In utero onset of long QT syndrome with atrioventricular block and spontaneous or lidocaine-induced ventricular tachycardia: compound effects of hERG pore region mutation and SCN5A N-terminus variant.
BACKGROUND
Mexiletine may protect patients with long QT syndrome (LQTS) type 3 from arrhythmias. However, we found an unusual in utero presentation of intermittent atrioventricular block and ventricular tachycardia (spontaneous or lidocaine-induced) in a fetus and his sibling with LQTS.


OBJECTIVE
The purpose of this study was to investigate the underlying channelopathy and functional alteration.


METHODS
Mutations were searched in KCNQ1, HERG, KCNE1, KCNE2, and SCN5A genes. In expressed mutants, whole-cell voltage clamp defined the electrophysiologic properties.


RESULTS
Novel missense mutations involving hERG (F627L) at the pore region and SCN5A (R43Q) at the N-terminus were found in the proband and in family members with prolonged QT interval. In oocytes injected with mRNA encoding hERG/ F627L, almost zero K(+) currents were elicited. In coinjected oocytes, the currents were decreased to half. In tsA201 cells transfected with SCN5A/R43Q, although the baseline kinetics of the Na current were similar to wild type, lidocaine caused a unique hyperpolarizing shift of the activation and increased the availability of Na currents at resting voltages. Window currents were enhanced due to a right shift of steady-state inactivation. These electrophysiologic alterations after lidocaine may lead to the development of ventricular tachycardia.


CONCLUSIONS
We identified a novel hERG/F627L mutation that results in LQTS with fetal onset of atrioventricular block and ventricular tachycardia. A coexisting SCN5A/R43Q variant, although it per se does not prolong repolarization, contributes to the development of ventricular tachyarrhythmias after lidocaine. Patients with such latent lidocaine-induced phenotype who are given lidocaine or mexiletine may be at risk.
Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
Ming-Tai
MT
Lin
Mei-Hwan
MH
Wu
Chien-Chih
CC
Chang
Shuenn-Nan
SN
Chiu
Olivier
O
Thériault
Hai
H
Huang
Georges
G
Christé
Eckhard
E
Ficker
Mohamed
M
Chahine
D017668:Age of Onset; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D054537:Atrioventricular Block / Q000235:genetics*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005865:Gestational Age; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008133:Long QT Syndrome / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011247:Pregnancy; D015222:Sodium Channels / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000235:genetics*
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008012:Lidocaine