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Cardiovasc Res. 2004 Nov 1;64(2):268-78.

A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia.

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Department of Pediatrics, College of Medicine, National Taiwan University, National Taiwan University Hospital, No. 7, Chung-Shen South Road, Taipei, 100 Taiwan.



Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth.


Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia.


A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation.


These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.

[Indexed for MEDLINE]

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