RESUMEN
We report a child with Beckwith-Wiedemann syndrome (BWS) as the consequence of an apparently balanced, maternally inherited reciprocal translocation t(11;17)(p15.5;q21.3). His mother and aunt, who inherited the translocation from their father, did not have BWS. At birth, long QT syndrome (LQTS) was diagnosed in this child and, secondarily, among apparently healthy family members carrying the translocation. By FISH analysis, the breakpoint in 11p15.5 interrupts the KCNQ1 gene between exons 2 and 10 and causes a loss of methylation of the IC2 (and thus BWS) on the maternally inherited der(11) chromosome. To explain the presence of LQTS segregating with the t(11;17) translocation in this family, we hypothesize that the translocation that interrupts KCNQ1 allow translation of an abnormal short allele that interferes in a dominant negative way with the normal isoform 1 of KCNQ1 in the heart (where this allele is not subject to parental imprint). This appears to be the first report of BWS with congenital LQTS, which should be considered as a rare but serious complication to be searched systematically in patients with BWS due to 11p15 rearrangements.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Translocación Genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/patología , Preescolar , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Femenino , Humanos , Patrón de Herencia , Cariotipificación , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/patología , LinajeRESUMEN
The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.
Asunto(s)
Sordera/genética , Pérdida Auditiva Bilateral/genética , Síndrome de QT Prolongado/genética , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Eliminación de Secuencia , Adulto , Animales , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Sordera/fisiopatología , Muerte Súbita Cardíaca/etiología , Oído Interno/irrigación sanguínea , Endolinfa/fisiología , Femenino , Pérdida Auditiva Bilateral/fisiopatología , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Hibridación in Situ , Lactante , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado/fisiopatología , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Mutations in the TGFßR2 gene have been associated with a life threatening risk of aortic dissection but no arrhythmic death has been previously reported. Two young females carrying a TGFßR2 mutation, initially diagnosed as Marfan syndrome or Loeys Dietz syndrome, presented sudden death with autopsy ruling out dissection. The ECGs of the 2 Sudden Cardiac Deaths revealed profound ventricular repolarization abnormalities with a sinusoidal T-U morphology associated with normal left ventricular ejection fraction. These data strongly suggest sudden cardiac arrhythmic deaths and prompted us to systematically study the repolarization pattern in the patients with TGFßR2 mutations. ECG findings from 58 mutation carriers patients (TGFßR2 group) were compared with those of 46 non-affected first degree relatives (control group). TGFßR2 mutation was associated with ventricular repolarization abnormalities in 47% of patients (p < 0.001 vs. controls), including a 19.6 ms (95%CI 8.7; 30.5) QTc interval prolongation compared to the non-affected first degree relatives (p < 0.001), higher prevalence of abnormal U waves (16% vs. 2%), and sinusoidal T-U morphology (10% vs. 0%). TGFßR2 mutations can be associated with abnormal ventricular repolarization pattern, longer QT interval than non-carrier relatives and an increased risk for sudden death.
Asunto(s)
Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/genética , Muerte Súbita Cardíaca/etiología , Mutación , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Adolescente , Electrocardiografía , Femenino , Humanos , Adulto JovenRESUMEN
UNLABELLED: Data on the Jervell and Lange-Nielsen syndrome (JLN), the long QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the IKs current, are still largely based on case reports. We analyzed data from 186 JLN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events and 50% were symptomatic already by age 3. Their QTc was markedly prolonged (557 +/- 65 ms). Most of the arrhythmic events (95%) were triggered by emotions or exercise. Females are at lower risk for cardiac arrest and sudden death (CA/SD). A QTc>550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD. Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. beta-blockers have only partial efficacy as 51% of the patients had events despite therapy and 29% had CA/SD. CONCLUSIONS: JLN syndrome is a most severe variant of LQTS, with a very early onset, major QTc prolongation, and is not well responsive to beta-blockers. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc pound550 ms, without events in the first year of life, and with mutations on KCNE1. Early therapy with ICDs has to be considered.
