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

• DOI: 10.1161/circep.108.788349
• Publication Date: 2008-12-03T03:24:22Z
• Authors: Dao W. Wang; Lia Crotti; Wataru Shimizu; Matteo Pedrazzini; Francesco Cantu; Paolo De Filippo; Kanako Kishiki; Aya Miyazaki; Tomoaki Ikeda; Peter J. Schwartz; Alfred L. George
• Keywords: Male; 0301 basic medicine; DNA Mutational Analysis; Mutation, Missense; 610; Action Potentials; Muscle Proteins; Gestational Age; Mexiletine; NAV1.5 Voltage-Gated Sodium Channel; Electrocardiography; 03 medical and health sciences; long qt syndrome, cardiac sodium channel, gentics, mutation, clinical severity, early onset, SCN5A; Humans; Genetic Predisposition to Disease; Dose-Response Relationship, Drug; Myocardium; Infant, Newborn; Propranolol; 3. Good health; Kinetics; Long QT Syndrome; Phenotype; Drug Therapy, Combination; Anti-Arrhythmia Agents

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 forSCN5Amutations, 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 ≈10-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 (≈5-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 ofSCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting.