Elsevier

Heart Rhythm

Volume 6, Issue 3, March 2009, Pages 341-348
Heart Rhythm

Original-clinical
Genetic
Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies

https://doi.org/10.1016/j.hrthm.2008.11.009Get rights and content

Background

Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed.

Objectives

We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.

Methods

We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with ≤90% (Mactive) or >90% (Minactive) peak INa reduction were analyzed separately.

Results

The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an Mactive mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak INa reduction (T and Minactive mutants) had a significantly longer PR interval, compared with Mactive mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and Minactive groups than in the Mactive group.

Conclusion

In loss-of-function SCN5A channelopathies, patients carrying T and Minactive mutations develop a more severe phenotype than those with Mactive mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

Introduction

Cardiac sodium channels, whose pore-forming subunit is encoded by SCN5A, control cardiac excitability by triggering the action potential. Loss-of-function sodium channelopathies are autosomal-dominant inherited conditions in which SCN5A mutations produce sodium channels that conduct less sodium current (INa). Such channelopathies lead to aberrant rhythm phenotypes,1 mainly Brugada syndrome (BrS)2 and progressive cardiac conduction disease (PCCD)3. PCCD and BrS present significant overlap and can coexist in the same family and even in the same individual.4, 5, 6 Sudden cardiac death (SCD) and syncope, a harbinger of SCD in these diseases,7 are associated with reduced cardiac excitability as witnessed by electrocardiographic (ECG) signs of conduction slowing.8 Moreover, BrS is characterized by signature ST-segment elevation9 that seems also to be related to conduction slowing,10, 11 although this is still a matter of debate.12 In support of the role of INa reduction, these ECG abnormalities are provoked and/or exacerbated by sodium channel blockers. Accordingly, such drug challenges have proven to be a good and safe tool to unmask silent disease carriers.13, 14

A clinical dilemma arises from the fact that disease penetrance and expressivity are highly variable, notably in BrS.15 This is particularly troublesome because the only generally accepted treatment for preventing SCD in BrS is an implantable cardioverter-defibrillator. Clearly, new tools for risk stratification are much needed. Given the role of INa reduction in the pathophysiology of BrS and PCCD, we hypothesized that those SCN5A mutations that reduce INa the most cause the most severe phenotype. SCN5A mutations may reduce INa by changing the functional properties (gating) of the sodium channel protein16 or by resulting in its failure to express in the sarcolemma (trafficking).17 Missense (M) mutations, in which a single amino acid is replaced by an aberrant amino acid, most often disrupt gating of the channel. In contrast, truncation (T) mutations, in which the sodium channel protein is truncated because of the presence of a premature stop codon, are usually not inserted into the sarcolemma, and cause haploinsufficiency. Because of this and the fact that mutant sodium channels with gating abnormalities confer no dominant-negative effects on normal sodium channels, T mutations potentially reduce INa more than M mutations. To test our hypothesis, we retrospectively studied clinical and ECG data of a cohort of patients affected by BrS and PCCD carrying SCN5A mutations that have known or predictable effects on INa magnitude. Although this regards only a minority of BrS patients (up to now, only in approximately 30% of BrS patients a SCN5A mutation is found18), we believe that this innovative use of the genetic substrate for risk stratification is highly promising. Also, it is likely that in the remaining BrS patients, in whom no mutations in SCN5A are found, an involvement of other gene(s) with modulating effects on cardiac INa may be present.19

Section snippets

Clinical and ECG analysis

We retrospectively included patients whose data were collected between 1999 and 2007 in 6 tertiary hospitals (Academic Medical Center of the University of Amsterdam, Nantes University Hospital, Bordeaux University Hospital, Rennes University Hospital, Tours University Hospital, and Brest University Hospital) in the Netherlands and in France. We included all BrS and/or PCCD probands that carried a loss-of-function SCN5A mutation whose effect on INa was known or could be predicted. Family members

