肥厚型心肌病分子遗传学研究进展

肥厚型心肌病(hypertrophic cardiomyopathy,HCM)是一种以常染色体显性遗传为特征的具有遗传异质性的心脏疾病,它是年轻人心源性猝死的首要病因。已发现至少有18种基因的突变可导致家族性肥厚型心肌病,加深对其分子遗传学的认识有利于促进该病的诊断和治疗。现就家族性肥厚型心肌病近期分子遗传学的研究进行了总结。     

老年心肌病的几个有关问题

目的探讨老年心肌病的临床特点、误诊、诊断与鉴别诊断及治疗等有关问题。方法(1)按临床特征 ,以排他法进行筛选诊断 ;(2)采用无创或有创法明确形态和血液动力学改变 ;(3)以心肌活检确定某些类型的病因。结果本病必须与冠心病、风心病、高心病、心包炎等疾病鉴别。(1)扩张型心肌病的治疗:包括休息、限制活动 ,避免使用对心肌有损害的药物 ,心肌营养药物 ,抗心衰 ,抗心律失常 ,中医中药治疗等。(2)肥厚型心肌病的治疗:一般无需特殊治疗。症状明显时可酌情选用β-受体阻滞剂、钙离子拮抗剂 ,治疗并发症 ,外科手术切除部分肥厚室间隔等。结论UCG对本病的诊断有一定的特殊价值     

家族性肥厚型心肌病与肌钙蛋白T

家族性肥厚型心肌病(FHCM)是一种常染色体显性遗传病, 由于编码心肌蛋白的基因突变引起,目前已识别出至少13个不同致病基因的200余种突变。目前,阐明FHCM的分子遗传学机制已经成为当前研究的热点之一。肌钙蛋白T通过与原肌宁蛋白结合,在将肌钙蛋白复合体锚钉到细肌丝上起重要作用。肌钙蛋白T基因突变是导致家族性肥厚型心肌病的主要原因,至今已经发现了大约30个突变,约占所有突变的15~20%。肌钙蛋白T基因突变所致FHCM有两个主要特征：（1）心肌肥厚程度较轻, 疾病外显率差别较大,（2）猝死率高。目前所发现的致FHCM突变,主要集中在肌钙蛋白T的T1和T2结构域。对肌钙蛋白T突变致FHCM分子机制的研究将有助于肥厚型心肌病的基因诊断和临床治疗。     

肥厚性心肌病相关基因的研究进展

肥厚性心肌病(hypertrophic cardiomyopathy,HCM)是以左心室或室间隔不对称性肥厚为基本特征的原发性心肌病,其发病率约为0.2％,是青少年和运动员心源性猝死的首要原因,目前被普遍认为是一种基因突变所致的常染色体显性遗传性疾病.至今为止,至少有20种基因的450余种突变被报道与HCM相关,主要定位于心脏肌节蛋白基因.此外越来越多的线粒体基因、修饰基因突变也被发现与HCM的发生发展有关.该文将对HCM的相关基因的研究进展作一个综述.     

成年人肥厚型心肌病表型的临床诊治研究进展

很多遗传代谢性心肌病可表现为肥厚型心肌病表型,但导致心肌肥厚的病因各不同,其治疗策略、预后也不相同。由于部分遗传代谢性心肌病在明确病因后进行病因治疗可以明显改善心功能状态,甚至完全逆转心肌病变。早期诊断、识别和治疗以左心室肥厚为主要表型的遗传代谢性心肌病尤为重要。笔者综述肥厚型心肌病、心脏淀粉样变、AndersonFabry病、线粒体心肌病及Danon病等表现为肥厚型心肌病表型的遗传性代谢性心肌病,分析其发病机制、临床表现,超声心动图特点,总结诊断及治疗方法。对于遗传代谢性心肌肥厚患者的超声心动图,大多无特异性,早期诊断还存在一定难度。因此,在日常工作中需要提高警惕,详细询问病史,结合相关生物化学检查和组织病理改变,甚至基因检查进行明确诊断。     

转化生长因子β对肥厚型心肌病作用的研究进展

肥厚型心肌病(HCM)是发病率较高的遗传性心肌病，也是青年人猝死的最常见原因，已成为全球性公共健康问题。转化生长因子-β(TGF-β)是一种多功能生长因子，在HCM进展关键环节心肌纤维化和心脏肥大中表达水平上调，通过影响心肌细胞及成纤维细胞功能诱发心脏形态改变，可能是HCM发病机制中的重要因子之一，其相关研究可为HCM治疗及预防提供借鉴。     

扩张型心肌病心律失常临床分析

目的 探讨扩张型心肌病发生心律失常的类型及原因,加深对本病的认识.方法 回顾分析212例扩张型心肌病心律失常的发生率、类型以及与心功能、房室大小的关系.结果 其心律失常发生率92.7%,以传导阻滞占首位,占心律失常68.5%,其次为室性心律失常,占心律失常65.1%,且室性心律失常的发生与左室扩大有关(P<0.05).心房颤动的发生与左房扩大有关(P<0.01).结论 扩张型心肌病的心律失常发生率高,且多样易变,其发生与广泛心肌纤维化致心电生理异常,影响心肌细胞的电传导和自律性有关.     

