Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response

Schulze‐Bahr, Eric; Fenge, Hartmut; Etzrodt, Dörte; Haverkamp, Wilhelm; Mönnig, Gerold; Wedekind, Horst; Breithardt, Günter; Kehl, Hans Gerd

doi:10.1136/heart.90.1.13

Cited by 49 publications

(35 citation statements)

References 20 publications

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“…Until now 3 genes have been associated with 2:1 AV block: SCN5A, KCNH2, and CACNA1. 17,[27][28][29][30][31][32][33][34][35][36][37][38] Our data suggest that perturbations in the SCN4B-encoded ␤4 subunit constitute another pathogenic mechanism for 2:1 AV block in patients with LQTS.…”

Section: Discussionmentioning

confidence: 94%

SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

Medeiros-Domingo¹,

Kaku²,

Tester³

et al. 2007

Circulation

325

219

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Background-Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming ␣-subunit associated with 1 or more auxiliary ␤-subunits. Four different ␤-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. Methods and Results-We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na v␤ -subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel ␣-subunit (hNa V 1.5). Compared with the wild-type, L179F-␤4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A ϩ WT-␤4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. Conclusions-We provide the seminal report of SCN4B-encoded Na v␤ 4 as a novel LQT3-susceptibility gene. (Circulation.

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Section: Discussionmentioning

confidence: 94%

SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

Medeiros-Domingo¹,

Kaku²,

Tester³

et al. 2007

Circulation

325

219

View full text Add to dashboard Cite

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“…Interestingly, 2 unrelated individuals (probands) carried this mutation, and both showed a remarkable shortening of the QT interval, suggesting that the effect is likely to be mutation specific. To support this view, it is worth noting that this very same mutation has been identified by another team of investigators 18,19 in an LQT3 patient who also showed a remarkable response to Mex administration.…”

Section: Scn5a Mutations Present In Lqt3 Patients With Long-term Mex mentioning

confidence: 92%

Gating Properties of SCN5A Mutations and the Response to Mexiletine in Long-QT Syndrome Type 3 Patients

et al. 2007

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Background-Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. Methods and Results-We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg · kg Ϫ1 · d

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“…3,[5][6][7][8][9][10][11] For example, recent progress in molecular biology has clarified that LQTS partly contributes to sudden infant death syndrome (SIDS). 12,13 Unfortunately, prenatal diagnosis of LQTS has been extremely difficult to confirm except for a limited number of cases for which prenatal gene screening 14 or fetal magnetocardiography (fMCG) [15][16][17] was applied.…”

mentioning

confidence: 99%

Clinical Characteristics and Genetic Background of Congenital Long-QT Syndrome Diagnosed in Fetal, Neonatal, and Infantile Life

Horigome

Nagashima

Sumitomo

et al. 2010

Circ: Arrhythmia and Electrophysiology

108

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Background-Data on the clinical presentation and genotype-phenotype correlation of patients with congenital long-QT syndrome (LQTS) diagnosed at perinatal through infantile period are limited. A nationwide survey was conducted to characterize how LQTS detected during those periods is different from that in childhood or adolescence. Methods and Results-Using questionnaires, 58 cases were registered from 33 institutions. Diagnosis (or suspicion) of LQTS was made during fetal life (nϭ18), the neonatal period (nϭ31, 18 of them at 0 to 2 days of life), and beyond the neonatal period (nϭ9). Clinical presentation of LQTS included sinus bradycardia (nϭ37), ventricular tachycardia/torsades de pointes (nϭ27), atrioventricular block (nϭ23), family history of LQTS (nϭ21), sudden cardiac death/aborted cardiac arrest (nϭ14), convulsion (nϭ5), syncope (nϭ5), and others. Genetic testing was available in 41 (71%) cases, and the genotype was confirmed in 29 (71%) cases, consisting of LQT1 (nϭ11), LQT2 (nϭ11), LQT3 (nϭ6), and LQT8 (nϭ1). Ventricular tachycardia/torsades de pointes and atrioventricular block were almost exclusively observed in patients with LQT2, LQT3, and LQT8, as well as in those with no known mutation. In LQT1 patients, clues to diagnosis were mostly sinus bradycardia or family history of LQTS. Sudden cardiac death/aborted cardiac arrest (nϭ14) was noted in 4 cases with no known mutations as well as in 4 genotyped cases, although the remaining 6 did not undergo genotyping. Their subsequent clinical course after aborted cardiac arrest was favorable with administration of ␤-blockers and mexiletine and with pacemaker implantation/implantable cardioverter-defibrillator. Conclusions-Patients with LQTS who showed life-threatening arrhythmias at perinatal periods were mostly those with LQT2, LQT3, or no known mutations. Independent of the genotype, aggressive intervention resulted in effective suppression of arrhythmias, with only 7 deaths recorded. (Circ Arrhythm Electrophysiol. 2010;3:10-17.)

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Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response

Cited by 49 publications

References 20 publications

SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

SCN4B -Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

Gating Properties of SCN5A Mutations and the Response to Mexiletine in Long-QT Syndrome Type 3 Patients

Clinical Characteristics and Genetic Background of Congenital Long-QT Syndrome Diagnosed in Fetal, Neonatal, and Infantile Life

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