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

Chang, Chien-Chih; Acharfi, Said; Wu, Mei‐Hwan; Chiang, Fu-Tien; Wang, Jou‐Kou; Sung, Tseng-Chen; Chahine, Mohamed

doi:10.1016/j.cardiores.2004.07.007

Cited by 71 publications

(47 citation statements)

References 32 publications

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“…In contrast, the results at low frequencies (secomd column) show longer APDs (red and yellow colors). As expected, the decrease in APD exerted by GS967 is more pronounced at low frequencies and especially APD 30 , whereas the slight increase of APD exerted by ranolazine does not result in any significant changes (approximately 110% of the baseline value).…”

Section: Discussionsupporting

confidence: 76%

“…Ranolazine had no significant effects, apparently, changing APD 30 to 100.9%, APD 60 to 103% and APD 90 to 105% of baseline values. In contrast, GS967 decreased APD 30 to 86.9%, APD 60 to 87.2% and APD 90 to 91.1% of baseline. The higher selectivity of GS967 for I NaL (IC 50 of 0.13 μM and > 10 μM for I NaL and I Kr , respectively) 10 compared with ranolazine, can account for its effect on APD compared with ranolazine.…”

Section: Resultsmentioning

confidence: 77%

“…5D) reveal that both ranolazine and GS967 slightly increase this parameter with respect to the baseline value. Specifically, ranolazine further increases APD 90 more than APD 30 , whereas GS967 decreases APD 30 more than APD 90 , at each stimulus rate.…”

Section: Discussionmentioning

confidence: 89%

“…Note that in all calculations the baseline condition is intended to mimic the enhanced I NaL , which is a hallmark feature of LQT3 syndrome. 30 Thus, I NaL was increased 2-fold over the value in the control conditions. The dashed line shows control AP.…”

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confidence: 87%

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In silico assessment of drug safety in human heart applied to late sodium current blockers

et al. 2013

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 89%

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confidence: 87%

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In silico assessment of drug safety in human heart applied to late sodium current blockers

et al. 2013

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“…Despite a designation as "congenital", the average age at LQTS diagnosis is 30 years [6]. Diagnosis in the first year of life occurs in only ∼4% of cases; neonatal LQTS is due to mutations in the 3 ion channels commonly associated with LQTS but has severe morbidity and mortality compared to LQTS in older patients [7][8][9][10][11]. In neonatal LQTS, compound heterozygous mutations, known to be associated with more severe LQTS phenotypes [12], are often noted.…”

Section: What Is Lqts?mentioning

confidence: 99%

Sudden infant death syndrome and long QT syndrome: The zealots versus the naysayers

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Benson²

2007

Heart Rhythm

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"Fools rush in where angels fear to tread." -Alexander Pope, Essay on Criticism, 1711Sudden infant death syndrome (SIDS), a leading cause of infant death, have a disproportionate psychosocial and medicolegal impact because they usually occur in otherwise healthy babies. While many pathophysiologic mechanisms for SIDS have been proposed, including respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, none has caused as much controversy as the cardiac dysrhythmia hypothesis. The existence of an association between SIDS and the long QT syndrome (LQTS) has been at the heart of this debate for over 30 years. In this issue of Heart Rhythm, Cronk et al report the first molecular and functional evidence to implicate CAV3 as a pathogenic basis of SIDS [1]; how does this elegant study fit into the controversy? What is SIDS?The definition of SIDS originally appeared in 1969, but as a result of research in the field, was redefined as the sudden unexpected death of an infant <1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including performance of a complete autopsy and review of the circumstances of death and the clinical history [2]. There has been a major decrease in the incidence of SIDS coincident with the American Academy of Pediatrics (AAP) release of recommendations in 1992 that infants be placed down for sleep in a nonprone position [3]. However, despite marked reductions in rates over the past decade, SIDS is still responsible for more infant deaths in the United States than any other cause of death during infancy beyond the neonatal period [4]. What is LQTS?LQTS is a heterogeneous disorder characterized by prolongation of the QT interval, multiform ventricular tachycardia (torsades de pointes), seizures, syncope, and sudden death; a positive family history of similar findings considerably aids the diagnosis. Of genes known to cause LQTS, 3 ion channels (KCNQ1 (LQTS1, ∼45%), KCNH2 (LQTS2, ∼45%), and SCN5A (LQTS3, ∼10%) are the most common. Mutations in ANK2 represent a nonchannel form of LQTS; mutations in CAV3 represent a second example [5]. Despite a designation as

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The genetic basis of long QT and short QT syndromes: A mutation update

et al. 2009

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Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

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

Abstract: 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.

Cited by 71 publications

References 32 publications

In silico assessment of drug safety in human heart applied to late sodium current blockers

In silico assessment of drug safety in human heart applied to late sodium current blockers

Sudden infant death syndrome and long QT syndrome: The zealots versus the naysayers

The genetic basis of long QT and short QT syndromes: A mutation update

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