杜氏进行性肌营养不良的临床实践指南

杜氏进行性肌营养不良(Duchemiemusculardystmphy.DMD)是最常见的X连锁隐性遗传性肌肉变性疾病,在男性新生儿中的发病率约为1/3500。DMD是由于Xp21.2区的抗肌萎缩蛋白基因(dystrop,DMD)突变所致,患者的主要临床表现包括进行性、对称性肌无力。由于呼吸肌和心肌受累,通常在30岁前死亡。通过基因检测,可以为93.1%的患者找到遗传学病因,为早期治疗和指导家庭成员的生育奠定基础,有利于改善患者的生存质量,预防这些家庭再次生育DMD患儿。本指南结合了国内外的相关研究和指南共识,总结了DMD相关的医学遗传学知识和临床处置要点,期望能给予临床工作者帮助,为DMD患者及其家庭提供规范的诊断、治疗和预防。     

扩张性心肌病的分子遗传学

扩张性心肌病可以常染色体显性、常染色体隐性及Ｘ染色体连锁方式遗传，家族性扩张性心肌病约占特发性扩张性心肌病的２０％，与家族性扩张心肌病有关的基因尚未发现。扩张性心肌病是进行性肌营养不良的常见临床表现，心力衰竭是该病常见的死亡原因。引起进行性肌营养不良的基因是位于Ｘ染色体上的抗肌营养不良蛋白基因。强直性营养不良是常染色体显性遗传性疾病，常累及心肌及传导组织，其基因是位于１９号染色体上的肌强直蛋白基因     

Barth综合征分子遗传学研究进展

现代遗传学的研究已发现一系列的遗传性心肌病，依据遗传方式的不同基本上可以分为常染体显性和Ｘ连２锁隐性遗传二大类。１９９６年Ｂｉｏｎｅ等克隆了Ｘｑ２８区带上１个称之为Ｇ４．５基因的全长ｃＤＮＡ，且发现Ｇ４．５基因的突变是Ｂａｒｔｈ综合征患者发病的分子遗传学基础，从而开创了遗传性民病分子遗传学研究所新纪元。本文就Ｂａｒｔｈ综合征分子遗传学的研究进展加以综述。     

Morphological and genetic causes of fetal cardiomyopathies

Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co-dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.     

Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.     

Metabolic cardiomyopathies

The energy needed by cardiac muscle to maintain proper function is supplied by adenosine Ariphosphate primarily (ATP) production through breakdown of fatty acids. Metabolic cardiomyopathies can be caused by disturbances in metabolism, for example diabetes mellitus, hypertrophy and heart failure or alcoholic cardiomyopathy. Deficiency in enzymes of the mitochondrial beta-oxidation show a varying degree of cardiac manifestation. Aberrations of mitochondrial DNA lead to a wide variety of cardiac disorders, without any obvious correlation between genotype and phenotype. A completely different pathogenetic model comprises cardiac manifestation of systemic metabolic diseases caused by deficiencies of various enzymes in a variety of metabolic pathways. Examples of these disorders are glycogen storage diseases (e.g. glycogenosis type II and III), lysosomal storage diseases (e.g. Niemann-Pick disease, Gaucher disease, I-cell disease, various types of mucopolysaccharidoses, GM1 gangliosidosis, galactosialidosis, carbohydrate-deficient glycoprotein syndromes and Sandhoff's disease). There are some systemic diseases which can also affect the heart, for example triosephosphate isomerase deficiency, hereditary haemochromatosis, CD 36 defect or propionic acidaemia.     

Twenty years of progress and beckoning frontiers in cardiovascular pathology: cardiomyopathies.

In the last 20 years, with the advent of cardiac transplantation and the availability of molecular biology techniques, major advancements were achieved in the understanding of cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic right ventricular, primary restrictive, and noncompacted myocardium) and added in the update of WHO classification. Myocarditis was also included with the name "inflammatory cardiomyopathy." Adenoviruses and parvoviruses were found to be frequent cardiotropic viruses in addition to enteroviruses. The extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed to establish hypertrophic and restrictive cardiomyopathies as sarcomeric ("force generation") diseases, dilated cardiomyopathies as cytoskeleton ("force transmission") disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC) as cell junction disease. If we consider also cardiomyopathy as ion channel disease (long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), because they are diseases of the myocardium associated with electrical dysfunction, then a genomic/postgenomic classification of inherited cardiomyopathies may be put forward: cytoskeletal cardiomyopathy, sarcomeric cardiomyopathy, cell junction cardiomyopathy and ion channel cardiomyopathy.     

