遗传性心肌病的临床实践指南

心肌病是一组异质性心肌疾病,可由各种原因(常为遗传因素)引起,能够导致心力衰竭、心律失常和猝死。原发性心肌病包括遗传性肥厚型心肌病、致心律失常右室心肌病、线粒体心肌病、混合性(遗传性及获得性)扩张型心肌病和限制型心肌病、左心室致密化不全以及其他未分类的心肌病。借助基因组学技术,在人群中发现的一些常见突变与疾病的关联已被鉴定。这些突变的体内和体外功能研究为疾病的发生机制和治疗提供了有用的线索。本指南在参考国内外本领域的基础研究、临床研究和其他国家的相关指南共识的基础上,对不同类型遗传型心肌病的表型、诊断、治疗及遗传咨询进行了总结,期望有助于患者临床管理的规范化。     

Sudden arrhythmic death and the cardiomyopathies: Molecular genetics and pathology

Cardiovascular disease is a significant cause of sudden death (SD) requiring autopsy investigation. Cardiomyopathies account for about one half of cases encountered, especially in young people <35 years of age. Among them, inherited cardiomyopathies at risk of SD include hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) as well as primary electrical disorders of the myocardium in the absence of structural abnormalities (channelopathies). The pathologist's task is to make the correct diagnosis and, when dealing with a genetic disease, to trigger widespread cardiological investigation of first-degree family members. This is especially important as SD can be the first and last clinical presentation of the underlying inherited cardiomyopathy and the only medical examination undertaken is that done by the pathologist. An accurate pathological diagnosis, which also includes access to molecular techniques (“molecular autopsy”), will provide vital information for the family in preventing a further tragedy. Therefore proper sampling to allow postmortem DNA analysis as well as accurate morphological evaluation, is mandatory, as recommended in the recently-published guidelines for autopsy investigation of SD from the Association for European Cardiovascular Pathology.     

Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) represents an inherited cardiomyopathy that manifests clinically with malignant ventricular arrhythmias, sudden cardiac death, and less commonly heart failure. The condition is characterized by replacement of the myocardium, primarily of the right ventricle, with fibrofatty tissue. Extensive fibrofatty replacement of the myocardium has been previously thought to be pathognomonic of ARVC; however, this report details two other forms of inherited cardiomyopathy, namely hypertrophic cardiomyopathy (HCM) and the PRKAG2 cardiac syndrome, that were found to have significant fibrofatty myocardial replacement at pathologic examination. This report represents the first documentation of inherited cardiomyopathies mimicking ARVC and highlights the concept that other cardiac conditions can be associated with fibrofatty replacement of the myocardium.     

Cell Biology of Sarcomeric Protein Engineering: Disease Modeling and Therapeutic Potential

The cardiac sarcomere is the functional unit for myocyte contraction. Ordered arrays of sarcomeric proteins, held in stoichiometric balance with each other, respond to calcium to coordinate contraction and relaxation of the heart. Altered sarcomeric structure–function underlies the primary basis of disease in multiple acquired and inherited heart disease states. Hypertrophic and restrictive cardiomyopathies are caused by inherited mutations in sarcomeric genes and result in altered contractility. Ischemia‐mediated acidosis directly alters sarcomere function resulting in decreased contractility. In this review, we highlight the use of acute genetic engineering of adult cardiac myocytes through stoichiometric replacement of sarcomeric proteins in these disease states with particular focus on cardiac troponin I. Stoichiometric replacement of disease causing mutations has been instrumental in defining the molecular mechanisms of hypertrophic and restrictive cardiomyopathy in a cellular context. In addition, taking advantage of stoichiometric replacement through gene therapy is discussed, highlighting the ischemia‐resistant histidine‐button, A164H cTnI. Stoichiometric replacement of sarcomeric proteins offers a potential gene therapy avenue to replace mutant proteins, alter sarcomeric responses to pathophysiologic insults, or neutralize altered sarcomeric function in disease. Anat Rec, 297:1663–1669, 2014. © 2014 Wiley Periodicals, Inc.     

