Mitochondrial myopathy presenting as ataxia with dilated cardiomyopathy

Mitochondrial disorders are multisystem diseases with very heterogeneous clinical manifestations. Common cardiac features include cardiomyopathy and conduction defects. We report a fiveyear-old boy who presented with signs of congestive cardiac failure and was diagnosed to have dilated cardiomyopathy. Six months later, he developed progressively worsening ataxia, hypotonia, other cerebellar signs, hearing loss, severe sensory peripheral neuropathy and lactic acidosis. Electronmicroscopy of skeletal muscle biopsy was consistent with mitochondrial myopathy     

Mitochondrial Cardiomyopathy: Molecular and Biochemical Analysis

Abnormalities in cardiac mitochondrial respiratory enzymes and mitochondrial DNA have been found in an increasing number of pediatric cases of both dilated and hypertrophic cardiomyopathy, giving rise to the entity known as mitochondrial cardiomyopathy. Histochemical, biochemical, and molecular findings are described in this review of mitochondrial cardiomyopathy, which should provide assistance in its diagnostic identification.     

Hypertrophic Cardiomyopathy with Mitochondrial DNA Depletion and Respiratory Enzyme Defects

We report the case of a child with severe hypertrophic cardiomyopathy, with decreased activity levels of cardiac mitochondrial respiratory complex I and III, and with a pronounced reduction in cardiac mitochondrial DNA copy number level. Mitochondrial DNA depletion has not been previously reported in hypertrophic cardiomyopathy and it may play a role in its pathogenesis.     

Early cardiac involvement in children carrying the A3243G mtDNA mutation

The phenotypic spectrum of the mitochondrial A3243G DKA mutation is highly variable, particularly when occuring in childhood. In contrast to the classical presentation in adulthood (MELAS syndrome; mitochondria! myopathy, encephalopathy, lactic acidosis and stroke-like episodes) children show a different pattern of symptoms, often without the typical encephalopathy or psychomotor regression. We present six children carrying the A3243G mtDNA mutation with a heteroplasmy above 50 % in muscle tissue. The age of diagnosis ranged from 2 weeks up to 14.5 years. The clinical presentation was rather non-specific including muscle weakness, developmental delay and epilepsy. In this small pediatric group we detected presymptomatic cardiac involvement in five out of six children already at an early stage of disease. The cardiac pathology included cardiomyopathy and biventricular hypertrophy with rhythm disturbances (for example long QT-syndrome). The observed cardiac changes do not always increase the risk of cardiac deterioration; however, two of our patients died early on. CONCLUSION: We hypothesize that the A3243G mutation might be underdiagnosed, as patients could suffer from an unexplained cardiac death before the diagnosis is made. We advise performing regular repeated ECGs and echocardiography in all children carrying a A3243G mtDNA mutation independently from the presence of cardiac symptoms.     

小儿扩张型心肌病68例临床分析

目的：探讨小儿扩张型心肌病（DCM）的心电图特点及DCM并心律失常的相关因素。方法：总结68例1998年1月至 2010年3月住院的 DCM 患儿的临床资料,根据有无心律失常及严重程度分为3组：严重心律失常组(42例),非严重心律失常组(20例),无心律失常组(6例),比较各组的左心室舒张末期内径（LVED）、左心室射血分数（LVEF）及短轴缩短率（LVFS）。结果：68例DCM患儿心电图均存在异常,以窦性心动过速（91%）和异位搏动（86%）最常见。严重心律失常组LVED（74±6 mm）大于非严重心律失常组（65±4 mm）和无心律失常组（61±3 mm）;非严重心律失常组LVED亦大于无心律失常组,各组间差异有统计学意义（P<0.05）。严重心律失常组LVEF、LVFS 分别是(30±11)%、（22±4)%,低于非严重心律失常组［（37±12）%、（28±5）%］和无心律失常组［（45±9）%、（34±7）%］; 非严重心律失常组LVEF、LVFS亦低于无心律失常组,各组间差异有统计学意义（P<0.05）。结论：DCM患儿心电图异常以窦性心动过速和异位搏动最常见;心律失常是DCM的主要临床表现之一;心律失常的发生与左心室大小、心功能关系密切。     

Dilated cardiomyopathy in children: Clinical course and prognosis

Summary The clinical profile of 19 patients with dilated cardiomyopathy ages 2–18 years (mean 13.4±4 years) was reviewed to detect any factors that might be predictive for their survival. Follow-up ranged from 5 to 105 months (mean 39±33 months). Routine treatment consisted of digitalis and diuretics: 14 patients received antiarrhythmics, 6 received vasodilators, and 12 were managed with immunosuppression. There were 12 survivors and 7 nonsurvivors: The 1-year mortality was 21.2% and the 2-year mortality 35.8%. All deaths were within first 2 years. Of the 12 patients who survived 2 years, a significant improvement was noticed in 9. In 3 patients tachycardia-induced cardiomyopathy was diagnosed, and abolition of supraventricular tachycardia was followed by improvement and regression of cardiomegaly. Endomyocardial boopsy was performed in 16 patients. Four with a histologic diagnosis of active myocarditis survived, and in 3 of them a considerable improvement was noticed. Of the 12 patients with nonspecific histologic findings, 6 died (p<0.05). There were no significant differences between survivors and nonsurvivors for any of the following parameters: incidence of severe heart failure (NYHA class III–IV) and severe ventricular arrhythmias (Lown class III–V), relative heart volume, echocardiographic left ventricular diastolic diameter and shortening fraction, and the hemodynamic parameters of cardiac index, left ventricular ejection fraction, left ventricular end-diastolic pressure, and left ventricular end-diastolic volume index.     