Cardiomyopathies due to defective energy metabolism: morphological and functional features

Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction and are classified by morphological characteristics as hypertrophic (HCM), dilated (DCM) arrhithmogenic right ventricular (ARVC) and restrictive cardiomyopathy. These were once considered as specific diagnoses but there is now considerable evidence that many different gene mutations can cause these pathologies. In recent years, big emphasis has been given to the possibility that deregulation of cardiac metabolism may play a role in the mechanisms that lead to cardiac maladaptive remodelling. Cardiac energy metabolism is tightly controlled in mammalian organisms during development and in response to diverse dietary, physiologic, and pathologic conditions. The cardiac phenotype of many genetic diseases caused by mutations in proteins involved in mitochondrial energy production and/or homeostasis, underscores the importance of energetic pathway on cardiac function. For example, inborn errors in nuclear-encoded mitochondrial fatty acid oxidation (FAO) pathway enzymes and defects in fatty acid uptake are an important cause of childhood HCM and sudden death. Abnormalities in mitochondrial respiratory chain function, particularly those caused by mitochondrial DNA (mtDNA) mutations, are responsible for a heterogeneous group of clinical disorders, including isolated HCM. Mitochondrial cardiomyopathies (MCM) are characterized by an adverse clinical course with biventricular dilation and failure, even at a young age. Mutations in genes encoding the gamma2 subunit of AMP-activated protein kinase (PRKAG2), alpha-galactosidase A (GLA) and lysosome-associated membrane proteine-2 (LAMP2) can cause profound myocardial hypertrophy in association with electrophysiological defects. Unlike HCM due to sarcomere gene mutations, which is characterized by myofiber disarray and fibrosis, large cytosolic vacuoles characterize cardiomyopathy due to defect in energy metabolism. Ultrastructural analysis revealed massive mitochondrial proliferation in MCM and glycogen in complexes with protein and/or lipids in cardiomyopathy due to PRKAG2, GLA and LAMP2 mutations.     

Dystrophin: from non-ischemic cardiomyopathy to ischemic cardiomyopathy

Dystrophin and its associated proteins form a scaffold underneath the cardiomyocyte membrane and connect the intracellular cytoskeleton to the extracellular matrix. Dystrophin localizes at the X chromosome, whose mutations might result in Duchenne muscular dystrophy, Becker muscular dystrophy and X-linked dilated cardiomyopathy. In addition to these genetic dilated cardiomyopathies, some acquired dilated cardiomyopathy like viral dilated cardiomyopathy is also related to dystrophin disruption or aberrant cleavage. In this review, we summarize the structure and distribution of dystrophin and researches of dystrophin in genetic and viral dilated cardiomyopathy. Moreover, we hypothesize that dystrophin play a critical role in ventricular remodeling in ischemic myocardium and treatment targeting restoration of dystrophin onto membrane could benefit for ischemic cardiomyopathy.     

Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity

Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy.     

Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy

Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of “idiopathic” cardiomyopathy. Recent molecular genetic analyses have now revealed that “idiopathic” cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy-associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.     

Fetal cardiomyopathy in neurofibromatosis type I: Novel phenotype and review of the literature

Neurofibromatosis type I (NF1) is a relatively common genetic disorder characterized by neurocutaneous lesions, neurofibromas, skeletal anomalies, iris hamartomas, and predisposition to other tumors. NF1 results from heterozygous loss‐of‐function mutations in neurofibromin (NF1), and diagnosis is most often made using clinical diagnostic criteria. Cardiac manifestations of NF1 include congenital heart disease (such as valvar pulmonary stenosis), left ventricular hypertrophy, and adult‐onset pulmonary hypertension. Prenatal features of NF1 are often nonspecific and diagnoses are infrequently made prenatally without a known family history. Herein, we report the first case, to the best of our knowledge, of fetal cardiomyopathy as the presenting feature in NF1 and review NF1‐related left ventricular hypertrophy. NF1 should be considered in the differential diagnosis for fetuses with cardiomyopathy, even in the absence of a known family history of the condition.     

Next-generation sequencing (NGS) as a fast molecular diagnosis tool for left ventricular noncompaction in an infant with compound mutations in the MYBPC3 gene

Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. LVNC is classified as a rare genetic cardiomyopathy. Molecular diagnosis is a challenge for the medical community as the condition shares morphologic features of hypertrophic and dilated cardiomyopathies. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified.In this report, we describe a case of a severe form of LVNC leading to death at 6 months of life. NGS sequencing using a custom design for hypertrophic cardiomyopathy panel allowed us to identify compound heterozygosity in the MYBPC3 gene (p.Lys505del, p.Pro955fs) in 3 days, confirming NGS sequencing as a fast molecular diagnosis tool. Other studies have reported neonatal presentation of cardiomyopathies associated with compound heterozygous or homozygous MYBPC3 mutations. In this family and in families in which parental truncating MYBPC3 mutations are identified, preimplantation or prenatal genetic screening should be considered as these genotypes leads to neonatal mortality and morbidity.