Cardiomyopathy in neurological disorders

According to the American Heart Association, cardiomyopathies are classified as primary (solely or predominantly confined to heart muscle), secondary (those showing pathological myocardial involvement as part of a neuromuscular disorder) and those in which cardiomyopathy is the first/predominant manifestation of a neuromuscular disorder. Cardiomyopathies may be further classified as hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or unclassified cardiomyopathy (noncompaction, Takotsubo-cardiomyopathy). This review focuses on secondary cardiomyopathies and those in which cardiomyopathy is the predominant manifestation of a myopathy. Any of them may cause neurological disease, and any of them may be a manifestation of a neurological disorder. Neurological disease most frequently caused by cardiomyopathies is ischemic stroke, followed by transitory ischemic attack, syncope, or vertigo. Neurological disease, which most frequently manifests with cardiomyopathies are the neuromuscular disorders. Most commonly associated with cardiomyopathies are muscular dystrophies, myofibrillar myopathies, congenital myopathies and metabolic myopathies. Management of neurological disease caused by cardiomyopathies is not at variance from the same neurological disorders due to other causes. Management of secondary cardiomyopathies is not different from that of cardiomyopathies due to other causes either. Patients with neuromuscular disorders require early cardiologic investigations and close follow-ups, patients with cardiomyopathies require neurological investigation and avoidance of muscle toxic medication if a neuromuscular disorder is diagnosed. Which patients with cardiomyopathy profit most from primary stroke prevention is unsolved and requires further investigations.     

心肌扩张型心脏病的病理形态特征及其临床意义

目的探讨单纯心壁病损造成的心脏扩张者的病理形态特征及其意义。方法收集2004年6月至2006年8月中国医学科学院北京协和医学院阜外心血管病医院60例心脏移植的受体心脏在离体后立即进行了肉眼观察、测量和摄影记录,并进行了全面的组织病理学观察。以其中40例单纯心壁病损造成的心脏扩张者进行临床-病理对照分析,并观察其形态特点。结果40例单纯心壁病损造成的心脏扩张者中21例（52．5％）为原发性扩张型心肌病,9例（22．5％）为致心律失常性右心室心肌病,6例（15．0％）为缺血性心肌病,其余的4例（10．0％）为局灶性心肌致密化不全、巨细胞性心肌炎和特异性心肌病中的酒精性心肌病和高血压性心肌病。40例中临床诊断与病理诊断不符15例（37．5％）,不相符率较高的依次为致心律失常性右心室心肌病（7／9）、缺血性心肌病（5／6）和巨细胞性心肌炎（1／1）。不相符的这几种病的原临床和影像学诊断都是扩张型心肌病。致心律失常性右心室心肌病、缺血性心肌病、心肌致密化不全和巨细胞性心肌炎都有特征性的病理形态表现,酒精性心肌病和高血压性心肌病等的病理诊断需要参考临床病史。该组病例没有观察到慢性心肌炎样病变发展成扩张型心肌病的形态学迹象。结论进行心脏移植病例受体心脏的病理学检查有利于提高心脏病的临床和影像诊断的正确率,病理形态检查是不可忽视的重要手段。     

Pathologic evidence of extensive left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (also known as arrhythmogenic right ventricular dysplasia) is characterized by adipose or fibroadipose tissue replacement of the right ventricular myocardium, whereas the left ventricle is substantively spared. Two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination are described. Hearts from two patients who died suddenly showed full-thickness right ventricular fatty infiltration associated with extensive left ventricular involvement (greater than 50% of myocardial thickness). These findings might explain the reported clinical features of left ventricle dysfunction in a subset of patients with arrhythmogenic right ventricular cardiomyopathy. In view of the biventricular involvement of the disease, it should simply be termed "arrhythmogenic cardiomyopathy."     

Review: Metabolic cardiomyopathy and conduction system defects in children

Metabolic cardiomyopathies include amino acid, lipid and mitochondrial disorders, as well as storage diseases. A number of metabolic disorders are associated with both myopathy and cardiomyopathy. These include the glycogen storage diseases, ie, acid maltase deficiency (infantile, childhood, and adult onset), McArdle disease, and debrancher and brancher deficiencies. Disorders of lipid metabolism include systemic carnitine deficiency and abnormalities of carnitine palmitoyltransferase (CPT), long-chain acyl-CoA dehydrogenase, and multiple acyl-CoA dehydrogenase. Disorders of mitochondrial metabolism affect complex I, II, III, IV and V, in addition to multiple respiratory chain defects. These may cause either hypertrophic or dilated cardiomyopathy. In addition, cardiomyopathy is frequently a component part of the storage disorders, including mucopolysaccharidosis, mucolipidosis, Fabry disease, gangliosidosis, and neuronal ceroid lipofuscinosis. Primary hypertrophic cardiomyopathy is caused by mutations in one of the genes that encode proteins of the cardiac sarcomere. Mutations in different genes are attended by different prognoses and different risks of sudden death. Mutations of the genes for myosin binding protein C (MBPC) and tropomyosin have low penetrance and cause mild forms of primary hypertrophic cardiomyopathy, while mutations of the troponin T and B-myosin genes carry a worse prognosis. Conduction disorders result in cardiac arrhythmias that may be fatal. Histiocytoid cardiomyopathy is usually an autosomal recessive disorder that results in the presence of abnormal Purkinje cells that interfere with normal cardiac conduction. Other conduction defects include arrhythmogenic right ventricular dysplasia (ARVD), congenital heart block, noncompaction of the left ventricle, and long Q-T syndrome (LQTS). The genetic loci for LQTS reside usually in the potassium channel, and, less frequently, in the sodium channel (channelopathies). Although the histological appearance of some of these disorders may be diagnostic, molecular analysis is necessary to define clearly the particular type of cardiomyopathy.     