Maternally Inherited Hypertrophic Cardiomyopathy: A Manifestation of Mitochondrial DNA Mutations—Clinical Course in Two Families

In the past decade, maternally inherited disorders have been described manifesting as hypertrophic cardiomyopathy. These are primarily associated with defects in oxidative metabolism due to an alteration in mitochondrial DNA. Although the biochemistry and molecular biology is well-defined, there is little information regarding clinical presentation and course. Reported manifestations can be broad and can include myopathy, encephalopathy, stroke-like episodes, hearing loss, cardiomyopathy, multiorgan dysfunction and sudden death. Predominant or exclusive involvement of the heart is rare. We report the clinical presentations, investigations, pathologic findings, and clinical course in two families with two mitochondrial tRNA defects with exclusive cardiac involvement and demonstrable clinical heterogeneity based on the percentage of mutant tRNA.     

线粒体心肌病研究进展

心肌细胞线粒体结构和功能的异常导致心肌能量代谢异常,临床表现为心肌病,称为线粒体心肌病.线粒体心肌病患儿具有肥厚型心肌病或扩张型心肌病的临床特征,常伴多系统损害,如身材矮小、感音性重听、肌张力低下、小脑共济失调、智力低下、视网膜色素变性、白内障等.该病主要由线粒体DNA突变所致.目前尚无特效治疗方法,治疗措施主要包括心肌病的一般治疗及并发症的对症治疗,可应用辅酶Q10、大剂量B族维生素等.目前开始探讨基因治疗的可能性.     

心肌炎及扩张型心肌病患儿人类巨细胞病毒的检测及其临床意义

目的探讨巨细胞病毒与心肌炎、扩张型心肌病之间的关系。方法应用ＰＣＲ基因扩增技术对４８例心肌炎、４例扩张型心肌病患儿及６０例同期无心肌疾病患儿进行人类巨细胞病毒（ｈｕｍａｎｃｙｔｏｍｅｇａｌｏｖｉｒｕｓ,ＨＣＭＶ）检测。结果心肌炎、扩张型心肌病组巨细胞病毒检出率明显高于对照组,差异有显著性（Ｐ＜００５）。结论巨细胞病毒与心肌炎、扩张型心肌病的发生有关     

儿童肥厚型心肌病临床分析

目的探讨儿童肥厚型心肌病的临床特点、诊治方法及预后。方法对2000年10月至2013年9月在北京儿童医院确诊为肥厚型心肌病的25例患儿的临床表现、实验室检查、治疗方法及预后进行回顾性分析。结果肥厚型心肌病以年长儿童多见,平均年龄8岁9个月,男女比例3．1：1。临床表现：气促乏力5例,胸闷长出气4例,心前区不适3例,因咳喘就诊发现心脏异常5例,无症状发现心脏杂音来诊治8例,伴晕厥发作2例,6例有明确的肥厚型心肌病家族史,3例家族史中有幼年死亡病例（具体疾病不详）。心电图：18例提示左室和（或）右室肥厚伴ST—T改变,3例伴有异常Q波,2例有I。房室传导阻滞,1例有左前分支阻滞,1例有完全性左束支阻滞。心肌酶升高5例。X线胸片心影扩大17例。心脏彩超提示非梗阻型肥厚型心肌病23例;梗阻型肥厚型心肌病2例。收缩功能减低2例,舒张功能减低3例。21例患儿口服美托洛尔治疗,1例异搏定,1例心得安,未用药2例。随访2个月～13年,2例患儿死亡,其余23例生存。结论 小儿肥厚型心肌病临床表现缺乏特异性,病情重,呈进行性发展,是青少年猝死的主要原因之一,预后差。     

