Recent advances in understanding the genetic etiology of congenital heart disease.

The genetic etiologies of multiple cardiovascular disorders have been identified recently. For the most part, familial cardiomyopathic, vascular, or arrhythmogenic disorders have been studied given the opportunity to identify the disease gene by linkage analyses, positional cloning, and analysis of candidate genes. Given that structural congenital heart disease rarely occurs in the context of large families, alternative approaches to understand the possible genetic etiologies have been taken. In particular, molecular evaluations of genetic syndromes in which cardiac defects are a cardinal feature are providing new insights into disease-related genes and developmental pathways. The identification of rare families with multiple affected members also has provided some insight into the genetic contribution to structural congenital heart defects. This review highlights the newest findings on the genetic etiology or implications in each of the subcategories of congenital cardiovascular disorders, and will provide the reader with both a brief overview and update. Particular note will be made of the genotype/phenotype analyses of hypertrophic cardiomyopathy and the long QT syndromes, as well as the identification of new disease-related genes for dilated cardiomyopathy, idiopathic ventricular fibrillation, and structural heart disease.     

Defective Myosin Genes in Mutant Mice and Human Diseases

Myosins are highly divergent actin-based molecular motors. In five of eight classes expressed in mammals, defects in genes have been identified in mutant mice and/or human diseases. A mutated myosin II-7 gene is one of the causes of human familial hypertrophic cardiomyopathy (FHC). The defective myosin Va gene is responsible for Griscelli disease, which is characterized by partial albinism and immunodeficiency, while in its mouse homologue coat color dilution is seen with or without neurological defects. There are three classes of myosins, VI, VII and XV, that are essential in the inner ear function. In humans, mutations in the VIIa gene are associated with three deafness-related diseases, Usher 1B/DFNB2/DFNA11, providing the first example of exhibition of recessive- and dominant-inherited disorders by different mutations in a single myosin gene.
There are variations in phenotype between human diseases and their mouse models, which appear to be explicable on the basis of differences in tissue expression patterns of the given myosin between mouse and man. In FHC and Usher 1BDFNB2DFNA11, a wide spectrum of clinical symptoms are observed. Evidence has accumulated suggesting that the more functionally important the mutation site of the molecule, the more serious and severe the symptoms, although involvement of additional factors such as modifier genes and genetic background can not be ruled out. Molecular genetic analyses of a variety of dilute alleles in mice have greatly facilitated our understanding of genotype-phenotype correlations, including information about structurally and functionally important domains of the myosin Va protein and cell-type-specific functions of different isoforms produced by alternative splicing.     

Mitochondrial dysfunction in skeletal muscle of children with cardiomyopathy

OBJECTIVES: This study sought to examine skeletal muscle of children with cardiomyopathy (CM) for changes in mitochondrial enzyme activities and in mitochondrial DNA (mtDNA). BACKGROUND: Heart mitochondrial enzymatic activity defects have been often found in dilated and hypertrophic CM. The defects primarily involve the activities of the electron transport system and oxidative phosphorylation pathway including respiratory complexes I, III, IV, and V. METHODS: Skeletal muscle biopsies of 8 children with CM were examined for specific mitochondrial enzyme activities, mtDNA copy number and the presence of pathogenic mutations and deletions in mtDNA. RESULTS: A marked deficiency in specific mitochondrial enzyme activities was found in 6 of 8 patients in skeletal muscle as well as in 2 of 3 hearts of those in whom cardiac tissue was available. Specific activity defects were found in complex I (2 cases), complex III (5 cases), complex IV (3 cases), and complex V (4 cases). Complex II and citrate synthase activities were unaffected. None of the previously reported pathogenic mutations associated with CM were detected, nor was there any evidence of mtDNA depletion. The incidence of defective respiratory complex activities in skeletal muscle was similar to the incidence of defective complex activities previously reported in cardiac tissue. CONCLUSIONS: Mitochondrial analysis of skeletal muscle is warranted in the overall clinical evaluation of children with CM, and particularly before consideration for cardiac transplantation.     

