11/347. Prominent bifid T waves observed in the QT prolongation caused by complete atrioventricular blockade in a hypokalemic diabetic patient. A 63-year-old diabetic man was admitted with general fatigue. Electrocardiogram (ECG) on admission showed complete atrioventricular (AV) blockade associated with prominent bifid T waves. The second component of the bifid T waves was distinguished from U waves by the beat-to-beat varying bifidity and the nadir between the two components located at > or = 1 mm above the isoelectric line. Range of absolute QT interval was 535 to 650 ms. hypokalemia (3.6 mEq/L) was noted at admission. Partial restoration of the potassium level (3.9 mEq/L) prior to temporary ventricular demand pacing obscured the bifid T waves and attenuated the QT prolongation and dispersion to some extent (absolute QT interval ranging 520 to 620 ms). It was concluded that marked bradycardia caused by complete AV blockade (ie, a junctional escaped rhythm at a rate of 42 beats/min), hypokalemia, and underlying diabetes mellitus contributed in concert to the QT prolongation and dispersion leading to the prominent bifid T waves. ( info) |
12/347. Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts. BACKGROUND: Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these. methods AND RESULTS: We initially analyzed one family using microsatellite markers and found linkage to KCNQ1. mutation detection showed a G to C change in the last base of exon 6 (1032 G-->C) that does not alter the coded alanine. Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in KCNQ1, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the KCNQ1 gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G-->C, in the acceptor site of intron 5, and 2 of the previously reported 1032 G-->A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript. CONCLUSIONS: The 6 cases already reported in the literature with the 1032 G-->A transition, the novel 1032 G-->C transversion, and a recent G-->T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in KCNQ1. ( info) |
13/347. Homozygous premature truncation of the HERG protein : the human HERG knockout. Background-In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 of the K( ) channel genes leads to prolongation of the cardiac action potential, because the aberrant protein exhibits "loss of function." HERG, which is involved in LQT2, is the gene encoding the rapid component of the delayed rectifier, I(Kr). methods and Results-In a consanguineous family, a stillbirth was followed by the premature birth of a child in distress due to ventricular arrhythmia in the presence of QT prolongation. LQTS was diagnosed, beta-blocker therapy was begun, and a pacemaker was implanted. She developed well and remained symptom-free for 1.5 years. In the index patient, we identified a duplication of bp 558 to 600 in exon 4 of HERG on both alleles. This will result in a frameshift and a premature stop codon before the S1 domain of the HERG protein. Because it is present on both alleles, no functional I(Kr) is anticipated. The same mutation was found heterozygously in both parents and homozygously in the stillborn brother. Conclusions-It is concluded that absence of I(Kr) gives rise to a severe cardiac phenotype, with no indication of malfunction of any other organ. ( info) |
14/347. Congenital long-QT syndrome: a case report illustrating diagnostic pitfalls. This article reviews the clinical course of a 10-year-old child with a lifelong history of seizures and congenital deafness who presented after an episode of sudden cardiac arrest secondary to long-QT syndrome-induced torsade de pointes. Jervell-Lange-Nielsen syndrome is a rare cardioauditory syndrome in which affected subjects are susceptible to recurrent syncope and sudden death from ventricular dysrhythmias, usually before the second decade of life. Careful evaluation of suspected subjects is important because of the variability of the QTc interval. Recent research has identified specific gene sequences that encode ion channels responsible for both prolonged QTc interval and deafness. Treatment of symptomatic cardiac disease with beta-blockers in combination with pacemakers and automated internal cardioverter defibrillators can markedly improve quality of life and suppress ventricular dysrhythmias even in the most severely affected subjects. The recent identification of gene sequences identifying some congenital long-QT syndromes may improve screening methods for affected patients and lead to potential therapeutic intervention. ( info) |
15/347. sodium channel abnormalities are infrequent in patients with long qt syndrome: identification of two novel SCN5A mutations. long qt syndrome (LQTS) is a heterogeneous disorder caused by mutations of at least five different loci. Three of these, LQT1, LQT2, and LQT5, encode potassium channel subunits. LQT3 encodes the cardiac-specific sodium channel, SCN5A. Previously reported LQTS-associated mutations of SCN5A include a recurring three amino acid deletion (DeltaKPQ1505-1507) in four different families, and four different missense mutations. We have examined the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange-Nielsen syndrome and the remainder with romano-ward syndrome. Screening portions of DIII-DIV, where mutations have previously been found, showed that none of these patients has the three amino acid deletion, DeltaKPQ1505-1507, or the other four known mutations. We identified a novel missense mutation, T1645M, in the DIV; S4 voltage sensor immediately adjacent to the previously reported mutation R1644H. We also examined all of the additional pore-forming regions and voltage-sensing regions and discovered another novel mutation, T1304M, at the voltage-sensing region DIII; S4. Neither T1645M nor T1304M were seen in a panel of unaffected control individuals. Five of six T1304M gene carriers were symptomatic. In contrast to previous studies, QT(onset-c) was not a sensitive indicator of SCN5A-associated LQTS, at least in this family. These data suggest that mutations of SCN5A are responsible for only a small proportion of LQTS cases. ( info) |
