The Long QT Syndrome with Impaired Atrioventricular Conduction: A Malignant Variant in Infants

Gorgels, Anton P.M.; Fadley, Fadel Al; Zaman, Liaqat; Kantoch, Michal J.; Halees, Zohair Al

doi:10.1111/j.1540-8167.1998.tb00096.x

Cited by 48 publications

(30 citation statements)

References 22 publications

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“…23 LQTS with AV conduction disturbances has been reported often in infants or young children with a major QTc prolongation, but without any positive familial history, [23][24][25][26][27][28] as in our case. Indeed, the fast atrial rate, which characterizes pediatric sinus rhythm, can lead to functional AV block in the setting of dramatic prolongation of ventricular repolarization as the P wave falls within the T wave.…”

Section: Discussionmentioning

confidence: 77%

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Lupoglazoff

Cheav

Baroudi

et al. 2001

Circulation Research

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Abstract-Heterozygous mutations in genes encoding cardiac ionic channel subunits KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 are causally involved in the dominant form of long-QT syndrome (LQTS) while homozygous mutations in KCNQ1 and KCNE1 cause LQTS with or without congenital deafness. In addition, two homozygous HERG mutations have been associated with severe LQTS with functional atrioventricular conduction anomalies in young children. A 2:1 atrioventricular block (AVB) with a major QTc prolongation (526 ms) was evidenced in a 5-year-old boy referred for syncope and seizure. LQTS was diagnosed and beta-blocking therapy initiated leading to normal atrioventricular conduction. Electrophysiological study provided support that location of the AVB was infra-Hisian. DNA analysis was performed in the proband and in asymptomatic family members. A novel missense mutation, V1777M, in the early C-terminal domain of SCN5A was identified. The proband was homozygous while the parents and two siblings were heterozygous carriers. Homozygote and heterozygote expression of the mutant channels in tsA201 mammalian cells resulted in a persistent inward sodium current of 3.96Ϯ0.83% and 1.49Ϯ0.47% at Ϫ30 mV, respectively, which was dramatically reduced in the presence of tetrodotoxin. This study provides the first evidence for a homozygous missense mutation in SCN5A and suggests that LQTS with functional 2:1 AVB in young children, a severe phenotype associated with bad prognosis, may be caused by homozygous or heterozygous compound mutations not only in HERG but also in SCN5A. T he congenital long-QT syndrome (LQTS) is a potentially lethal cardiac disease caused by mutations in specific ion channels. Heterozygosity for a mutation in the potassium channel genes HERG (LQT2) and KCNE2 (LQT6) causes defects in the rapid component of the delayed rectifier I Kr , whereas mutations in KCNQ1 (LQT1) and KCNE1 (LQT5) cause defects in the slow component of the delayed rectifier I Ks . 1 Mutations in SCN5A cause a persistent cardiac sodium current that is responsible for LQT3. 2 This form has been associated with a lower rate of cardiac events but a higher rate of lethal events. 3 Homozygosity for mutations in KCNQ1 and KCNE1 have been associated with the recessively inherited Jervell and Lange-Nielsen syndrome, in which QT prolongation is associated with a bilateral neurosensitive deafness. 4 -6 Nevertheless, several LQT1 recessive variants without deafness have also been described. 7,8 Recently, homozygosity for HERG mutations associated with atrioventricular (AV) conduction disturbances have been reported. 9,10 We describe the first case of an LQTS patient with functional 2:1 AV block (AVB) due to a homozygous missense mutation in SCN5A. Materials and Methods Clinical DataThe proband of a 9-member family was referred for syncope. The father originated from Senegal and the mother from Guinea without any known consanguinity. Both parents and the 7 children underwent clinical evaluation and cardiovascular examination, including a 12-lead ECG (ECG...

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Section: Discussionmentioning

confidence: 77%

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Lupoglazoff

Cheav

Baroudi

et al. 2001

Circulation Research

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“…Consequently, drugs that affect His-Purkinje conduction and refractoriness and hence exaggerate these AV conduction abnormalities likely have a major effect on arrhythmogenesis in LQTS. We demonstrate differential pharmacogenomic effects of I Kr or I Ks blockers on His-Purkinje conduction in LQT rabbits, indicating that the rarely described true infranodal AV blocks in LQTS patients (16,31) may be more frequent when LQT2 patients are exposed to I Ks blockers and, moreover, that these I Ksblocker-induced AV conduction blocks may increase the risk for arrhythmias in LQT2. Indeed, we have previously shown that I Ks -blocker-induced AV conduction blocks initiated pVT in LQT2 rabbits (29).…”