PTPN11 Mutation Associated with Aortic Dilation and Hypertrophic Cardiomyopathy in a Pediatric Patient with Noonan Syndrome

Noonan syndrome is an autosomal dominant disease that manifests a wide variety of clinical characteristics. The syndrome is also associated with some cardiac defects. Half of all Noonan syndrome cases are caused by mutations in the PTPN11 gene, but only limited data are available regarding aortic involvement in these cases. No reports exist regarding PTPN11 mutations in association with both aortic dilation and hypertrophic cardiomyopathy. We describe an 8-year-old girl who had Noonan syndrome involving a PTPN11 mutation, hypertrophic cardiomyopathy, main pulmonary artery dilation, and aortic root dilation. To our knowledge, this is the first case in which all three of these cardiovascular features have been observed in a single patient with Noonan syndrome.     

代谢性心肌病

心肌代谢活跃,代谢紊乱导致心肌能量产生不足,引起心肌病变。先天性代谢缺陷是儿童心肌病常见病因之一,表现为肥厚型或扩张型心肌病等类型,导致心力衰竭或心源性休克,甚至猝死。据报道,可引起心肌病的先天性代谢缺陷有40余种,包括脂肪酸氧化障碍、糖原累积病、溶酶体贮积病、线粒体病、有机酸血症、肌酸病和先天性糖基化障碍等。存在多系...     

Aetiology and pathogenesis of hypertrophic cardiomyopathy

The term hypertrophic cardiomyopathy is used to describe an autosomal dominant cardiac disorder, characterized by myocyte hypertrophy and disarray, interstitial fibrosis and small vessel disease, with or without macroscopic hypertrophy. More than 100 mutations in ten genes, all encoding sarcomeric proteins, have been identified as responsible for this disease. Mutations in the genes for β-myosin heavy chain, myosin binding protein-C, and cardiac troponin T are the most common. Other genes involved are α-tropomyosin, cardiac troponin-I, essential and regulatory light chains, α-cardiac actin, titin, and α-myosin heavy chain. Some mutations are more frequently associated with a given phenotype, but no particular phenotype is mutation specific; in fact, some mutations exhibit highly variable clinical, electrocardiographic and echocardiographic manifestations. This variability in the phenotypic manifestations is probably due to the influence of environmental factors and/or modifier genes. While the aetiology of hypertrophic cardiomyopathy has been extensively elucidated, its pathogenesis is not completely understood. Mutated proteins are incorporated in the sarcomere and impair myocyte contractility. This probably triggers the compensatory local release of trophic factors, which influence the development of the typical anatomical features of the disease, with a pathway similar to that observed in secondary, pressure overload hypertrophy.
Conclusions : The various pathological cardiac changes seen in hypertrophic cardiomyopathy are probably due to a compensatory response to impaired myocyte function resulting from mutations in the genes encoding sarcomeric proteins.     

Familial dilated cardiomyopathy

Considerable progress has been made to identify genetic causation of dilated cardiomyopathy (DCM). DCM is characterized by left ventricular dilatation and systolic dysfunction, and after known causes have been excluded has been termed idiopathic dilated cardiomyopathy (IDC). Studies of IDC that occurs in families, termed familial dilated cardiomyopathy (FDC) provided the initial phenotypic data to suggest genetic causation. The study of large families with linkage analysis and gene mapping methods have recently implicated 16 autosomal genes and two X-linked genes. Mutations in these genes account for approximately 20–30% of genetic causation, suggesting that additional genetic causation remains unknown. FDC demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making diagnosis complex. Echocardiographic and electrocardiographic screening of first-degree relatives of individuals with IDC and FDC is indicated, as detection and treatment are possible prior to the onset of advanced, symptomatic disease. Genetic counseling for IDC and FDC may also be appropriate. It is anticipated that a great deal of additional genetic information yet to be discovered will add greatly to our understanding of the genetics of dilated cardiomyopathy.     

