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.

Abstract

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.

CONCLUSION:

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.

• Authors: Ming-Tai Lin, Mei-Hwan Wu, Chien-Chih Chang, Shuenn-Nan Chiu, Olivier Thériault, Hai Huang, Georges Christé, Eckhard Ficker, Mohamed Chahine
• Journal: Heart rhythm (Heart Rhythm) Vol. 5 Issue 11 Pg. 1567-74 (Nov 2008) ISSN: 1556-3871 [Electronic] United States
• PMID: 18848812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• Muscle Proteins
• NAV1.5 Voltage-Gated Sodium Channel
• SCN5A protein, human
• Sodium Channels
• Lidocaine

Topics

• Age of Onset
• Anti-Arrhythmia Agents (pharmacology)
• Atrioventricular Block (genetics)
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (genetics)
• Female
• Gestational Age
• Humans
• Lidocaine (pharmacology)
• Long QT Syndrome (genetics)
• Muscle Proteins (genetics)
• Mutation
• NAV1.5 Voltage-Gated Sodium Channel
• Pregnancy
• Sodium Channels (genetics)
• Tachycardia, Ventricular (chemically induced, genetics)