Europace Advance Access originally published online on September 26, 2008
Europace 2008 10(11):1253-1255; doi:10.1093/europace/eun267
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EDITORIALS
SCN5A overlap syndromes: no end to disease complexity?
Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Room K2-110, Meibergdreef 9, PO Box 22700, 1100 DE Amsterdam, The Netherlands
Manuscript submitted 28 August 2008. Accepted after revision 3 September 2008.
* Corresponding author. Tel: +31 20 5663262; fax: +31 20 6976177. E-mail address: c.a.remme{at}amc.uva.nl
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 Europace, represents yet another example within the expanding body of evidence for the existence of SCN5A-related overlap syndromes. In a three-generation Chinese family, they identified a heterozygous deletion of three amino acids (delQKP) at position 1507–1509 in two female patients who presented with frequent syncope, QT-prolongation as well as atrioventricular and intraventricular conduction abnormalities, and ventricular dilatation with reduced ejection fraction on echocardiography. Within this family, one obligate male carrier of the mutation had died suddenly in his thirties, and sudden death had occurred in a 13-year-old female of unknown genotype. Although the family pedigree is relatively small, it is apparent that the observed phenotype displays features of both LQT3 and conduction disorder, and possibly even DCM. This mutation is located in the intracellular region linking the third (DIII) and fourth domain (DIV) of SCN5A, the pore-forming 
-subunit of the cardiac sodium channel, which contains at least two other mutations associated with heterogeneous disease expressivity. The KPQ deletion mutation at position 1505–1507 (delKPQ) was classically described as a pure LQT3 mutation, but other studies have also reported clinical signs of conduction disease in addition to QT-prolongation in carriers.5 Furthermore, patients carrying a deletion of a lysine close to this region (delK1500) also display a heterogeneous clinical phenotype with symptoms of LQT3, Brugada syndrome and conduction disease.6 Other regions of SCN5A have also been shown to contain mutations associated with mixed clinical symptoms and disease heterogeneity.1 In general, linkage analysis is not feasible in small family pedigrees, and the possibility of an additional disease-causing mutation underlying the complex nature of the observed phenotype still exists. In large multigenerational cohorts, as with our SCN5A-1795insD family, a potential role for another mutation is rather unlikely. In fact, transgenic mice carrying the heterozygous Scn5a-1798insD mutation (Scn5a1798insD/+), equivalent to human SCN5A-1795insD+/–, displayed a heterogeneous phenotype similar to patients, including sinus node dysfunction, prolonged PQ-, QRS-, and QT-intervals, and right ventricular conduction slowing.7 Our observations from these mice thus confirmed that a single SCN5A mutation may indeed be sufficient to cause an overlap syndrome of cardiac sodium channel disease, although other genetic factors may modify the clinical phenotype.8 Similar evidence is so far still lacking for most other SCN5A mutations associated with multiple disease phenotypes, including delQKP1507–1509. Although mutations in KCNQ1, HERG, and LAMIN A/C were excluded in the study by Shi et al.,4 the possibility of another pathogenic mutation in an (unknown) gene cannot be ruled out completely. This is also of potential relevance in light of the observed clinical signs of DCM in two carriers of delQKP1507–1509.4 Although a reduced left ventricular ejection fraction is not uncommon in a 65-year-old individual, the observed clinical signs of DCM in the young female are certainly of potential interest, if related to the delQKP1507–1509 mutation. In this patient, bradycardia, incessant tachyarrhythmias, and frequent episodes of abnormal ventricular activation as a consequence of the mutation may be causally related to the development of DCM. Although other SCN5A mutations have been previously linked to DCM, most of these are associated with biophysical properties consistent with loss of sodium channel function.9 Thus, the potential association of delQKP1507–1509, a gain-of-function mutation, with the development of DCM would represent a significant novel finding.