Clinical Presentations of Mitochondrial Cardiomyopathies

To determine the clinical manifestations and interfamilial variability of patients diagnosed with a mitochondrial cardiomyopathy, we reviewed the charts of 14 patients with cardiomyopathy out of 59 patients with mitochondrial disorders who attended the mitochondrial disease clinic at Wolfson Medical Center from 1996 to 2001. All patients underwent a metabolic evaluation including blood lactate, pyruvate, carnitine, and amino acids and urine organic acids. Respiratory chain enzymes were assessed in 10 patients. The mitochondrial DNA (mtDNA) was assessed for mutations.The age at presentation ranged between 6 months and 24 years. Six of the patients died, 5 from heart failure. The cardiomyopathy was hypertrophic in 10 and dilated in 4. Conduction and rhythm abnormalities were present in 6. Eleven patients had family members with mitochondrial disorders. All the patients had additional involvement of one or more systems. Seven patients exhibited a deficiency of a respiratory chain enzyme in the muscle. The MELAS mtDNA point mutation (3243) was found in one patient. Blood lactic acid levels were increased in 5. Brain MRI abnormalities were observed in 4.Conclusions Mitochondrial dysfunction frequently affects the heart and may cause both hypertrophic and dilated cardiomyopathy. The cardiomyopathy is usually a part of a multisystem involvement and may rarely be isolated. The course may be stable for many years, but rapid deterioration may occur. Understanding the biochemical and genetic features of these diseases will enable us to comprehend the clinical heterogeneity of these disorders.     

Neonatal muscular manifestations in mitochondrial disorders

During the last decade rapid development has occurred in defining nuclear gene mutations causing mitochondrial disease. Some of these newly defined gene mutations cause neonatal or early infantile onset of disease, often associated with severe progressive encephalomyopathy combined with other multi-organ involvement such as cardiomyopathy or hepatopathy and with early death. Findings suggesting myopathy in neonates are hypotonia, muscle weakness and wasting, and arthrogryposis. We aim to describe the clinical findings of patients with mitochondrial disease presenting with muscular manifestations in the neonatal period or in early infancy and in whom the genetic defect has been characterized. The majority of patients with neonatal onset of mitochondrial disease have mutations in nuclear genes causing dysfunction of the mitochondrial respiratory chain, leading to defective oxidative phosphorylation.     

CARDIOVASCULAR INVOLVEMENT IN METABOLIC DISEASES

Cardiomyopathies are a group of disorders that result in dysfunction of the contractility of the myocardium and a decrease in cardiac function. Cardiomyopathies may be primary or idiopathic or secondary due to an underlying definable systemic disorder. Cardiomyopathies may be further defined as according to the World Health Organization (WHO) as: 1) congestive or dilated; 2) obstructive as in hypertrophic cardiomyopathy; 3) restrictive as in infiltrative disorders such as storage diseases. Two additional categories have been added that include arrhythmogenic right ventricular cardiomyopathy and unclassified cardiomyopathies. A number of metabolic disorders result in cardiomyopathy and are frequently the cause of death in these disorders.     

Molecular mechanisms of sarcomere dysfunction in dilated and hypertrophic cardiomyopathy

The sarcomeres form the molecular motor of the cardiomyocyte and consist of a complex multi-protein of thick and thin filaments which are anchored to the cytoskeleton. The thick filament, composed of myosin and associated proteins, and the thin filament composed of actin, tropomyosin and the troponins develop actinmyosin crossbridges which cycle in response to calcium resulting in sliding of the filaments and contraction. The thin filament in fixed to the cardiomyocyte cytoskeleton at the Z-disc, a complex of structural and regulatory proteins. A giant protein, titin, provides an external scaffold and regulates passive force in diastole. Both genetic disorders and acquired conditions may affect proteins of the sarcomere. Genetic disorders of the thick and thin filament proteins are the predominant cause of hypertrophic cardiomyopathy. These mutations lead to abnormal sarcomere function, often an enhanced sensitivity to calcium, and impaired relaxation. This may result in secondary changes in calcium cycling and amplification of hypertrophic signaling cascades. Correcting the abnormal function of the sarcomere as well as intervening in later stages of the pathophysiologic cascades may ameliorate disease. In dilated cardiomyopathy genetic abnormalities in the sarcomere, Z-disc, calcium regulatory and cytoskeletal proteins as well as the dystrophin complex may be causal for disease. In dilated cardiomyopathy, disturbances in post-translational modifications of the sarcomere my also play a prominent role. Experimental models indicate that altered phosphorylation of sarcomeric proteins may impair systolic and diastolic function as well as the response to heart rate and afterload. Thus correcting these post-translational changes are legitimate targets for future therapeutic strategies for dilated cardiomyopathy.     