Distribution of biventricular disease in arrhythmogenic cardiomyopathy: an autopsy study

Arrhythmogenic cardiomyopathy is a rare cardiomyopathy characterized by fibrofatty replacement primarily of the right ventricular myocardium. It is a major cause of sudden death in the young and in athletes. There are few autopsy studies of the ventricular distribution of the disease. Fifty cases of sudden cardiac death with fibrofatty replacement in either ventricle from a single medical examiner's office were studied. Distribution of disease as determined grossly and microscopically was correlated with activity at time of death, race, and presence of inflammation. Extent of disease was right ventricular in 6 cases (12%; age, 25 ± 5 years), biventricular in 25 (50%; age, 36 ± 3 years), and left ventricular in 19 (38%; age, 37 ± 3 years) (P = .13). Inflammation was present in 44% of biventricular arrhythmogenic cardiomyopathy versus 74% of left ventricular arrhythmogenic cardiomyopathy and 83% of right ventricular arrhythmogenic cardiomyopathy (P = .06). Arrhythmogenic cardiomyopathy, when presenting with sudden death, is usually biventricular. There is a trend that univentricular involvement occurs at an earlier age and that right ventricular involvement shows more inflammation, suggesting different stages of disease.     

Juvenile sudden death in a family with polymorphic ventricular arrhythmias caused by a novel RyR2 gene mutation: evidence of specific morphological substrates

We report on a family with a history of sudden death and effort-induced polymorphic ventricular arrhythmias. The index case was a 17-year-old boy who died suddenly and at postmortem had evidence of fibrofatty replacement in the right ventricular free wall, consistent with arrhythmogenic right ventricular cardiomyopathy, as well as calcium phosphate deposits within the myocytes. A molecular genetics investigation carried out in the paraffin-embedded myocardium of the subject and in blood samples of family members disclosed a missense mutation in exon 3 (230C-->T; A77V) of the cardiac ryanodine receptor type 2 gene. The carriers showed effort-induced polymorphic ventricular tachycardia in the setting of normal resting electrocardiogram and trivial echocardiographic abnormalities, consistent with catecholaminergic polymorphic ventricular tachycardia. The observation of both arrhythmogenic right ventricular cardiomyopathy type 2 and catecholaminergic polymorphic ventricular tachycardia in the same family suggests that the two entities might correspond to different degrees of phenotypic expression of the same disease. This experience underscores the importance of a precise autopsy diagnosis in the case of sudden cardiac death, including molecular genetics, and the mission of pathologists to guide further clinical investigation of family members.     

Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat?

Whether fatty infiltration of the right ventricle has to be considered "per se" a sufficient morphologic hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still a source of controversy; ARVC should be kept distinct from both fatty infiltration of the right ventricle and adipositas cordis. In fact, it is well known that a certain amount of intramyocardial fat is present in the right ventricular antero-lateral and apical regions even in the normal heart and that the epicardial fat increases with increasing body weight. However, both the fibro-fatty and fatty variants of ARVC show, besides fatty replacement of the right ventricular myocardium, degenerative changes of the myocytes and interstitial fibrosis, with or without extensive replacement-type fibrosis. The need to adopt strict diagnostic criteria is warranted not only in the clinical setting but also in the forensic and general pathology arena. When dealing with a case of sudden death, in which the only morphologic finding consists of an increased amount of epicardial or intramyocardial fat, a more convincing arrhythmogenic source such as myocardial inflammatory infiltrates, fibrosis, anomalous pathways, and ion channel disease should always be searched for, in order to avoid an over-diagnosis of ARVC cases.     

