致心律失常性右室心肌病的研究进展

致心律失常性右室心肌病（ARVC）是以右室心肌不同程度的被脂肪组织或纤维组织替代为特征的一种常染色体遗传性心肌病。临床上常表现为室性心律失常,进行性心力衰竭,甚至心源性猝死。有时起病隐匿,无症状患者于尸检后才作出诊断,也有部分患者以猝死为首发症状。临床上主要靠心电图,电生理学检查,以及影像学检查提供诊断依据,但心内膜心肌活检仍是确诊的金标准。ARVC治疗包括抗心律失常药物,置入埋藏式心律转复除颤器（ICD）,导管射频消融以及心脏移植。     

Spin-echo nuclear magnetic resonance for tissue characterisation in arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disorder characterised clinically by ventricular arrhythmias that can cause cardiac arrest and morphologically by fatty or fibro-fatty myocardial atrophy of the right ventricle. In vivo tissue characterisation without endomyocardial biopsy would be useful. The aim of this study was to investigate the diagnostic accuracy of spin-echo nuclear magnetic resonance (NMR) for tissue characterisation in ARVC. PATIENTS AND METHODS: Twenty three subjects (15 men and eight women, aged 18-49, mean 34) were studied with spin-echo T1-weighted NMR and multislice scan. Fifteen had a clinical diagnosis of ARVC and eight were controls (age and sex matched subjects). Data were independently evaluated by two expert observers. RESULTS: In the control group NMR was always negative (100% specificity). Ten of the 15 patients with ARVC had an abnormal NMR result (67% sensitivity), with areas that had a signal intensity close to that of pericardial or subcutaneous fat. In the remaining five cases the NMR signal was inadequate. Nine patients underwent both NMR and endomyocardial biopsy; biopsy was positive in eight (89%) and NMR was positive in five (56%). CONCLUSIONS: NMR is a useful non-invasive diagnostic tool in the evaluation of fatty replacement in ARVC. The technique can be used with other procedures in the initial diagnostic evaluation and is a useful alternative tool in the long term follow up of patients with ARVC.     

Arrhythmogene rechtsventrikuläre Kardiomyopathie

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary, genetically determined heart muscle disease and a major cause of ventricular tachyarrhythmia and sudden cardiac death in young, apparently healthy individuals and athletes. In ARVC, mutations in genes encoding for desmosomal cell contact proteins result in myocardial atrophy with subsequent fibrofatty replacement, predominantly affecting the right ventricular myocardium. Left ventricular involvement can also occur early in the disease process. The structural abnormalities lead to global and/or regional dysfunction of the right or both ventricles and to the dominant clinical manifestation with ventricular tachyarrhythmia. A primary manifestation of ARVC with clinically relevant signs and symptoms of heart failure is rare. Genetic counselling is indicated in all index patients with ARVC and their families. Genetic testing, however, is recommended only under particular circumstances (e.g. cascade screening). An early and correct diagnosis is crucial for risk stratification, treatment and prognosis of ARVC. The catalogue of diagnostic criteria (major and minor criteria) includes electrocardiogram (ECG) findings of depolarization and repolarization, arrhythmia, morphological and functional imaging, histopathology and genetics. These diagnostic criteria are currently under prospective validation in clinical studies and registries.     

致心律失常性右室心肌病诊断进展

摘要：致心律失常性右室心肌病,又称致心律失常性右室发育不良,是一种遗传性心肌病,其特征为右心室心肌进行性被纤维脂肪组织所替代,临床常表现为右心室扩大、心律失常和猝死。致心律失常性右室心肌病的具体发病机制不十分明确,在此病的临床诊断方面仍值得进一步探讨。     

Electron microscopical observations of the myocardium in patients with idiopathic cardiomyopathy using endomyocardial biopsy

An electron microscopical study of the human myocardium obtained from eight cases of idiopathic cardiomyopathy and two cases of valvular heart disease was performed employing Konno's endomyocardial biopsy method. Except for one control case of aortic stenosis with no remarkable haemodynamic findings of the right side heart, most of the cases revealed the following ultrastructural changes: (i) Accumulation of mitochondria; (ii) various kinds of mitochondrial degeneration; (iii) widening and increase of the sarcotubular system; (iv) fragmentation and scarcity of myofibrils; (v) increased glycogen deposition; (vi) widened intercalated disc; (vii) increased rough-surfaced endoplasmic reticulum and Golgi apparatus; and (viii) appearance of small dense granules. Although none of these findings are exclusively characteristic, it is concluded that they seem to be more advanced, especially findings (iv), (v) and (vi), in cases of idiopathic hypertrophic cardiomyopathy.     