Asunto(s)
Síndrome de Jervell-Lange Nielsen/complicaciones , Adolescente , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Factores de Edad , Niño , Preescolar , Muerte Súbita Cardíaca/etiología , Electrocardiografía , Emociones , Ejercicio Físico/fisiología , Femenino , Paro Cardíaco/etiología , Humanos , Lactante , Síndrome de Jervell-Lange Nielsen/tratamiento farmacológico , Síndrome de Jervell-Lange Nielsen/genética , Canal de Potasio KCNQ1/genética , Masculino , Mutación/genética , Canales de Potasio con Entrada de Voltaje/genética , Estudios Retrospectivos , Factores Sexuales , Síncope/etiologíaRESUMEN
The SCN5A gene encodes the alpha subunit of the human heart sodium channel (hH1), which plays a critical role in cardiac excitability. Mutations of SCN5A underlie Brugada syndrome, an inherited disorder that leads to ventricular fibrillation and sudden death. This study describes changes in cellular localization and functional expression of hH1 in a naturally occurring SCN5A mutation (R1432G) reported for Brugada syndrome. Using patch-clamp experiments, we show that there is an abolition of functional hH1 expression in R1432G mutants expressed in human tsA201 cells but not in Xenopus oocytes. In tsA201 cells, a conservative positively charged mutant, R1432K, produced sodium currents with normal gating properties, whereas other mutations at this site abolished functional sodium channel expression. Immunofluorescent staining and confocal microscopy showed that the wild-type alpha subunit expressed in tsA201 cells was localized to the cell surface, whereas the R1432G mutant was colocalized with calnexin within the endoplasmic reticulum. The beta(1) subunit was also localized to the cell surface in the presence of the alpha subunit; however, in its absence, the beta(1) subunit was restricted to a perinuclear localization. These results demonstrate that the disruption of SCN5A cell-surface localization is one mechanism that can account for the loss of functional sodium channels in Brugada syndrome. The full text of this article is available at http://www.circresaha.org.
Asunto(s)
Muerte Súbita Cardíaca/etiología , Canales de Sodio/genética , Canales de Sodio/metabolismo , Fibrilación Ventricular/etiología , Fibrilación Ventricular/fisiopatología , Sustitución de Aminoácidos , Animales , Bloqueo de Rama/etiología , Membrana Celular/metabolismo , Células Cultivadas , Electrofisiología , Expresión Génica , Humanos , Inmunohistoquímica , Activación del Canal Iónico/genética , Mutación , Canal de Sodio Activado por Voltaje NAV1.5 , Oocitos/citología , Oocitos/metabolismo , Técnicas de Placa-Clamp , Subunidades de Proteína , Transporte de Proteínas/genética , Sodio/metabolismo , Síndrome , Transfección , Fibrilación Ventricular/complicaciones , XenopusRESUMEN
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 3.96+/-0.83% and 1.49+/-0.47% at -30 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. The full text of this article is available at http://www.circresaha.org.
Asunto(s)
Bloqueo Cardíaco/fisiopatología , Síndrome de QT Prolongado/genética , Canales de Sodio/genética , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular , Preescolar , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Haplotipos , Homocigoto , Humanos , Síndrome de QT Prolongado/patología , Síndrome de QT Prolongado/fisiopatología , Masculino , Potenciales de la Membrana/genética , Mutación , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.5 , Linaje , Polimorfismo Conformacional Retorcido-Simple , Homología de Secuencia de Aminoácido , Canales de Sodio/fisiologíaRESUMEN
BACKGROUND: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. METHODS AND RESULTS: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On beta blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2-37) years. CONCLUSION: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with beta blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of beta blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.
Asunto(s)
Bradicardia/genética , Catecolaminas/metabolismo , Mutación , Polimorfismo Genético , Canal Liberador de Calcio Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Síncope/genética , Taquicardia/genéticaRESUMEN
BACKGROUND: The 2 genes KCNQ1 (LQT1) and HERG (LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients. METHODS AND RESULTS: The T-wave morphology of carriers of mutations in KCNQ1 (n=133) or HERG (n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively, P:<0.001). G1 notches were relatively more frequent in LQT2 (18% versus 8% [LQT1] and 4% [control], P:<0.01), and G2 notches were seen exclusively in LQT2 (63%). Predictors for G2 were young age, missense mutations, and core domain mutations in HERG. CONCLUSIONS: This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting HERG core domain missense mutations.