Study group

In total, 147 individuals (45 families) met the inclusion criteria. These subjects constitute the study group. The population study comes from a total population of 232 carriers of a loss-of-function SCN5A mutation (147 French and 85 Dutch). There were 32 different SCN5A mutations, including 2 insertions (in-frame insertion 1570insI and frameshift insertion c.3142-3143insTG), 4 deletions (c.2582-2583delTT, c.3816delG, c.4299delG, c.5131delG), 7 nonsense mutations (p.W156X, p.E346X, p.R535X,

Discussion

The cardiac sodium channel is the main determinant of impulse formation and propagation in the heart. Accordingly, INa reduction by loss-of-function SCN5A mutations slows cardiac conduction velocity at various levels in patients with BrS24 and PCCD.3

Given the fact that BrS and PCCD are both associated with conduction slowing and that a significant overlap exists between them, even in the same individual, it is likely that BrS and PCCD represent 2 aspects of the same disease rather than separate

Study limitations

Although we excluded SCN5A mutations with unknown or unpredictable effects on peak INa magnitude from our study, published biophysical data are not available for all included T mutations. We thought it reasonable to assume that T mutations reduce peak INa magnitude by approximately 100%. Moreover, we did not screen for the contemporaneous presence of other SCN5A variants in the included patients; neither did we look at the possible co-presence of other known determinants of impulse conduction

Conclusion

In loss-of-function sodium channelopathies, individuals carrying a T mutation develop, at parity of age, a more severe phenotype compared with Mactive mutant carriers. Atrioventricular and intraventricular depolarization reserve is also significantly reduced in T mutant carriers, in comparison with Mactive mutant carriers, as unmasked by pharmacologic challenge. The Minactive group, with a drastic reduction in peak INa, shows the same behavior as T mutants with regard to the severity of

Acknowledgment

The authors thank Dr. A. C. Linnenbank, Heart Failure Research Center, Academic Medical Center, Amsterdam, for making Figure 1.

References (47)

  • Schott JJ Alshinawi C Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet...
  • G. Vorobiof et al.

    Brugada syndrome with marked conduction disease: dual implications of a SCN5A mutation

    Pacing Clin Electrophysiol

    (2008)
  • F. Kyndt et al.

    Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family

    Circulation

    (2001)
  • A.K. Gehi et al.

    Risk Stratification of Individuals with the Brugada electrocardiogram: a meta-analysis

    J Cardiovasc Electrophysiol

    (2006)
  • H.L. Tan et al.

    A sodium-channel mutation causes isolated cardiac conduction disease

    Nature

    (2001)
  • A.A. Wilde et al.

    Proposed diagnostic criteria for the Brugada syndrome

    Eur Heart J

    (2002)
  • R. Tukkie et al.

    Delay in right ventricular activation contributes to Brugada syndrome

    Circulation

    (2004)
  • Z.S. Zhang et al.

    Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease

    Am J Physiol Heart Circ Physiol

    (2007)
  • P.G. Meregalli et al.

    Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder or more?

    Cardiovasc Res

    (2005)
  • P.G. Meregalli et al.

    Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome

    J Cardiovasc Electrophysiol

    (2006)
  • K. Hong et al.

    Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations

    Circulation

    (2004)
  • C. Antzelevitch et al.

    Brugada syndrome: a decade of progress

    Circ Res

    (2002)
  • Stuhmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channe....
  • Cited by (0)

    Drs. Meregalli, Tan, and Probst contributed equally to this work.

    Dr. Tan was supported by the Royal Netherlands Academy of Arts and Sciences (KNAW) and the Netherlands Organization for Scientific Research (NWO, grant ZonMW-Vici 918.86.616). Dr. Bezzina is an Established Investigator of the Netherlands Heart Foundation, grant 2005/T024. This work also was supported by de Fondation Leducq Trans-Atlantic Network of Excellence, (grant 05-CVD-01), Preventing Sudden Death, (Drs. Schott and Wilde) and by the Agence Nationale de la Recherche grant 05-MRAR-028 and 06-MRAR-022 and Fondation pour la recherche Médicale FRM (Dr. Schott).

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