Abstract 359: Highly Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional SCN5A Mutation Successfully Treated with Mexiletine and Propranolol
Perinatal presentation of long-QT syndrome (LQTS) is uncommon but typically more severe and often fatal. We studied the functional and pharmacological properties of a novel SCN5A mutation associated with a highly malignant perinatal variant of LQTS successfully treated with mexiletine and propranolol. The proband was delivered by emergency C-section at 32-weeks because of fetal arrhythmia. Immediately after birth, the infant had polymorphic ventricular tachycardia and a slow sinus rate that were unresponsive to Mg and isoproterenol. Lidocaine controlled ventricular arrhythmia and allowed recognition of a prolonged QTc (520 ms). Treatment with propranolol (1 mg/kg/d) and mexiletine (11 mg/kg/d) normalized the QTc (410 ms) and suppressed ventricular ectopy. One month after discharge, the infant survived ventricular fibrillation and later developed paroxysmal atrial flutter. Genetic testing revealed a novel, de novo missense SCN5A mutation (G1631D) located immediately before the 4th arginine residue in D4/S4. In vitro electrophysiological studies using whole-cell patch clamp recording of channels expressed in tsA201 cells revealed a profound defect in channel function characterized by ∼10-fold slowing of inactivation, increased persistent current, marked slowing of recovery from inactivation, depolarized voltage-dependence of activation and steady-state channel availability. Single channel recordings demonstrated increased frequency of late openings, increased open times and bursting. These biophysical properties were distinct from typical LQT3 mutations and represent the most severely dysfunctional SCN5A mutation ever reported. The mutant also exhibited 2-fold enhancement of tonic and use-dependent block by mexiletine as compared with wild-type channels. Unexpectedly, the mutant channel also exhibited enhanced tonic block (2.4-fold) and use-dependent block (∼5-fold) by propranolol. Our study demonstrated the molecular basis for a highly malignant perinatal variant of LQTS, illustrated novel functional and pharmacological properties of SCN5A-G1631D which caused the disorder, and illustrated an unexpected clinical benefit of propranolol in blocking mutant Na channels in this setting.