Loss-of-Function Sodium Channel Mutations in Infancy

Abstract

The role of channelopathies in the pathogenesis of sudden cardiac death in patients with structurally normal hearts is a rapidly evolving story.1 Many ion channels are involved, including loss-of-function sodium channelopathies, of which the phenotypic spectrum ranges from lethal arrhythmias to asymptomatic carriers and includes Brugada syndrome (BrS), cardiac conduction disease, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. BrS, characterized by right precordial ST elevation on the ECG, is frequently associated with conduction delay, potentially lethal arrhythmias, and a positive family history of sudden premature death. BrS is estimated to be responsible for ≈4% of all sudden deaths and 20% of sudden deaths in patients with structurally normal hearts. Despite an overall prevalence of ≈5/10 000 individuals,2 BrS is considered extremely rare in the pediatric population. However, children harboring loss-of-function mutations in the gene coding for the sodium channel α-subunit ( SCN5A ) have been reported to present with life-threatening arrhythmias, especially during febrile episodes.3 While SCN5A mutations account for 11% to 28% of BrS probands, mutations of the L-type calcium channel, including the gene coding for the L-type calcium channel β-subunit ( CaCNB2 ), among others, have recently been implicated in ≈13% of patients with BrS-related phenotypes and sudden cardiac death.4 Article see p 14 In this issue of Circulation , Kanter et al5 describe their experience with very young children manifesting ventricular arrhythmias due to previously undetected loss-of-function sodium and/or calcium channelopathies. Twenty of 32 patients <2 years of age with rapid ventricular tachycardia (VT) or ventricular fibrillation (VF), had known structural heart disease, and 9 of the remaining 12 patients had intraventricular conduction delay (IVCD) or Brugada pattern (coved) ECG, of which 4 had associated conditions (myocarditis, Barth syndrome, and drug use). The clinical features and subsequent management and follow-up of the remaining 5 patients …