Section: Discussionmentioning

confidence: 99%

“…Atrioventricular (AV) conduction block due to markedly prolonged ventricular refractoriness, termed pseudo-AV block by Rosenbaum and Acunzo (35), has been described as the primary mechanism responsible for conduction abnormalities in patients with LQTS (14). However, a few case reports also described true infranodal AV block in these patients (16,31). Despite the relatively infrequent overall occurrence of AV conduction abnormalities (30), they are clearly associated with a poorer prognosis.…”

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confidence: 99%

Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

Odening

Kirk

Brunner

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction. Am J Physiol Heart Circ Physiol 299: H643-H655, 2010. First published June 25, 2010; doi:10.1152/ajpheart.00074.2010.-We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K ϩ current [IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayedrectifier K ϩ current [IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/ His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P Ͻ 0.05) or LMC (P Ͻ 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.long QT syndrome; His-Purkinje conduction; rapidly activating delayed-rectifier potassium current; slow delayed-rectifier potassium current; transgenic rabbit model; pharmacogenomics; ventricular effective refractory period dispersion; in vivo electrophysiological study THE INHERITED LONG-QT SYNDROME (LQTS) is a genetically heterogeneous arrhythmic disease characterized by impaired cardiac repolarization leading to QT prolongation, polymorphic ventricular tachycardia (pVT), and sudden cardiac death (SCD) (reviewed in Ref. 34). The most common forms of LQTS, type 1 and type 2 (LQT1 and LQT2), account for Ͼ90% of the genotyped cases and are due to loss-of-function mutations in KvLQT1 [␣-subunit of slow delayed-rectifier K ϩ current (I Ks )] (11) or HERG [␣-subunit of rapidly activating delayed-rectifier K ϩ current (I Kr )] (9), respectively. The known triggers for pVTs in LQTS vary f...

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“…As with SIDS, fetal LQTS and neonatal LQTS are rarely familial, and death may occur in the absence of a documented ventricular tachyarrhythmia or suggestive family history. 16,17 Since Schwartz 18 originally proposed that some SIDS cases may reflect congenital LQTS, several lines of supportive evidence have emerged, including an ECG screening study of newborns, 19 a case of a near-miss SIDS infant who carried an apparently de novo SCN5A mutation, 5 and a case of a SIDS infant in whom postmortem molecular screening identified an apparently de novo mutation on KCNQ1. 7 More recently, 2 of 93 sequential cases of SIDS were found to have missense mutations in SCN5A.…”

Section: Discussionmentioning

confidence: 99%

“…3,25 The severe phenotype manifested by these infants is typical of a subset of LQTS patients who present in fetal and early neonatal life. 5,13,16,17,26 A review of 22 case studies from the English language literature 16 described a subset of LQTS patients with a severe neonatal-onset phenotype characterized by very long QTc intervals (mean, 665 milliseconds), 2:1 AV block, T-wave alternans, functional bradycardia, and a poor prognosis, with 9 of 22 dead in the first year of life and 50% mortality by 4 years of age. In comparison, a study of LQTS in a large pediatric collaborative study (mean age at diagnosis, 7 years) 27 found a mean QTc of 520 milliseconds and a low rate of AV block (4%).…”

Section: Discussionmentioning

confidence: 99%

Recurrent Third-Trimester Fetal Loss and Maternal Mosaicism for Long-QT Syndrome

et al. 2004

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Background-The importance of germ-line mosaicism in genetic disease is probably underestimated, even though recent studies indicate that it may be involved in 10% to 20% of apparently de novo cases of several dominantly inherited genetic diseases. Methods and Results-We describe here a case of repeated germ-line transmission of a severe form of long-QT syndrome (LQTS) from an asymptomatic mother with mosaicism for a mutation in the cardiac sodium channel, SCN5A. A male infant was diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks and with LQTS after birth, ultimately requiring cardiac transplantation for control of ventricular tachycardia. The mother had no ECG abnormalities, but her only previous pregnancy had ended in stillbirth with evidence of cardiac decompensation at 7 months' gestation. A third pregnancy also ended in stillbirth at 7 months, again with nonimmune fetal hydrops. The surviving infant was found to have a heterozygous mutation in SCN5A (R1623Q), previously reported as a de novo mutation causing neonatal ventricular arrhythmia and LQTS. Initial studies of the mother detected no genetic abnormality, but a sensitive restriction enzyme-based assay identified a small (8% to 10%) percentage of cells harboring the mutation in her blood, skin, and buccal mucosa. Cord blood from the third fetus also harbored the mutant allele, suggesting that all 3 cases of late-term fetal distress resulted from germ-line transfer of the LQTS-associated mutation. Conclusions-Recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQTS-associated mutations, with important implications for genetic counseling.

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The Long QT Syndrome with Impaired Atrioventricular Conduction: A Malignant Variant in Infants

Cited by 48 publications

References 22 publications

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

Recurrent Third-Trimester Fetal Loss and Maternal Mosaicism for Long-QT Syndrome

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