Génétique des cardiomyopathies héréditaires

Hereditary cardiomyopathy is a primitive disorder in which the heart muscle is structurally and functionally abnormal in the absence of any other cause of cardiomyopathy. They are separated into four phenotypic groups, hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic cardiomyopathy of the right ventricle. Hypertrophic cardiomyopathy was the first identified at the molecular level and then the first to benefit of molecular testing. The molecular analyses were then extended the following years to the dilated cardiomyopathy and restrictive cardiomyopathy. The arythmogenic right ventricular cardiomyopathy was the latest to be analyzed at the molecular level because the identification of genes involved in that phenotype was published only in 2002 to 2006. The genetics analysis of these diseases has developed over the past decade and, although still complex, is now available in current hospital practice. The objectives of these tests are to confirm a diagnosis difficult to achieve by classic clinical approach and to perform predictive and presymptomatic diagnosis in families when the mutation was identified. This allows for appropriate care of patients at risk, and may respond to a request for prenatal diagnosis in particularly serious forms. These tests are framed in the context of genetic counselling consultation and patients are the subjects of a multidisciplinary care in reference centres.     

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.     

Embryonic stem cell therapy of heart failure in genetic cardiomyopathy

Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K(+) (K(ATP)) channel subunits. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional K(ATP) channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure. Disclosure of potential conflicts of interest is found at the end of this article.     

Genetic testing for inherited heart diseases: longitudinal impact on health-related quality of life

PurposeA genetic diagnosis is an extremely useful tool in the management and care of families with inherited heart diseases, particularly in allowing clarification of risk status of asymptomatic family members. The psychosocial consequences of genetic testing in this group are poorly understood. This longitudinal pilot study sought to determine changes in health-related quality of life in patients and asymptomatic family members undergoing genetic testing for inherited heart diseases.MethodsIndividuals attending two specialized multidisciplinary cardiac genetic clinics in Australia were invited to participate. Patients undergoing proband or predictive genetic testing for an inherited cardiomyopathy or primary arrhythmogenic disorder were eligible. The Medical Outcomes Short Form-36 (version 2) was administered before the genetic result was given, and follow-up surveys were completed 1–3, 6, and 12 months after the result was given.ResultsA total of 54 individuals with hypertrophic cardiomyopathy, familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and long QT syndrome completed baseline and at least one follow-up survey, including 33 probands and 21 asymptomatic relatives. Physical and mental component scores analyzed at baseline and 1–3 months were found to be unchanged in all groups. Furthermore, no significant differences were observed up to 12 months after result.ConclusionIn this longitudinal pilot study, no change in health-related quality of life was observed up to 12 months after the result was given in patients and their asymptomatic family members undergoing genetic testing for an inherited heart disease.Genet Med 2012:14(8):749–752.     

Arrhythmogenic right ventricular cardiomyopathy versus fatty replacement of the right ventricle. An autopsy case report

We report an autopsy case of a cardiomyopathy characterized by fatty replacement of the right ventricular myocardium and compare its clinical and histologic characteristics with those of the arrhythmogenic right ventricular cardiomyopathy. A 39-year old male died suddenly in a hospital room. He had an alcoholic cirrhosis with ascitis, but the clinical examination and the biology showed no abnormalities explaining the death. Histologically, in the right ventricle, large areas of cardiomyocytes were replaced by fat, but there was no fibrosis. In contrast, fibrosis is present in association with fat in arrhythmogenic right ventricular cardiomyopathy. Fatty replacement of the right ventricle is likely to be a distinct entity. Right ventricular failure has been shown to be a possible complication. Sudden death is probably rare and is likely to occur when other arrhythmogenic factors are associated.     

Prevention of sudden cardiac death in the young and in athletes: dream or reality?

Cardiovascular diseases account for 40% of all deaths in the Western countries, and nearly two thirds of them occur suddenly. Young people (<35 years) are not spared from sudden death (SD) with a rate of 1/100,000 per year. Effort is a trigger with a threefold risk in athletes vs. nonathletes, and sports disqualification is by itself life-saving in people with underlying concealed cardiovascular diseases. Several culprits of cardiac SD may be identified at postmortem and atherosclerotic coronary artery disease is the leading cause (25% of SD cases in the young), mostly consisting of a single obstructive plaque with fibrocellular intimal proliferation. However, the spectrum of cardiovascular substrates is wide and include also congenital diseases of the coronary arteries (mainly anomalous origin), myocardium (arrhythmogenic and hypertrophic cardiomyopathies, myocarditis), valves (aortic stenosis and mitral valve prolapse), and conduction system (ventricular preexcitation, accelerated atrioventricular conduction and block). In up to 20% of cases, the heart is grossly and histologically normal at autopsy (unexplained SD or “mors sine materia”), and inherited ion channel diseases have been implicated (long and short QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia).Targets to treat and prevent SD in the young consist of the following: (a) avoid triggers like effort or emotion, (b) inhibit the onset of arrhythmias with drugs or ablation, (c) switch off arrhythmias with defibrillator, and (d) hinder the recurrence of the disease with genetic counseling and/or therapy. In vivo detection of cardiomyopathies is nowadays feasible by electrocardiogram and/or echocardiography, which resulted in a sharp decline of SD in the athletes in Italy, thanks to obligatory preparticipation screening for sport activity. Genetic screening could play a pivotal role in early detection of asymptomatic mutation carriers of cardiovascular diseases at risk of SD.     

