SCN5A overlap syndromes: no end to disease complexity?

Abstract

Mutations in the gene encoding the cardiac sodium channel ( SCN5A ) have been implicated in a number of arrhythmia syndromes, including long-QT syndrome type 3 (LQT3), Brugada syndrome, and conduction disease. Originally, the various SCN5A -related arrhythmia syndromes were considered separate clinical entities with distinct phenotypical characteristics, even though they were caused by mutations in the same ion channel. For instance, LQT3 patients were considered to experience cardiac death predominantly at rest or during sleep, and typically no signs of conduction slowing would be observed on the electrocardiogram (ECG). On the other hand, Brugada syndrome would manifest as ST-segment elevation in the right precordial leads with or without signs of conduction disease, in the presence of a normal QT-interval. However, in contrast to these classical distinctions, more recent reports have demonstrated more clinical and biophysical overlap among the various types of SCN5A mutations than previously appreciated. Now, a wide spectrum of (mixed) disease phenotypes [including LQT3, Brugada syndrome, conduction disturbances, sick sinus syndrome, atrial standstill, atrial fibrillation, and dilated cardiomyopathy(DCM)] has been demonstrated in arrhythmia syndromes related to SCN5A mutations, referred to as ‘overlap syndromes’ of cardiac sodium channel disease.1 The first example, SCN5A -1795insD+/−, was characterized by our group in a large multigenerational family presenting with extensive variability in type and severity of symptoms, including ECG features of sinus node dysfunction, bradycardia, conduction disease, Brugada syndrome (ST-segment elevation), and LQT3 (bradycardia-related QT-interval prolongation), either in isolation or in combinations thereof.2,3 Since our original description of the SCN5A -1795insD+/− family, other SCN5A mutations have also been reported in which carriers exhibit similar features of clinical overlap between various arrhythmia syndromes.1 The current description of diverse phenotypes in carriers of the SCN5A mutation delQKP1507–1509 by Shi et al .4 in this issue of … *Corresponding author. Tel: +31 20 5663262; fax: +31 20 6976177. E-mail address : c.a.remme{at}amc.uva.nl