Diagnostic value of endomyocardial biopsy guided by electroanatomic voltage mapping in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Introduction: To improve the endomyocardial biopsy (EMB) diagnostic sensitivity for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), we hypothesized a biopsy sampling focused on selected right ventricle (RV) low‐voltage areas identified by electroanatomic voltage mapping. Methods and Results: The study population (22 patients, 10 men; mean age 34 ± 10 years) included 11 patients with overt ARVC/D (group A) and 11 patients with suspected ARVC/D (group B), according to both arrhythmic profile and standardized noninvasive diagnostic criteria. In all 22 patients, an RV bipolar voltage mapping was performed with CARTO? system sampling multiple endocardial sites (262 ± 61), during sinus rhythm, with a 0.5–1.5 mV color range setting of voltage display. All 11 (100%) group A patients and 8 of the 11 (73%) group B patients (P = nonsignificant [NS]) presented RV low‐voltage areas (<0.5 mV). In 8 group A patients and in all 8 group B patients with a pathological RV voltage map, an EMB focused on the low‐voltage areas was performed. In 6 (75%) group A patients and in 7 (87%) group B patients (P = NS), voltage mapping‐guided EMB was diagnostic for ARVC/D. In the remaining 3 patients, only nonspecific histological findings were observed. Conclusions: The results of our study (1) confirm the high diagnostic sensitivity of RV voltage mapping in patients with overt ARVC/D, (2) document a high prevalence of RV low‐voltage areas even in patients with suspected ARVC/D, and (3) demonstrate that in patients with clinical evidence or suspicion for ARVC/D, presenting RV low‐voltage areas, EMB guided by voltage mapping may provide ARVC/D diagnosis confirmation.     

Endomyocardial biopsy guided by electroanatomic voltage mapping in arrhythmogenic right ventricular cardiomyopathy: a case report

A positive endomyocardial biopsy (EMB) is a major diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC). Nevertheless, its sensitivity is low due to the focal nature of the disease. Moreover, myocardial samples are usually taken from the uncommonly involved interventricular septum to minimize the risk of perforation. In this report, we describe a novel bioptical approach for ARVC diagnosis guided by the identification of right ventricle (RV) affected regions by means of electroanatomical voltage mapping.     

Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia

In the last two decades the extraordinary advances in molecular biology of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) have provided significant insights into our understanding of the disease aetiology by showing that it is a genetic disorder of the cardiac desmosomes and that interactions between mechanical disruption of cell-cell adhesion and defects of desmosomal-mediated intracellular signalling are likely to be involved in the pathogenesis of the ARVC/D phenotype. The discovery of the causative genes for ARVC/D offers the possibility of identifying genetically-affected individuals before potentially malignant clinical phenotype occurs. Moreover, the evaluation of abnormal localisation of desmosomal proteins by immunohistochemical analysis on endomyocardial biopsy samples represents a promising test for ARVC/D diagnosis. Early detection of ARVC/D and preventive therapy of young individuals at highest risk of experiencing sudden cardiac death may be improved by molecular genetic screening within affected families and may alter the clinical management of patients. At present, however, the clinical use of genotyping is limited by the incomplete knowledge of causative mutations and the complex genetic background of the disease, which accounts for the incomplete penetrance and the marked variability of the phenotype expression. This review addresses the advances in the molecular biology of ARVC/D, with particular reference to the genetic basis of the disease, and how these advances have impacted on understanding the disease pathogenesis, on diagnosis and in establishing management strategies.     

Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?

PURPOSE OF REVIEW: Recent developments in the elucidation of genes underlying arrhythmogenic right ventricular cardiomyopathy and possible pathogenic mechanisms will be highlighted. RECENT FINDINGS: The cardiac desmosome is a multiprotein structure involved in cell-cell interactions. Mutations in genes encoding desmosomal proteins such as PKP2, DSP, JUP, DSC2 and DSG2 underlie arrhythmogenic right ventricular cardiomyopathy, which can therefore be considered a desmosome cardiomyopathy. Mutations in the plakophilin-2 gene are most prevalent. Current pathophysiological insights suggest a final common pathway in which plakoglobin release from the desmosome, independent of the primarily affected desmosomal protein, results in desmosome impairment, intercalated disc remodeling and Wnt/beta-catenin pathway signaling defects. The recognition of left ventricular involvement associated with mutations in desmosomal protein genes and low penetrance suggests that formal criteria should not be followed too closely in selecting patients for DNA analysis, because finding a mutation may have important implications for clinical practice. SUMMARY: Recent developments have demonstrated that arrhythmogenic right ventricular cardiomyopathy can be considered a desmosome cardiomyopathy. Left ventricular involvement is not uncommon in this type of cardiomyopathy. Such findings are important for diagnostics and family screening and form a starting-point for the elucidation of other (non)-genetic factors influencing disease progression and outcome.     