Cardiac manifestations of inherited metabolic disease in children

Inborn errors of metabolism (IEM) are responsible for around 5% of all cases of cardiomyopathy (CM) and for 15% of non‐idiopathic cases. Storage disorders such as Pompe disease (glycogen storage disease type II) typically cause hypertrophic CM, whereas the accumulation of toxic metabolites, as seen in the organic acidurias, is associated with dilated cardiomyopathy (DCM). Mixed pathology is also possible, particularly in late presentations. IEM such as Barth syndrome, a disorder of cardiolipin stability usually associated with DCM, have been associated with rarer types of CM such as endocardial fibroelastosis and left ventricular non‐compaction. Conduction disturbances can also occur, particularly in disorders of glycogen metabolism associated with PRKAG2 mutations. Cardiac screening of patients with metabolic diseases is important to guide treatment and stratify risk. Supportive cardiac treatment may be required, and although associated myocardial disease may improve or even resolve with correction of the underlying metabolic disturbance, progression to cardiac transplantation has been described. In this article we document all IEM known to be associated with cardiac disease in children, focusing on common and clinically important diagnoses. We also discuss the pathophysiology of the various types of CM, and present a recommended approach to screening in the pediatric population.     

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.     

Pediatric myocardial disease

Cardiomyopathies are diseases of the heart muscles. This article reviews the causes, clinical presentation, diagnosis, management, and long-term outcomes of dilated and hypertrophic cardiomyopathy.     

Neonatal cardiomyopathies and metabolic crises due to oxidative phosphorylation defects

Neonatal cardiomyopathies due to mitochondrial oxidative phosphorylation (OXPHOS) defects are extremely severe conditions which can be either isolated or included in a multi-organ disease, with or without metabolic crises, of which profound lactic acidosis is the prominent feature. Cardiomyopathy is?more often hypertrophic than dilated. Antenatal manifestations such as fetal cardiomyopathy, arrhythmia and/or hydrops have been reported. Pathophysiological mechanisms are complex, going beyond ATP deficiency of the high-energy-consuming neonatal myocardium. Birth is a key metabolic period when the myocardium switches ATP production from anaerobic glycolysis to mitochondrial fatty acid oxidation and OXPHOS. Heart-specificity of the defect may be related to the specific localization of the defect, to the high myocardium dependency on OXPHOS, and/or to interaction between the primary genetic alteration and other factors such as modifier genes. Therapeutic options are limited but standardized diagnostic procedures are mandatory to confirm the OXPHOS defect and to identify its causal mutation, allowing genetic counseling and potential prenatal diagnosis.     

What makes the heart fail? New insights from defective genes

Dilated cardiomyopathy (DCM) is an idiopathic, genetically heterogeneous disorder characterized by heart failure and arrhythmia. Over the past decade, the molecular basis for DCM has been partially uncovered by discovery of mutation in genes encoding cystoskeletal, sarcomeric, nuclear membrane, and sarcoplasmic reticulum proteins. These findings have implicated pathogenic mechanisms whereby structural integrity, contractile force dynamics, and calcium regulation within the cardiac myocyte are perturbed. Recognition of dilated and hypertrophic cardiomyopathies as allelic disorders has provided the opportunity to identify genotype-phenotype relationships and to gain new insight into pathways leading to cardiac failure and hypertrophy.
Conclusion: Collectively, family-based studies of DCM provide the rationale for clinical screening in first-degree relatives, regardless of family history or age of the index case.     

<Emphasis Type="Italic">PTPN11</Emphasis> Gene Mutation and Severe Neonatal Hypertrophic Cardiomyopathy: What Is the Link?

