López-Ayala Jose María, Gómez-Milanés Ivan, Sánchez Muñoz Juan José, Ruiz-Espejo Francisco, Ortíz Martín, González-Carrillo Josefa, López-Cuenca David, Oliva-Sandoval M J, Monserrat Lorenzo, Valdés Mariano, Gimeno Juan R
Department of Cardiology, University of Murcia, Virgen de la Arrixaca University Hospital, Murcia, Spain.
Department of Clinical Analysis, Virgen de la Arrixaca University Hospital, Murcia, Spain.
Europace. 2014 Dec;16(12):1838-46. doi: 10.1093/europace/euu128. Epub 2014 Jun 17.
Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations.
Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging.
DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.
在临床实践中，致心律失常性右室心肌病（ARVC）猝死的风险分层具有挑战性。我们缺乏针对单纯左侧表型风险分层的建议。本研究的目的是调查携带新型DSP基因c.1339C>T突变患者的基因型-表型相关性，并回顾关于DSP截短突变患者临床表型和预后的文献。
对47例连续的患者进行DSP基因的遗传筛查，这些患者具有ARVC表型（n = 24）或特发性扩张型心肌病（DCM）表型，伴有室性心律失常或猝死家族史（n = 23）（年龄40±19岁，62%为男性）。发现3例无关的DCM先证者携带一种新型突变（c.1339C>T）。通过级联家系筛查确定了15名携带该突变的亲属。c.1339C>T突变携带者的外显率为83%。持续性室性心动过速是6例患者的首发临床表现，9例患者被诊断为左心室功能受损（2例有明显严重疾病，7例有轻度功能障碍）。心脏磁共振成像显示9例患者左心室受累，3例患者双心室受累。6例患者出现广泛纤维化模式，5例患者出现心肌致密化不全表型，这些是影像学特征。
DSP基因c.1339C>T与以左心室为主的致心律失常性心肌病和左心室心肌致密化不全的侵袭性临床表型相关。桥粒斑蛋白的截短突变始终与侵袭性表型相关，必须被视为猝死的危险因素。由于即使在没有严重收缩功能障碍的情况下也会发生室性心动过速，应及时植入植入式心脏复律除颤器。