Asunto(s)
Proteínas de Transporte de Catión , Proteínas de Unión al ADN , Electrocardiografía Ambulatoria/métodos , Síndrome de QT Prolongado/genética , Mutación , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Transactivadores , Adulto , Canal de Potasio ERG1 , Electrocardiografía , Canales de Potasio Éter-A-Go-Go , Femenino , Humanos , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado/fisiopatología , Masculino , Regulador Transcripcional ERGRESUMEN
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.
Asunto(s)
ADN Recombinante/genética , Síndrome de QT Prolongado/genética , Mutación/genética , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Preescolar , Codón/genética , Humanos , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Masculino , Repeticiones de Microsatélite , Linaje , Sistemas de Lectura/genética , Transcripción GenéticaRESUMEN
BACKGROUND: The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. METHODS AND RESULTS: We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. CONCLUSIONS: Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
Asunto(s)
Síndrome de QT Prolongado/genética , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Arritmias Cardíacas/etiología , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Muerte Súbita Cardíaca/etiología , Electrocardiografía , Emociones , Ejercicio Físico , Femenino , Genotipo , Humanos , Canales Iónicos/genética , Síndrome de QT Prolongado/clasificación , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/tratamiento farmacológico , Síndrome de QT Prolongado/fisiopatología , Masculino , Fenotipo , Factores Sexuales , Sueño , Tasa de Supervivencia , Síncope/etiologíaRESUMEN
Catecholinergic ventricular tachycardia is an adrenergic induced polymorphic ventricular arrhythmia. It occurs in infancy and is responsible for syncope and sudden death in the absence of any morphological cardiac abnormality. Without treatment the mortality in catecholinergic ventricular tachycardia is very high. We report genetic and clinical data from 25 cases of catecholinergic ventricular tachycardia referred with syncope (n=19) or resuscitated sudden death during exercise (n=6). A family history from the 25 families identified 41 apparent subjects considered as being clinically affected, with an average age of 30 +/- 10 years (11 to 62 years). Analysis of the RyR2 gene showed mutations in 13 of the 25 cases and in 39 of apparent subjects. With betablocker treatment (nadolol: 1.6 +/- 0.15 mg/kg), 96% of patients remained asymptomatic over an average follow-up of between 7.5 +/- 1.5 years, although some of them continued to display polymorphic ventricular extrasystoles on exercise. Nevertheless, 12% of the cases suffered sudden death or further syncope during follow-up. An automatic defibrillator was implanted in 2 patients who had a RyR2 mutation. High dose betablockers are effective in preventing serious rhythm disturbance in children. In adolescence, implanting an automatic defibrillator should be discussed in cases with a history of syncope or resuscitated sudden death. We confirm the importance of genetic studies in these families at high risk of sudden death.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Muerte Súbita Cardíaca , Taquicardia Ventricular/genética , Taquicardia Ventricular/patología , Adolescente , Adulto , Catecolaminas/farmacología , Niño , Análisis Mutacional de ADN , Desfibriladores Implantables , Electrocardiografía , Ejercicio Físico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Canal Liberador de Calcio Receptor de Rianodina/genética , Síncope , Taquicardia Ventricular/tratamiento farmacológicoRESUMEN
INTRODUCTION: In case of an accessory pathway, children are exposed to severe cardiac events including sudden death. Radiofrequency ablation is a standardized procedure, which can be applied to a significant number of children although complications can still potentially occur. In this context, transesophageal evaluation of the accessory pathway evaluation can be discussed. MATERIALS AND METHODS: Among 140 procedures performed in 19 years, 70 were done for accessory pathway evaluation. The preexcitation was overt in 59 children older than 5 years, which form the basis in this study. RESULTS: Anterograde refractory period was determined in 88% cases and was found<220 ms in 12 cases justifying an ablation procedure. Conversely, in case of a long refractory period (>250 ms), the ablation procedure was not performed in 8 asymptomatic cases and was postponed in 11/20 mildly symptomatic children. Transesophageal electrophysiologic study seems legitimate in asymptomatic or mildly symptomatic children. CONCLUSION: This technique is probably less useful in case of an overt preexcitation and recurrent reciprocating tachycardia requiring long-term antiarrythmic treatment. In this case, endocavitary electrophysiological study eventually followed by an ablation procedure seems the best option.