Arrhythmogenic right ventricular cardiomyopathy/dysplasia: An update

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic cardiomyopathy characterized by ventricular arrhythmias and structural abnormalities of the right ventricle (RV). The diagnosis is based on the International Task Force criteria. Cardiologists may not be aware of these diagnostic criteria for ARVC/D and may place too much importance on the results of MRI imaging of the right ventricle. Patients with ARVC/D usually have an abnormal 12-lead electrocardiogram, abnormal echocardiogram, and ventricular arrhythmias with a left bundle branch block morphology. If noninvasive testing suggests ARVC/D, invasive testing with an RV angiogram, RV biopsy, and electrophysiologic study is recommended. Once a diagnosis of ARVC/D is established, the main treatment decision involves whether to implant an implantable cardioverter-defibrillator. We also recommend treatment with β blockers. Patients with ARVC/D are encouraged to avoid competitive athletics. Recent advances in the understanding of the genetic basis of ARVC/D have revealed that ARVC/D is a disease of desmosomal dysfunction.     

Apoptotic cell death in arrhythmogenic right ventricular cardiomyopathy: a comparative study with idiopathic sustained ventricular tachycardia

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a specific heart muscle disease of unknown etiology characterized by fatty and fibrofatty replacement of the right ventricular myocardium. It often manifests life-threatened ventricular arrhythmias. Previous studies have hypothesized that myocyte apoptosis contributes to the myocyte cell loss and fatty change in ARVC and may be induced by recurrent ventricular tachycardia (VT). We examined whether these progressive pathological changes result from apoptotic cell death in both autopsied and biopsied right ventricular myocardium from 35 patients with ARVC by using in situ terminal deoxynucleotidyl transferase assay (TUNEL) and agarose gel electrophoresis. We also studied the biopsied myocardium from 30 patients with idiopathic sustained VT whose origin was the outflow tract of the right ventricle. TUNEL-positive cells indicating DNA fragments were observed in some cardiomyocytes and fibroblasts in ARVC, but the numbers of TUNEL-positive myocytes were very low in idiopathic VT. DNA laddering was confirmed in two autopsied cases in ARVC, but not in a non-cardiac case who died. These results suggest that at least some cardiomyocytes and fibroblasts are subjected to apoptosis in ARVC, leading to the loss of myocardium with characteristic pathological changes and subsequently progressive cardiomyopathy. Furthermore, the apoptotic process may not result from myocardial ischemia due to repetitive VT.     

Arrhythmogenic right ventricular cardiomyopathy with an initial manifestation of severe left ventricular impairment and normal contraction of the right ventricle

A case of arrhythmogenic right ventricular cardiomyopathy (ARVC) with an initial manifestation of severe impairment of the left ventricle (LV) and normal contraction of the right ventricle (RV) is presented. A 43-year-old man was admitted to hospital because of congestive heart failure following a common cold. The LV function was diffusely and severely hypokinetic. Coronary arteriogram revealed normal vessels. An endomyocardial biopsy specimen obtained from the RV septum revealed mild infiltration of lymphocytes with focal myocytes necrosis and so healing myocarditis was suspected. The specimen did not include any fatty replacement of myocytes. Since then, the patient suffered from recurrent congestive heart failure as well as nonsustained ventricular tachycardia and required frequent hospitalization. Progressive impairment, dilation, and thinning of both ventricles were observed on serial echocardiographic examinations. Although the RV gradually enlarged and became impaired, severe dilatation and impairment of the LV has always been predominant in the patient's clinical course. After medical follow-up for 10 years, he died suddenly of ventricular fibrillation and pump failure. The autopsy revealed extensive fibrofatty replacement of myocytes in both the ventricles, extending from the outer layer to the inner layer of myocardium in the RV and to the middle layer in the LV. These features were compatible with arrhythmogenic right ventricular cardiomyopathy or perimyocarditis, although only the rightsided bundle of the interventricular septum was completely replaced by fatty tissue, which can not be explained as a sequel of perimyocarditis. Moreover, apoptosis was present in the myocyte nuclei of the myocardial layers bordering the area of fatty replacement. Therefore, myocarditis may have triggered or accelerated the process of apoptosis leading to ARVC.     