Myopathic Skeletal Muscle Fiber Abnormalities in Cardiomyopathies of Childhood

Skeletal muscle fibers isolated from 50 muscle specimens from 10 children with cardiomyopathy of unknown cause are compared to those from 18 specimens from 5 patients with skeletal muscle myopathies, 45 specimens from 18 patients with congenital heart disease, and 15 specimens from 7 patients with no genetic, chromosomal, or cardiac disease. Muscle fibers from the myopathy specimens show increased nucleilmm of fiber and increased nucleilmm/µm of diameter (R value), as well as reduced surface area and volume of cytoplasm per nucleus, compared to control values. The values for cardiomyopathy deviate from normal in the same way as, but to a lesser degree than, those for myopathy—namely, in this material, diseases with cardiomyopathy tend also to produce mild myopathy. Since cardiac and skeletal muscle pathologic findings have not been adequately studied for the majority of the approximately 50 genetic disorders causing cardiomyopathy or otherwise affecting cardiac function described to date, the data indicate primarily that skeletal muscle biopsy will undoubtedly be more useful in cardiomyopathic disorders when the appropriate correlative studies of cardiac and skeletal muscle in such diseases have been done. Because larger biopsy specimens can be obtained, skeletal muscle merits further exploitation in biochemical research on basic mechanisms of disorders causing cardiomyopathy.     

肥厚型心肌病诊治的辅助检查进展

肥厚型心肌病是一种常染色体显性遗传性心肌疾病,其遗传特性、临床表型、病程和预后存在显著异质性,临床诊治极具挑战性.多普勒组织成像、定量组织速度成像、组织应变率成像、心脏磁共振及延迟钆增强等辅助检查对早期诊断、指导治疗及判断预后起重要作用.该文就肥厚型心肌病在辅助检查方面的进展作一综述.     

Maternal Inheritance and Study of Human Mitochondrial Genome

Several diseases with non-mendelian maternal inheritance patterns have been described, some of which appeared to be associated with abnormal mitochondrial structure or function and might result from the inheritance of an abnormal mitochondrial genome. New techniques in molecular genetics should clarify the molecular basis of these maternally inherited developmental disorders. From families with maternally inherited mitochondrial disorders we conducted a search for an alteration in nucleotide analysis of the mitochondrial DNA obtained from the lymphocytes of the patients. Although it was possible to identify a single substitution (CTT/ATT) in one of five clones in which were transcribed the gene of cytochrome C oxidase subunit II, it was impossible to define the mismatched site by the method of RNA/DNA mapping (Myers, 1985) using a labelled RNA probe containing a cytochrome C oxidase gene which was obtained from normal placenta cells. A congenital myotonic dystrophy is known to be inherited through an autosomal dominant gene, and yet the age of onset and the severity of the disease are influenced by non-mendelian maternal inheritance. We previously proposed that an abnormality of bile acid metabolism could affect the fetus, resulting perhaps in delayed development. A possible model for this effect might involve the interaction of mitochondrial function with an autosomal gene product, leading to erroneous replication with a mutant form of the polymerase subunit.     

Mitochondrial DNA abnormalities and autistic spectrum disorders

OBJECTIVES: To further characterize mtDNA defects associated with autistic features, especially the A3243G mtDNA mutation and mtDNA depletion.Study design Five patients with autistic spectrum disorders and family histories of mitochondrial DNA diseases were studied. We performed mtDNA analysis in all patients and magnetic resonance spectroscopy in three. RESULTS: Three patients manifested isolated autistic spectrum features and two had additional neurologic symptoms. Two patients harbored the A3243G mutation. In two others, the A3243G mutation was not found in accessible tissues but was present in tissues from their mothers. The fifth patient had 72% mtDNA depletion in skeletal muscle. CONCLUSIONS: Autistic spectrum disorders with or without additional neurologic features can be early presentations of the A3243G mtDNA mutation and can be a prominent clinical manifestation of mtDNA depletion. Mitochondrial dysfunction should be considered in patients who have autistic features and associated neurologic findings or who have evidence of maternal inheritance.     

The effect of treatment with angiotensin-converting enzyme inhibitors on survival of pediatric patients with dilated cardiomyopathy

Summary Outcome in 81 pediatric patients with dilated cardiomyopathy was reviewed to assess whether treatment with angiotensin-converting enzyme (ACE) inhibitors affected survival. Age at onset was 3.6±0.6 years. Twenty-seven children (group 1) were treated with ACE inhibitors. Conventional therapy was used in the remaining 54 patients (group 2). There were no significant differences between the two groups in age at onset, left ventricular shortening fraction, left ventricular end-diastolic pressure, or mean pulmonary artery pressure. Patients treated with ACE inhibitors had a significantly better survival during the first year (p<0.05) with continuation of this trend throughout the second year (p=0.06). Beyond 2 years there was a tendency toward better survival in ACE inhibitor-treated patients, but the differences were no longer significant (p=0.14). These data, along with observations in adult patients with chronic cardiac failure, indicate that converting enzyme inhibitors have a beneficial effect on prolonging survival of infants and children with severe left ventricular dysfunction from dilated cardiomyopathy.     

儿童扩张型心肌病发病机制研究进展

儿童扩张型心肌病(DCM)发病率近年来有逐渐增高的趋势,其发病机制尚未完全阐明,其中遗传因素、病毒感染、自身免疫和心肌细胞凋亡在DCM发生发展中可能起重要作用.该文就近年来关于DCM发病机制的认识和研究进展作一综述.