Asunto(s)
Estimulación Cardíaca Artificial/métodos , Taquicardia/diagnóstico , Adolescente , Ablación por Catéter , Niño , Preescolar , Electrocardiografía , Electrofisiología , Esófago/fisiología , Humanos , Selección de Paciente , Taquicardia/terapia , Fibrilación Ventricular/prevención & controlRESUMEN
UNLABELLED: Familial long QT syndrome (LQTS) and Brugada syndrome are two distinct human hereditary cardiac diseases known to cause ventricular tachyarrhythmias (torsade de pointes) and idiopathic ventricular fibrillation, respectively, which can both lead to sudden death. OBJECTIVE: In this study we have identified and electrophysiologically characterized, in patients having either LQTS or Brugada syndrome, three mutations in SCN5A (a cardiac sodium channel gene). METHOD: The mutant channels were expressed in a mammalian expression system and studied by means of the patch clamp technique. RESULTS: The R1512W mutation found in our first patient diagnosed with Brugada syndrome produced a slowing of both inactivation and recovery from inactivation. The R4132G mutation found in our second patient who also presented Brugada syndrome, resulted in no measurable sodium currents. Both Brugada syndrome patients showed ST segment elevation and right bundle-branch block, and had experienced syncopes. The E1784K mutation found in the LQTS showed a persistent inward sodium current, a hyperpolarized shift of the steady-sate inactivation and a faster recovery from inactivation. CONCLUSION: The different clinical manifestations of these three mutations most probably originate from the distinct electrophysiological abnormalities of the mutant cardiac sodium channels reported in this study.
Asunto(s)
Bloqueo de Rama/genética , Muerte Súbita Cardíaca , Síndrome de QT Prolongado/genética , Mutación Missense , Canales de Sodio/genética , Síncope Vasovagal/genética , Adulto , Bloqueo de Rama/fisiopatología , Niño , Electrocardiografía , Femenino , Humanos , Síndrome de QT Prolongado/fisiopatología , Masculino , Canal de Sodio Activado por Voltaje NAV1.5 , Técnicas de Placa-Clamp , Polimorfismo Conformacional Retorcido-Simple , Síncope Vasovagal/fisiopatología , SíndromeRESUMEN
OBJECTIVES: We report the functional expression of four KCNQ1 mutations affecting arginine residues and resulting in Romano-Ward (RW) and the Jervell and Lange-Nielsen (JLN) congenital long QT syndromes. RESULTS: The R539W and R190Q mutations were found in typical RW families with an autosomal dominant transmission. The R243H mutation was found in a compound heterozygous JLN patient who presents with deafness and cardiac symptoms. The fourth mutation, R533W, was a new case of recessive form of the RW syndrome since homozygous carriers experienced syncopes but showed no deafness, whereas the heterozygous carriers were asymptomatic. The R190Q mutation failed to produce functional homomeric channels. The R243H, R533W and R539W mutations induced a positive voltage shift of the channel activation but only when co-expressed with IsK, pointing out the critical role of these positively charged residues in the modulation of the gating properties of KvLQT1 by IsK. The positive shift induced by R533W was merely 15%. This small effect was compatible with the recessive character of the RW phenotype transmission. The average QTc was significantly longer (P < 0.01) in patients carrying mutations inducing a total loss of channel function and those patients were also prone to cardiac adverse symptoms (whether syncopes or sudden death) to a greater extent (62 vs. 21%, P < 0.001). CONCLUSIONS: Novel mutations are described that induce a voltage shift of the channel activation only in the presence of IsK. They appear associated with a milder cardiac phenotype.