Arrhythmogenic right ventricular cardiomyopathy (dysplasia): etiology, clinical presentation, diagnosis and treatment

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder characterised by progressive replacement of right ventricle myocardium by either segmental or diffuse fibro-fatty tissue, often with the involvement of the left ventricular wall and manifestations of arrhythmia. Familial occurrence with autosomal dominant inheritance, variable expression and incomplete penetrance is estimated as 1/5000. The recessive form called Naxos disease has also been reported. The etiology and pathogenesis of ARVC are still unknown. Advanced theories of inflammatory or infective etiology and possible mechanism of myocyte loss through apoptosis and/or transdifferentiation into adipocytes are presented in this article. The patterns of two distinct pathomorphology of ARVC based on the nature of myocardial replacement are also presented. The presentation encompasses the wide spectrum of clinical diagnostic features of the disease, including sudden death in the family and abnormalities in ECG, Echo, MRI, angiography, PES exhibiting morphologic and functional changes, and replacement of myocytes by fibro-fatty tissue observed in endomyocardial biopsy specimens. Special attention is drawn to the subtle clinical manifestations and ECG clues of the disease in children and young people. Treatment modalities including drug therapy, ablation, implantable cardioverter defibrillators, antiarrhythmic surgery or heart transplantation are also presented.     

Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects

BACKGROUND: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study. AIMS: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects. METHODS AND RESULTS: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and alphaB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon-intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative. CONCLUSIONS: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical.     

LMNA‐Mediated Arrhythmogenic Right Ventricular Cardiomyopathy and Charcot‐Marie‐Tooth Type 2B1: A Patient‐Discovered Unifying Diagnosis

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon cardiomyopathy most classically associated with mutations in genes encoding desmosomal proteins. Recent literature has identified mutations in several non‐desmosomal proteins including lamins that may result in the ARVC phenotype. We describe a patient who discovered her own pathogenic LMNA mutation that offered a unifying diagnosis explaining her ARVC and Charcot‐Marie‐Tooth phenotypes as well as musculoskeletal abnormalities. Suspicion for LMNA‐mediated cardiomyopathy should arise in patients with extracardiac manifestations of laminopathies and testing for specific gene mutations may be helpful in establishing an unifying diagnosis.     

Endomyocardial biopsy in right ventricular cardiomyopathy

Right ventricular cardiomyopathy is characterized by a progressive myocyte loss and fibro-fatty substitution of the right ventricle. The aim of our study was to assess the diagnostic accuracy of right ventricular endomyocardial biopsy. Using an imaging analyser system, histomorphometric parameters of myocytes, interstitium, fibrous tissue and fatty tissue were evaluated on endomyocardial biopsy from 30 patients with arrhythmogenic right ventricular cardiomyopathy, 29 patients with dilated cardiomyopathy and 30 control patients. The percent area of myocytes decreased from 78.10 ± 7.34 in control to 63.39 ± 9.22 in dilated cardiomyopathy (P < 0.05) and to 47.28 ± 15.01 in arrhythmogenic right ventricular cardiomyopathy (P < 0.01). Fibrous tissue increased from 8.10 ± 3.89 in control to 21.80 ± 9.29 in dilated cardiomyopathy (P < 0.05) and to 24.60 ± 11.37 in arrhythmogenic right ventricular cardiomyopathy (P < 0.05). Fatty tissue varied from 0.33 ± 1.44 in control and 0.07 ± 0.31 in dilated cardiomyopathy to 13.30 ± 17.30 in arrhythmogenic right ventricular cardiomyopathy (P < 0.05). Fatty tissue was a feature of arrhythmogenic right ventricular cardiomyopathy (67% of patients vs. 6% of control and dilated cardiomyopathy patients). Diagnostic values typifying arrhythmogenic right ventricular cardiomyopathy, obtained by excluding any overlapping between confidence intervals in the three groups, were: myocytes <44.95%; fibrous tissue >40.38%, and fatty tissue >3.21%, with 67% sensitivity and 91.53% specificity for at least one parameter. In conclusion, a significant difference between arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and control exists in terms of amount of myocytes, fibrous tissue and fatty tissue. Presence of fatty tissue and fibrous tissue exceeding 3.21% and 40.38%, respectively should be considered highly suspect for arrhythmogenic right ventricular cardiomyopathy in right ventricular endomyocardial biopsy.     

Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

OBJECTIVE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous disorder characterized by fibro-fatty replacement of the right ventricular myocardium, associated with high risk of sudden death. The objective of this study is to identify the gene involved in ARVD1, which has been elusive ever since its locus was mapped to chromosome 14q24.3. METHODS AND RESULTS: Mutation screening of the promoter and untranslated regions (UTRs) of the transforming growth factor-beta3 (TGFbeta3) gene was performed by direct sequencing of genomic DNA of one index case belonging to an ARVD1 family including 38 members in four generations. We detected a nucleotide substitution (c.-36G>A) in 5' UTR of TGFbeta3 gene, invariably associated with the typical ARVC clinical phenotype in the affected family members, according to the established diagnostic criteria. Investigation extended to 30 unrelated ARVC patients, performed by denaturing high-performance liquid chromatography (DHPLC), led to the identification of an additional mutation (c.1723C>T) in the 3' UTR of one proband. Neither nucleotide change was found in 300 control subjects. In vitro expression assays with constructs containing the mutations showed that mutated UTRs were twofold more active than wild-types. CONCLUSION: We identified TGFbeta3 as the disease gene involved in ARVD1. The identification of a novel ARVC gene will increase the power of the genetic screening for early diagnosis of asymptomatic carriers among relatives of ARVC patients.     

Myopericarditis associated with ECHO virus type 3 infection--A case report

A case with myopericarditis caused by type 3 ECHO virus was reported. The diagnosis was based on a significantly increased hemagglutination-inhibiting antibody titer (from 4:6 to 4:516) against type 3 ECHO virus in the acute and the convalescent phase. A 29-year-old male was hospitalized for chest pain and fever. The patient had congestive heart failure, pericardial effusion and temporarily appearing abnormal Q waves on his electrocardiogram in the acute phase all of which gradually improved within about 3 weeks. Cardiac catheterization performed on the 21st day of hospitalization disclosed normal coronary arteries, but a partially hypokinetic region was found in the left ventricular free wall. A right ventricular endomyocardial biopsy study revealed histological features of a small number of mononuclear cell infiltrations, myocardial cell necrosis and early fibrosis associated with an increased number of fibroblasts and ultrastructural changes including myocytolysis, vacuolation in sarcoplasm and dissociation of some intercalated discs. The endomyocardial biopsy study, and the electrocardiographic and cineangiographic findings in this case suggest that viral infection may induce clinical signs of myocardial infarction in the heart with normal coronary arteries.     

Apoptotic myocardial cell death in the setting of arrhythmogenic right ventricular cardiomyopathy

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive atrophy of the right ventricular myocardium accompanied by fibro-fatty replacement. We examined whether the loss of myocardial cells in the setting of ARVC could result from cell death by apoptosis as demonstrated by the detection of DNA fragmentation and the expression of apoptosis regulatory proteins (e.g. CPP-32, Bcl-2, and Bax). METHODS: Specimens obtained from the right ventricular myocardium of 11 patients with ARVC (ARVC group) and 10 age-matched normal individuals (control group) were analysed. To identify individual cells undergoing apoptosis, paraffin sections were examined with the TdT-mediated dUTP-biotin nick end labelling method (TUNEL) and the rabbit polyclonal anti-single stranded DNA method (ssDNA). The apoptotic index was calculated as the percentage of nuclei staining positive by the TUNEL or ssDNA method. We also used immunohistochemical techniques to examine the levels of CPP-32, Bcl-2, and Bax expression. RESULTS: Apoptosis was detected in the ARVC group with a mean apoptotic index of 5.7 +/- 4.5% (ssDNA) and 23.8 +/- 7.5% (TUNEL), but not in the control group (p < 0.01). CPP-32 expression and Bax overexpression were observed in the ARVC group. However, Bcl-2 expression was not seen in either group. CONCLUSIONS: Apoptotic myocardial cell death occurs in the setting of ARVC and may contribute to the loss of myocardial cells.     

Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease.

AIMS: Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation. METHODS AND RESULTS: We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%. CONCLUSION: Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The low prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV disease, childhood disease expression, and incomplete penetrance.