Noonan syndrome (NS) is an autosomal dominant disorder characterized by multiple dysmorphic features and a broad spectrum of congenital heart defects. Specific mutations of the PTPN11 gene are associated with 50% of the NS cases and 90% of the multiple lentigines/LEOPARD syndrome (ML/LS) cases. These two allelic conditions have several overlapping clinical features. This study describes the association between the Gln510Glu mutation of the PTPN11 gene and lethal progressive hypertrophic cardiomyopathy (HCM) in a newborn with the NS phenotype. The findings confirm the intriguing relationship between site-specific mutations of the PTPN11 gene and rapidly progressive HCM.     

Cardiac dysrhythmias in children with idiopathic dilated or hypertrophic cardiomyopathy

To assess the incidence and prognostic significance of cardiac dysrhythmias in children with idiopathic dilated or hypertrophic cardiomyopathy, the clinical course of 59 patients was retrospectively reviewed over a period of 27 years. Dilated cardiomyopathy (DCM) was diagnosed in 28 patients and hypertrophic cardiomyopathy (HCM) in 31 patients. The mean age at the time of diagnosis was 2.8±0.7 years in DCM patients and 6.7±0.8 years in HCM patients. Mean follow-up time after diagnosis of cardiomyopathy was 4.1±1.0 years in DCM patients and 6.6±0.8 years in HCM patients. Clinically significant cardiac dysrhythmias were found in 17 of 59 patients (29%): 7 of 28 patients (25%) with DCM and 10 of 31 patients (32%) with HCM. The initial diagnosis of a cardiac dysrhythmia was made by standard electrocardiography in 12 of 17 patients (71%) and by 24-hour Holter monitoring in 5 of 17 patients (29%). Ventricular dysrhythmias were present in 5 of 7 patients with dilated cardiomyopathy and in 5 of 10 patients with hypertrophic cardiomyopathy. During the follow-up time, death occurred in 18 of 59 patients (31%): 8 of 59 patients (14%) died from congestive heart failure and 10 of 59 patients (17%) died suddenly. Among the sudden deaths were 4 of 28 patients (14%) with dilated cardiomyopathy and 6 of 31 patients (19%) with hypertrophic cardiomyopathy. Cardiac dysrhythmias had been documented in 6 of the 10 patients dying suddenly (3 of 4 patients with DCM and 3 of 6 patients with HCM). It is concluded that (1) cardiac dysrhythmias are not a rare finding in children with idiopathic dilated or hypertrophic cardiomyopathy, and (2) their occurrence is not a predictor for sudden death.     

Aetiology and pathogenesis of hypertrophic cardiomyopathy

The term hypertrophic cardiomyopathy is used to describe an autosomal dominant cardiac disorder, characterized by myocyte hypertrophy and disarray, interstitial fibrosis and small vessel disease, with or without macroscopic hypertrophy. More than 100 mutations in ten genes, all encoding sarcomeric proteins, have been identified as responsible for this disease. Mutations in the genes for beta-myosin heavy chain, myosin binding protein-C, and cardiac troponin T are the most common. Other genes involved are alpha-tropomyosin, cardiac troponin-I, essential and regulatory light chains, alpha-cardiac actin, titin, and alpha-myosin heavy chain. Some mutations are more frequently associated with a given phenotype, but no particular phenotype is mutation specific; in fact, some mutations exhibit highly variable clinical, electrocardiographic and echocardiographic manifestations. This variability in the phenotypic manifestations is probably due to the influence of environmental factors and/or modifier genes. While the aetiology of hypertrophic cardiomyopathy has been extensively elucidated, its pathogenesis is not completely understood. Mutated proteins are incorporated in the sarcomere and impair myocyte contractility. This probably triggers the compensatory local release of trophic factors, which influence the development of the typical anatomical features of the disease, with a pathway similar to that observed in secondary, pressure overload hypertrophy. CONCLUSIONS: The various pathological cardiac changes seen in hypertrophic cardiomyopathy are probably due to a compensatory response to impaired myocyte function resulting from mutations in the genes encoding sarcomeric proteins.     

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.