From a biophysical perspective, mutations causing LQT3 syndrome are generally considered to cause a persistent inward current during the action potential plateau phase (gain-of-function mutations), while mutations associated with Brugada syndrome and conduction disease are typically thought to reduce the total amount of available sodium current (loss-of-function mutations). Thus, prior to our description of the 1795insD family, the simultaneous presence of LQT3 and Brugada syndrome or conduction disease in one patient due to a single SCN5A mutation was considered improbable. However, heterogeneous biophysical properties of this and other SCN5A mutations underlying the mixed disease expressivity are now increasingly recognized. The delK1500 mutation, associated with LQT3, Brugada syndrome, and conduction disease, gives rise to a substantial persistent current but also reduces sodium channel availability through enhanced channel inactivation.6 Similarly, the delF1617 mutation (observed in both LQT3 and Brugada syndrome patients) displays both delayed inactivation (gain of function) and reduced peak current density with impaired recovery from inactivation (loss of function).10 However, in many cases there are still obvious discrepancies between clinical symptoms and biophysical properties of a certain mutation. For example, delQKP1507–1509 was previously shown to cause a persistent inward sodium current in the presence of normal peak current without any biophysical property consistent with loss of sodium channel function, which is not in line with the currently observed conduction disease phenotype.11 Similarly, reduced peak current density due to defective trafficking of sodium channels to the cell surface membrane has been sporadically observed in LQT3 mutations, but these have (so far) not been associated with clinical signs of conduction disease.12,13 In our original patch-clamp studies on the 1795insD mutation in various heterologous expression systems, different biophysical characteristics potentially underlying the mixed clinical phenotype were observed depending on the system used.2,14 In isolated myocytes from Scn5a1798insD/+ mice, the mutation was shown to cause a drastic reduction in peak sodium current density, a delayed time course of fast inactivation, and a small persistent sodium current, explaining the biophysical characteristics underlying the observed multiple phenotypes.7 These observations have clearly underlined the danger of misinterpretation of the biophysical properties of a certain mutation based solely on transfection studies. In heterologous systems, results may vary considerably depending on expression system (mammalian vs. non-mammalian), temperature, and membrane potential used. Thus, an unknown number of other overlap syndrome SCN5A mutations may, similar to 1795insD, prove to display different biophysical properties in the native myocyte environment, possibly more in line with the observed clinical mixed phenotype.
Clinical and genetic diagnosis of SCN5A-related overlap syndromes is often further complicated by reduced penetrance and variable disease expression, even within one single family. One particular mutation may lead to a full-blown mixed clinical phenotype in one carrier, and to a single arrhythmia syndrome (either LQT3, Brugada syndrome, or conduction disease) in another, the reasons for which are still largely unclear. Since most SCN5A overlap syndromes have so far been identified in extensive family pedigrees, one might speculate that every SCN5A mutation may in fact lead to multiple clinical phenotypes or combinations thereof, if studied in larger families. Clinical parameters including age, gender, drug therapy, and concomitant disease such as fever may modify disease expressivity. In addition, genetic modifiers may also play a role, with the genetic background of a patient (largely) determining the clinical phenotype resulting from a particular mutation.8 Many loss-of-function SCN5A mutations display defective trafficking of mutant sodium channels to the cell surface. In SCN5A mutations related to overlap syndromes, the possible presence of a (small) persistent current may be masked due to this inefficient channel trafficking. In some cases, improvement of membrane expression of trafficking-deficient SCN5A mutations has been known to occur due to sodium channel blocking drugs or certain SCN5A polymorphisms (for example H558R), which may then unmask the LQT3 phenotype and minimize the Brugada syndrome or conduction disease phenotype.12,15 Preferably, large cohorts of patients carrying the same overlap syndrome SCN5A mutation should be studied to gain more insight into the different factors determining disease severity, expressivity, and outcome. This knowledge would ultimately be beneficial to improved diagnostic and treatment strategies in patients with SCN5A-related sodium channel disease.
This work was supported by the Netherlands Heart Foundation (Grant 2003/B195) and by a Fondation Leducq Trans-Atlantic Network of Excellence Grant (05 CVD 01, Preventing Sudden Death).
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.
References
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