Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel

Abstract

Background-Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity. Methods and Results-Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by Ϸ10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block (Ϸ5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant. Conclusions-Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting. (Circ Arrhythmia Electrophysiol.

Infant Ventricular Fibrillation After ST-Segment Changes and QRS Widening

“…The most common cause is long-QT syndrome, with most of these infants having significant QT prolongation. [6][7][8] Among infants with normal resting ECGs, Brugada or Brugada-like syndrome seems to be the most common cause, [2][3][4] although some of these infants may demonstrate intermittent ST changes or intraventricular conduction delay. Kanter et al 2 found disease-causing mutations in SCN5A or CaCNB2b channels in 5 infants with ventricular tachycardia or VF, in whom a diagnosis could not be initially determined.…”

“…1 Infants with this dramatic presentation are often diagnosed with a cardiac tumor, metabolic disorder, or primary electric disease. [2][3][4][5][6][7][8][9] There have been no previous reports of young infants with ventricular fibrillation (VF) in which a primary diagnosis could not be determined. We present 3 unrelated infants <2 months of age who survived VF arrests.…”

Phenotypic Manifestations of Mutations in Genes Encoding Subunits of Cardiac Potassium Channels

“…Some evidence points to more severe arrhythmia consequences of SCN5A mutations. 68 In general, male patients experience their first cardiac events at a younger age than female patients. 69 Approximately 90% of first cardiac events occur before the age of 15 years in male patients, particularly in males with LQT1, whereas female patients rarely experience their first cardiac event occasionally after the age of 20 years.…”

Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+channels

“…I Na was recorded from HEK-293 cells that expressed SCN5A or SCN5A-GFP using the whole cell patch-clamp technique as previously described (37). In brief, the bath solution contained (in mmol/l) 145 NaCl, 4 KCl, 1.8 CaCl 2, 1 MgCl2, 10 HEPES, and 10 glucose (pH 7.35, adjusted with NaOH).…”

“…Electrode resistance ranged from 0.8 to 1.5 M⍀. From a holding potential of Ϫ120 mV, standard voltage-clamp protocols were used to examine the voltage dependence of channel activation, steadystate availability, and recovery from fast inactivation (37). For pharmacological experiments, PMA was freshly prepared before experiments from 100 M stock solutions stored at Ϫ20°C.…”