Asunto(s)
Activación del Canal Iónico , Síndrome de QT Prolongado/genética , Mutación Missense , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Potenciales de Acción/genética , Adolescente , Adulto , Animales , Células COS , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado/metabolismo , Masculino , Mutagénesis Sitio-Dirigida , Técnicas de Placa-Clamp , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Canales de Potasio/metabolismoRESUMEN
Mutations in KvLQT1, a gene encoding a potassium channel, cause both the recessive Jervell and Lange-Nielsen (JLN) syndrome and the dominant Romano-Ward (RW) syndrome. These diseases are characterised by a prolonged QT interval on the ECG, syncopes and sudden death due to cardiac arrhythmias. The JLN syndrome is also associated with a congenital bilateral deafness. We report here a novel missense mutation, W305S, in the pore region of KvLQT1 identified by PCR-SSCP analysis in two consanguineous JLN families. In contrast to several missense mutations found in the same region of KvLQT1 in RW patients which are associated with severe cardiac phenotypes, the W305S mutation is responsible for an apparently normal phenotype in heterozygous JLN carriers.
Asunto(s)
Heterocigoto , Síndrome de QT Prolongado/genética , Mutación Missense , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Consanguinidad , Femenino , Humanos , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Masculino , Linaje , FenotipoRESUMEN
To assess the cardiac and extracardiac safety and efficacy of flecainide versus propafenone in patients suffering from episodes of paroxysmal atrial fibrillation (AF) or atrial flutter, 97 patients were enrolled in a randomized, open-label, long-term, parallel, comparative multicenter study. The diagnosis of paroxysmal AF or atrial flutter had to be fully documented prior to inclusion in the study. Of the 97 patients enrolled in the study, 48 patients (25 men, 23 women, mean age 62.4 +/- 12.3 years) received flecainide; 49 patients (26 men, 23 women, mean age 63.6 +/- 12.2 years) received propafenone. The initial dose of flecainide was 50 mg twice daily, and this could be increased in steps of 50 mg twice daily every 4 days to a maximum of 300 mg/day. The initial dose of propafenone was 300 mg twice daily and this could be increased in steps of 300 mg every 4 days to a maximum of 1200 mg/day. At each visit, medical events, vital sign measurements (blood pressure, pulse rate), concomitant medications, adverse experiences, and study drug dosage changes were evaluated. Routine clinical laboratory tests were evaluated at the month 6 visit, and a 24-hr Holter recording was obtained at the month 1 visit. Almost half (45) of the patients were discontinued from the study before completing 1 year of therapy. The probability of successful treatment versus time--i.e., the proportion of patients who remained on therapy over the course of 1 year therapy--was 0.619 for the flecainide group and 0.469 for the propafenone group (p = 0.079; difference not significant). The difference is largely attributed to the higher proportion of patients in the propafenone group (9) than in the flecainide group (2) who experienced side effects important enough to stop the treatment. (The incidence of side effects was not statistically different between treatment groups, although it was higher in the propafenone group.) The proportion of patients who discontinued treatment due to inadequate response was similar in the 2 groups: 11 patients (22.9%) in the flecainide group and 12 patients (24.4%) in the propafenone group withdrew from the study, primarily because of an inadequate response, i.e., they experienced an increase in duration, frequency, and severity of attacks of AF or atrial flutter. Neurologic signs, central and peripheral, were mostly encountered in the flecainide group (8.5%), and, gastrointestinal effects were more often reported in the propafenone group (16.7%). In paroxysmal AF and paroxysmal atrial flutter, flecainide and propafenone are equally effective. However, in this study the probability of a patient's staying on flecainide after 1 year had a tendency to be higher than the probability of staying on propafenone, due to a greater proportion of secondary effects with propafenone.
