E1784K mutation in SCN5A and overlap syndrome.

the conduction system. In some PCCD patients, a conduction defect is documented from birth. Depending on the consequence of the mutation on the sodium channels, the phenotype may be progressive or congenital (Table).4 If the action potential generation and/or propagation is more severely impaired in the atria than in the ventricles in SCN5A mutation patients, the sinus node dysfunction caused by failure of the impulses to conduct into the adjacent atrial myocardium (exit block) has been suggested as a cause of SSS, atrial standstill, and atrial fibrillation (Table).5 Mutations of E1784K in SCN5A cause a persistent (late) inward Na+ current, and also cause a reduction in the peak Na+ current.9,11,12 Some LQT3 patients present with ECG findings characteristic of BrS (overlap syndrome), and one of the causes of this overlapping syndrome can be explained by E1784K,11,12 1795insD,13,14 ∆KPQ,12,15 and ∆K1500.16 However, several other biophysical mechanisms may be related to the reduction in the peak Na current.17 Sodium-channel blockers are commonly used in patients with LQT3 because of the blocking effect on persistent Na currents.18–20 However, in overlap syndrome, sodium-channel blockers shorten the QT interval, possibly reducing the peak Na current, and thus uncover a concealed BrS resulting in typical ST segment elevation in the right precordial leads, and may provoke malignant ventricular arrhythmias.14 In this issue of the Journal, Takahashi et al report that the E1784K mutation in SCN5A is the most prevalent mutation in school children with LQTS in the Okinawa islands.21 The most common mutation in LQTS is reported to be a KCNQ1 mutation.22,23 It is noteworthy that there is a high prevalence rate of ongenital long QT syndrome (LQTS) is characterized by prolongation of the QT interval on the surface ECG and may cause syncope and seizures; there is a certain risk of fatal ventricular arrhythmias, torsade de pointes or ventricular fibrillation.1 The QT interval is determined by the cardiac action potential duration and is related to the many ion channels in the myocardial cells. The most important state of the ion currents for prolonging the QT interval is a decrease in the outward K current, and increase of the inward Na or Ca current. SCN5A is the gene encoding the most prevalent cardiac Na channel α subunit, and an SCN5A mutation is responsible for many hereditary arrhythmias including type 3 LQTS (LQT3),2 Brugada syndrome (BrS),3 progressive cardiac conduction disturbances (PCCD),4 sick sinus syndrome (SSS),5,6 atrial fibrillation,6,7 atrial standstill, and sudden infant death syndrome (SIDS).8–10