on December 2, 2008
Published online before print December 2, 2008, doi: 10.1161/CIRCEP.108.788349
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Original Article |
Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel
1 Vanderbilt University, Nashville, TN;
2 University of Pavia and IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy;
3 National Cardiovascular Center, Osaka, Japan;
4 IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy;
5 Ospedali Riuniti, Bergamo, Italy
6 E-mail: al.george{at}vanderbilt.edu
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 ~10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, 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 wildtype 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 two 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.
Key Words: antiarrhythmia agents • arrhythmia • death, sudden (if surviving, use heart arrest) • heart arrest • ion channels • SCN5A • mexiletine • propranolol • sodium channel
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