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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Chang
Chien-Chih
CC
Department of Pediatrics, College of Medicine, National Taiwan University, National Taiwan University Hospital, No. 7, Chung-Shen South Road, Taipei, 100 Taiwan.
Acharfi
Said
S
Wu
Mei-Hwan
MH
Chiang
Fu-Tien
FT
Wang
Jou-Kou
JK
Sung
Tseng-Chen
TC
Chahine
Mohamed
M
D001919:Bradycardia / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008012:Lidocaine / Q000494:pharmacology; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D013779:Tetrodotoxin; D008012:Lidocaine