16/347. Characterization of a novel missense mutation in the pore of HERG in a patient with long qt syndrome. INTRODUCTION: A new strategy to elucidate the molecular mechanisms underlying the long qt syndrome (LQTS) is now available with genetic mutational analyses and characterization of ion channel mutations. methods AND RESULTS: In a 26-year-old woman with LQTS, we identified a novel missense mutation in the pore of HERG by using polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) and sequencing of her genomic dna. The mutation resulted in an amino acid substitution of a positively charged lysine for a highly conserved uncharged asparagine at codon 629 (N629K). Whole cell, patch clamp studies were conducted in COS7 cells by transfecting with wild-type (WT) and/or the mutant N629K HERG. The WT HERG produced an I(Kr)-like, E-4031-sensitive conductance with an inward rectification. In contrast, the cells transfected with the N629K HERG did not display any time-dependent current. Cotransfection of WT and N629K HERG (at a ratio of 1:1) produced a significantly smaller conductance when compared with WT HERG (WT 59.9 /- 7.3 pA/pF [n = 22] vs WT N629K 5.5 /- 2.3 pA/pF [n = 11]; P < 0.01), but did not alter K ion selectivity and tail current-voltage dependence. Because aprindine hydrochloride was effective in preventing ventricular tachycardias, we also tested the effect of the drug on WT HERG (I(Kr)) and KvLQT1/KCNE1 (I(Ks)) currents expressed in COS7. CONCLUSION: Functional analyses of a novel missense mutation in the pore of HERG suggest that the mutation causes marked reduction of I(Kr) via a dominant negative effect. ( info) |
17/347. fetus with long qt syndrome manifested by tachyarrhythmia: a case report. We encountered a fetus who exhibited transient (at most 30 s), repeated episodes of tachyarrhythmia (240 bpm). This female neonate was born at 36 weeks of gestation and showed a markedly prolonged QT interval and transient, repeated episodes of polymorphic ventricular tachycardia. Congenital long qt syndrome was diagnosed. Retrospective analysis of the videotape showing fetal cardiac movement revealed that atrio-ventricular dissociation was present prenatally and thus, the fetal tachyarrhythmia was due to ventricular tachycardia. To our knowledge, there are few reports of a fetus with the long qt syndrome who exhibited ventricular tachycardia in utero. In the presence of unexplained fetal tachyarrhythmia, long QT syndrome should be considered as a possible underlying cause disorder. The presence of atrio-ventricular dissociation may be useful in prenatal diagnosis of long qt syndrome. ( info) |
18/347. nicorandil abolished repolarisation alternans in a patient with idiopathic long qt syndrome. A 23 year old woman with idiopathic long qt syndrome had repeated syncopal attacks associated with torsades de pointes. T wave alternans (TWA) was recorded and the QT interval was abnormally prolonged during treadmill exercise test. Monophasic action potential (MAP) alternans also appeared after an abrupt shortening of the cycle length in electrophysiological study. After intravenous administration of nicorandil 6 mg, both TWA and MAP alternans disappeared. ( info) |
19/347. haloperidol-induced torsade de pointes. OBJECTIVE: To report a case of torsade de pointes related to the administration of high-dose intravenous haloperidol for the treatment of severe agitation. CASE SUMMARY: Reports in the literature of intravenous haloperidol-induced torsade de pointes are rare. We describe the case of a 41-year-old white woman with no predisposing factors who developed torsade de pointes 55 minutes after a dose of intravenous haloperidol 80 mg (total dosage 915 mg over 7 d). The results of the electrocardiogram were consistent with torsade de pointes and showed a prolonged QTc interval of 610 milliseconds. Intravenous magnesium sulfate 2 g/100 mL NaCl 0.9% was administered, which controlled the arrhythmia. The patient received one additional 80-mg haloperidol dose six hours after the arrhythmia-triggering dose, without reoccurrence of torsade de pointes. haloperidol was then discontinued, and the patient had no further arrhythmias. CONCLUSIONS: Our case report and others from the literature suggest that intravenous haloperidol administration may prolong QT intervals in some patients, precipitating the potentially life-threatening arrhythmia torsade de pointes. Clinicians should be aware of haloperidol's potential to induce torsade de pointes, since it is used regularly for agitation and delirium in the critical care arena. ( info) |
20/347. Cardio-auditory syndrome of Jervell and Lange-Nielsen. An 8-year-old deaf-mute girl experienced syncopal attacks. Past medical history revealed cardiac arrhythmia which had developed following an abdominal surgery for a twisted ovarian cyst. Electrocardiogram showed a Q-Tc interval of 40/100 second. The diagnosis was Jervell and Lange-Nielsen syndrome. Etiology, physiopathology, clinical picture, and management of the disease are discussed. ( info) |