Asunto(s)
Atención Ambulatoria , Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Aleteo Atrial/tratamiento farmacológico , Flecainida/uso terapéutico , Propafenona/uso terapéutico , Adulto , Anciano , Antiarrítmicos/efectos adversos , Femenino , Flecainida/efectos adversos , Estudios de Seguimiento , Francia , Humanos , Tablas de Vida , Masculino , Persona de Mediana Edad , Propafenona/efectos adversosRESUMEN
Flecainide (100 mg twice daily) was used for prevention of paroxysmal atrial fibrillation (PAF) in 52 patients with frequent symptomatic attacks that were resistant or intolerant to quinidine (600-900 mg/day). Underlying heart disease was present in only 8 cases and left ventricular ejection fraction was always greater than 30%. No patient had had a myocardial infarction. Vagally induced PAF was clinically documented in 35 patients. Amiodarone, previously used and ineffective, was combined with flecainide in 33 patients. After 1-5.8 years of follow-up, complete disappearance of PAF was observed in 38 patients (73%). The success rate was slightly higher in patients with vagally induced PAF (p = 0.07). Extracardiac side effects necessitated withdrawal in only 3 cases. Permanent pacemaker was needed in 7 patients on amiodarone and flecainide because of excessive sinus bradycardia. Two patients, with previously documented atrial flutter, experienced presyncopal episodes of atrial flutter with 1:1 atrioventricular (AV) conduction and wide QRS complex. No death occurred during the follow-up. In this series, quinidine proved to be unsuccessful in 46 patients and it was withdrawn in 6. We concluded that flecainide is efficient and well tolerated for long-term prevention of PAF in patients resistant to quinidine. The possibility of 1:1 AV conduction during atrial flutter may suggest the use of verapamil or beta blockers in combination with flecainide in patients with previously documented atrial flutter.
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Flecainida/uso terapéutico , Quinidina/uso terapéutico , Amiodarona/uso terapéutico , Arritmias Cardíacas/inducido químicamente , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Quimioterapia Combinada , Electrocardiografía Ambulatoria , Femenino , Flecainida/efectos adversos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
In order to assess efficacy, safety, and long-term tolerance of flecainide for the prevention of paroxysmal atrial fibrillation (PAF), 944 patients (555 male) were enrolled in an open multicenter study. All patients had had greater than or equal to 1 episodes of atrial fibrillation and were in sinus rhythm at the time of entry. The mean age was 65.3 +/- 11 years, and 43% of patients had no detectable heart disease. The mean daily dose of flecainide was 190 +/- 34 mg. Clinical examination, electrocardiogram (ECG) and 24-hour Holter monitoring were performed at entry into the study and on months 3, 6, and 9. Of the patients, 189 were lost to follow-up. Of the remaining 755 patients, 562 (74%) continued the treatment during the 9-month period and 193 (26%) dropped out. A total of 84 adverse effects were reported in 7.6% enrolled patients and in 9% of patients during follow-up, with treatment interruption in 50% of the cases. There were only 3 minor cardiovascular side effects, all leading to treatment discontinuation. No deaths in patients with recurrent PAF and no proarrhythmic events were reported. Flecainide appears to be effective in preventing PAF, with 65% of patients being arrhythmia-free after 9 months of treatment at a mean daily dose of 200 mg. Side effects were common, but clinically significant adverse events were infrequent.
Asunto(s)
Fibrilación Atrial/prevención & control , Flecainida/uso terapéutico , Fibrilación Atrial/epidemiología , Evaluación de Medicamentos , Tolerancia a Medicamentos , Electrocardiografía Ambulatoria , Femenino , Flecainida/administración & dosificación , Flecainida/efectos adversos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The congenital long QT syndrome (LQTS) is a variable clinical and genetic entity characterised by prolongation of the QT interval on the ECG associated with the risk of serious ventricular arrhythmias (torsades de pointe, ventricular fibrillation) which may cause syncope and sudden death in patients with otherwise normal hearts. To date, 6 loci have been identified with the genes responsible for the forms LQT1, LQT2, LQT5 and LQT6, coding for the potassium channels (KCNQ1, HERG, KCNE1 and KCNE2, respectively) which, in the heterozygote state, are responsible for the main forms of LQTS without deafness and, in the homozygote state (KCNQ1 and KCNE1) for the recessive forms of LQTS with or without deafness. The gene for the LQT3 form codes for the cardiac sodium channel (SCN5A). The genetic variability observed in the LQTS corresponds to the diversity of cardiac ionic channels implicated in the genesis of the action potential, so making the LQTS a disease of the ionic channels or a "channelopathy". The potential severity of the prognosis justifies testing of subjects with long QT intervals on the ECG and Holter recording. In order to identify subjects with the genetic abnormality who are asymptomatic, these investigations associated with genetic testing should be made in all close members of the family of an affected person. The major problem remains the evaluation of the risk of sudden death in asymptomatic subjects with a genetic abnormality. At present, in the absence of clearly proven prognostic factors and in the knowledge that effective treatment without major secondary effects is available, all patients should be given prophylactic betablocker therapy.