or proximal muscle weakness who had little or no CNS involvement clinically, 8 of 22 had abnormal EEGs and 5 of 10 had abnormal EPs, suggesting that electrophysiological tests are of value in demonstrating subclinical CNS disease in mitochondrial myopathy, although the abnormalities are not specific.     

线粒体肌病合并周围神经病的临床病理研究

目的:分析线粒体肌病合并周围神经病的临床特点、电生理和病理特征。方法:对10例肌肉活检确诊为线粒体肌病同时又合并周围神经病的患者从临床症状与体征、电生理检查和腓肠神经活检等几方面予以分析,并探讨周围神经病的病理基础。结果:本组10例患者中1例仅有临床下受累,另外9例表现为轻中度感觉运动性周围神经病,以感觉症状为重。结论:对线粒体肌病患者应将详细的神经系统查体与神经电生理检查相结合,提高周围神经病的检出率。电生理检查和腓肠神经活检有助于诊断。周围神经病的发病机制可能与线粒体功能异常有关。     

Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study

Since the popularization of routine creatine kinase (CK) measurement, an increasing number of patients with unexplained CK elevation ("asymptomatic hyper-CK-emia") are being identified. We studied 19 patients with persistent CK elevation of unknown etiology with electromyography (EMG) and muscle biopsy. Needle EMG was abnormal in 14 patients. Muscle biopsy was positive in all individuals with abnormal EMG and in one patient with normal EMG. Diagnoses included polymyositis in five patients, morphologically nonspecific myopathy in three, mitochondrial myopathy in two, and sarcoid myopathy, central core disease, multicore disease, inclusion body myopathy, and McArdle's disease in one case, respectively. Five patients with abnormal biopsies developed weakness within 1 year of presentation. We conclude that persistent asymptomatic CK elevation represents mild or early myopathy in a majority of cases.     

Mosaicism of mitochondria in mitochondrial myopathy: an electronmicroscopic analysis of cytochrome c oxidase

Summary Electron microscopic histochemistry was applied to the study of cytochrome c oxidase activity in each mitochondrion of biopsied muscles from four patients with mitochondrial myopathy [one case of fatal infantile mitochondrial myopathy, one case of myoclonus epilepsy associated with ragged-red fibers (MERRF), and two cases of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)]. In the patient with fatal infantile mitochondrial myopathy, intercellular heterogeneity of mitochondria was recognized. In the three patients with either MERRF or MELAS, cytochrome c oxidase activity was segmentally changed from positive to negative within single muscle fibers. In the two patients with MELAS, small groups of positive-stained mitochondria were located among negative-stained mitochondria in the negative segment of a few muscle fibers. These findings revealed that there were heterogeneous populations of normal and abnormal mitochondria intracellularly or intercellularly within the muscles of these patients.Supported in part by Grant-in-Aid for Scientific Research 63570422 from the Ministry of Education, Science and Culture, and Grant 62A-5-08 from the National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan     

Venous oxygen levels during aerobic forearm exercise: An index of impaired oxidative metabolism in mitochondrial myopathy.

A cardinal feature of impaired skeletal muscle oxidative metabolism in mitochondrial myopathies is a limited ability to increase the extraction of O(2) from blood relative to the increase in O(2) delivery by the circulation during exercise. We investigated whether aerobic forearm exercise would result in an abnormal increase in venous effluent O(2) in patients with impaired skeletal muscle oxidative phosphorylation attributable to mitochondrial disease. We monitored the partial pressure of O(2) (PO(2)) in cubital venous blood at rest, during handgrip exercise, and during recovery in 13 patients with mitochondrial myopathy and exercise intolerance and in 13 healthy control and 11 patient control subjects. Resting and recovery venous effluent PO(2) were similar in all subjects, but during exercise venous PO(2) paradoxically rose in mitochondrial myopathy patients from 27.2 +/- 4.0mmHg to 38.2 +/- 13.3mmHg, whereas PO(2) fell from 27.2 +/- 4.2mmHg to 24.2 +/- 2.7mmHg in healthy subjects and from 27.4 +/- 9.5mmHg to 22.2 +/- 5.2mmHg in patient controls. The range of elevated venous PO(2) during forearm exercise in mitochondrial myopathy patients (32 to 82mmHg) correlated closely with the severity of oxidative impairment as assessed during cycle exercise. We conclude that measurement of venous PO(2) during aerobic forearm exercise provides an easily performed screening test that sensitively detects impaired O(2) use and accurately assesses the severity of oxidative impairment in patients with mitochondrial myopathy and exercise intolerance.     

Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy

Abstract– We will present 8 children with progressive infantile or juvenile poliodystrophy (Alpers' disease), associated with a defect in pyruvate metabolism. Laboratory studies showed elevated levels of lactate in CSF and, in 4 children, elevated levels in serum. Histopathologic studies revealed lipid storage in liver and/or muscle tissue, sometimes myopathy with abnormal mitochondria and slight axonal degeneration in the peripheral nerve. Autopsy showed the characteristics of progressive poliodystrophy with degeneration and loss of neurons. Electron microscopy of cerebral cortex showed no mitochondrial abnormalities in neurons or astroglia. Biochemical studies in muscle and/or liver and/or cerebral tissue showed different deficiencies in pyruvate metabolism: in the pyruvate dehydrogenase complex, in the second part of the citric acid cycle (after the oxoglutarate dehydrogenase complex), in the NADH oxidation, in cytochrome aa ₃ and in pyruvate carboxylase.     

Mitochondrial myopathy with peripheral neuropathy]

This paper reported mitochondrial myopathy with peripheral neuropathy of 2 cases. Both patients were males. Age: 22, 32. Duration: 11, 14 years respectively. They showed recurrent paralysis and asthenia of limbs. Case 1 was motor sensory neuropathy, whose EMG revealed neurogenic injury. Case 2 involved only the lower limbs, whose lactic acid level was increased. In both patients, muscle biopsy showed Ragged Red fibers and abnormal mitochondria. Sural nerve biopsy revealed moderate reduction in the number of mylinated fibers and chronic axonal degeneration without regeneration cluster and hypertrophic neuropathy. Electron microscopic examination showed the increase of Schwann cells and mitochondria, and abnormal mitochondria being less marded in Case 2. Mitochondrial myopathy with peripheral neuropathy and its pathogenesis were discussed.     

The aerobic forearm exercise test, a non-invasive tool to screen for mitochondrial disorders

The diagnosis of a mitochondrial disorder is often difficult. Therefore, new approaches and diagnostic criteria are being developed. One of these tests is the aerobic forearm exercise test, a screening tool that can contribute to assess whether or not the patient suffers from a mitochondrial myopathy. With this simple, non-invasive test, the oxidative metabolism of muscle can be evaluated in rest and during exercise. We performed the aerobic forearm exercise test in patients with a mitochondrial disorder and an identified pathogenic gene mutation, in patients with a suspected mitochondrial disorder based on their clinical presentation and biochemical results, but without a molecular diagnosis, and in patients with atypical fatigue and no characteristics of a mitochondrial myopathy. In the first two groups, abnormal oxygen extraction from the blood during exercise was observed in four out of twelve patients. In the third group no abnormalities were found. The number of patients that we could test so far was limited, but all the patients experienced the aerobic forearm exercise as an easy test. We would like to stimulate clinicians to perform this test whenever a mitochondrial myopathy is suspected, as it can be a valuable diagnostic screening tool.     

Evoked potentials in mitochondrial disorders

Twenty-eight adult patients with mitochondrial disease were evaluated with muitimodal evoked potentials (EPs) to assess a possible CNS involvement The patients were classified into five groups: encephalopathy (two cases), progressive external ophthalmoplegia (PEO; four cases), pure myopatby (15 cases), cardiomyopathy (five cases) and asymptomatic relatives (two cases). EPs showed differences between encephalopathy (all EP modalities affected) and PEO groups (all patients with at least one EP altered), with lesser degrees of affection in pure myopathy and cardiomyopathy groups. The asymptomatics registered normal EPs. In view of these results, progressive CNS damage in mitochondriopathies, expressed by abnormal EPs, can be established as follows (from greatest to minor severity): encephalopathy, PEO, pure myopathy/cardiomyopathy and asymptomatic condition.     

Myopathies presenting with head drop: Clinical spectrum and treatment outcomes

Dropped head syndrome can be the presenting feature of a wide spectrum of neurological conditions. In this study, we aimed to define the clinical characteristics and treatment outcomes of 107 patients, where head drop was the presenting or predominant clinical feature of a myopathy. Median age at presentation was 68 years (range 42–88). A specific diagnosis was reached in 53% of patients: Inflammatory myopathy (n = 16), myopathy with rimmed vacuoles (n = 10), radiation-induced myopathy (n = 8), sporadic late-onset nemaline myopathy (n = 7), myofibrillar myopathy (n = 4), facioscapulohumeral dystrophy (n = 3), inclusion body myositis (n = 2), mitochondrial myopathy (n = 2), scleroderma-associated myopathy (n = 2), and single cases of necrotizing autoimmune myopathy, drug-induced myopathy, and B-cell chronic lymphocytic leukemia-myopathy. Splenius capitis had the highest diagnostic yield for a muscle biopsy (67%). When tested, 31/35 (89%) of patients had abnormal pulmonary function tests, 15/30 (50%) abnormal swallow evaluation, 24/65 (37%) abnormal electrocardiogram and 5/38 (13%) abnormal transthoracic echocardiogram. 23/43 (53%) treated patients responded to treatment. Patient-reported limb weakness and neck flexion weakness on physical examination were associated with good response to treatment. A wide spectrum of acquired and hereditary myopathies can present with head drop, some of which are potentially treatable. Establishing a diagnosis is crucial for timely treatment administration, screening for swallowing and cardiorespiratory involvement, and counseling regarding prognosis.