Myocyte transdifferentiation: a possible pathogenetic mechanism for arrhythmogenic right ventricular cardiomyopathy

Adipose substitution of ventricular myocardium is characteristic of arrhythmogenic right ventricular cardiomyopathy, but is also found in other heart conditions. It is thought to be a consequence of myocyte loss due to myocarditis or other noxious stimuli. We describe a unique case of cardiomyopathy with a morphologic pattern suggestive of transdifferentiation from myocytes to mature adipocytes. Gross, histologic, and ultrastructural examination were performed on the heart of a female transplant patient with a clinical diagnosis of familial dilated cardiomyopathy. Gross examination showed fibroadipose substitution of the left ventricle and adipose replacement of the right. Histology, immunohistochemistry, and ultrastructure were highly suggestive of transdifferentiation from cardiac muscle to adipose tissue. Myocyte transdifferentiation could represent an alternative pathogenetic pathway to the myocyte-loss and adipose-replacement mechanism in arrhythmogenic right ventricular cardiomyopathy, or it could be the basis of a new type of familial cardiomyopathy.     

Histological assessment of apoptotic cell death in cardiomyopathies

Apoptosis in the myocardium is complex and often difficult to recognise. Myocyte apoptosis is scattered across the myocardial wall and is restricted to individual cells. In the present study, we describe the amount of apoptosis in 50 endomyocardial biopsies taken from 50 patients with dilated cardiomyopathy, in 14 hearts with hypertrophic cardiomyopathy and in five hearts with arrhythmogenic dysplasia of the right ventricle. As a control group, 15 endomyocardial biopsies from 15 transplanted hearts (of live patients) were used. Apoptosis was immunohistochemically determined in paraffin sections with the TUNEL method. In each specimen the TUNEL index was calculated as the percentage of TUNEL-positive nuclei among a total number of 200 counted nuclei. Cellular morphology was assessed in conjunction with TUNEL staining. The mean percentage of TUNEL-positive myocardial cells varied from 4% for dilated cardiomyopathy to 17.5% for arrhythmogenic right ventricle dysplasia and 18.5% for hypertrophic cardiomyopathy, whereas no signs of apoptotic myocardial cell death were found in normal subjects. The numbers of apoptotic cells in dilated cardiomyopathy specimens were significantly lower by comparison with both those of hypertrophic cardiomyopathy and those of arrhythmogenic right ventricular dysplasia specimens. It is evident that apoptosis constitutes a major biological phenomenon in the development of at least some heart diseases, but its role in their pathophysiology has yet to be delineated.     

Role of novel DSP_p.Q986X genetic variation in arrhythmogenic right ventricular cardiomyopathy

Introduction

Arrhythmogenic right ventricular cardiomyopathy is an inherited disease characterized by a progressive myocardium fibrofatty replacement. This abnormality disrupts electrical transmission causing ventricular arrhythmias and sudden cardiac death. This genetic disease is transmitted mainly with an autosomal dominant pattern. Our aim was to identify the genetic defect responsible for the pathology in a Spanish family, and to perform its phenotype connotations.

Material and methods

A total of 15 individuals in a three-generation Spanish family were screened after the sudden cardiac death of one family member. All they underwent a complete physical examination, 12-lead electrocardiogram, 2-dimensional echocardiography, magnetic resonance imaging, exercise stress test, 24-h Holter and genetic testing.

Results

Autopsy revealed the presence of biventricular arrhythmogenic dysplasia in deceased member. Six family members showed clinical symptoms but only three of them fulfilled definite diagnostic criteria of the disease. Genetic analysis showed a novel nonsense genetic variation in nine family members. All family members with clinical symptoms carried the genetic variation.

Conclusions

Genetic testing in families affected by arrhythmogenic right ventricular cardiomyopathy helps to identify the genetic cause responsible for the disease. The incomplete penetrance and variable phenotypic expression highlights the need of comprehensive genetic analysis and further phenotype implications of genetics to clarify the pathophysiology of the disease.