RESUMEN
Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1-/- mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.
Asunto(s)
Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Síndrome de Jervell-Lange Nielsen/terapia , Canales de Potasio con Entrada de Voltaje/genética , Canales Semicirculares/cirugía , Animales , Animales Recién Nacidos , Dependovirus , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos/genética , Audición/genética , Humanos , Inyecciones/métodos , Síndrome de Jervell-Lange Nielsen/genética , Masculino , Ratones , Ratones Noqueados , Parvovirinae/genética , Propiocepción/genéticaRESUMEN
A 7-year-old female suffering from syncope attacks and deafness was genetically diagnosed with Jervell and Lange-Nielsen syndrome (JLNS). A transvenous-designed shock lead and implantable cardioverter-defibrillator (ICD) were atypically implanted subcutaneously, because the patient's body was small. Six years after implantation, we confirmed the patient's eligibility for a subcutaneous ICD (S-ICD) based on electrocardiogram screening. The implanted ICD system was replaced with a new standard S-ICD system. Implantation of the S-ICD may be considered a reliable and safe option in young patients with JLNS, even if their electrocardiograms show remarkable prolongation of the QT interval and T-wave alternans.
Asunto(s)
Desfibriladores Implantables/efectos adversos , Electrocardiografía/métodos , Síndrome de Jervell-Lange Nielsen/diagnóstico , Síndrome de Jervell-Lange Nielsen/terapia , Canal de Potasio KCNQ1/genética , Niño , Remoción de Dispositivos/métodos , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Síndrome de Jervell-Lange Nielsen/complicaciones , Linaje , Retratamiento , Síncope/diagnóstico , Síncope/etiología , Síncope/terapia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Jervell and Lange-Nielsen syndrome (JLNS), a rare autosomal recessive congenital QT prolongation syndrome, is characterized by cardiac arrhythmias, syncopal episodes, and profound deafness. A cochlear implant (CI) for patients with JLNS is expected to result in hearing improvement. Sometimes, defibrillation is required if a patient experiences lethal arrhythmia. In this paper, we report a pediatric patient with JLNS who received defibrillation after CI surgery in his right ear at the age of 2 years. With intensive care, the post-operative course was uneventful, and the patient acquired satisfactory speech and hearing abilities. Five years after the surgery, he underwent defibrillation because of the incidence of syncopal attack. Thereafter, arrhythmic syncope recurred three times, which necessitated defibrillation therapy. To prevent recurrence of cardiac arrhythmia, he underwent ICD (implantable cardioverter-defibrillator) implantation at the age of 11 years. At present, CI works well and provides good hearing, while syncopal attack is prevented by ICD. From the experience of this case, electronic circuit of CI is thought to tolerate emergency countershock if the speech processor is removed.
Asunto(s)
Implantación Coclear , Implantes Cocleares , Cardioversión Eléctrica , Síndrome de Jervell-Lange Nielsen/terapia , Síncope/prevención & control , Niño , Desfibriladores Implantables , Falla de Equipo , Humanos , Síndrome de Jervell-Lange Nielsen/complicaciones , Masculino , Síncope/etiologíaRESUMEN
BACKGROUND: Patients with Jervell and Lange-Nielsen syndrome (JLNS) exhibit severe phenotypes that are characterized by congenital deafness, very long QT intervals, and high risk of life-threatening arrhythmias. Current treatment strategies include high doses of beta-blocker medication, left cardiac sympathetic denervation, and ICD placement, which is challenging in young children. OBJECTIVE: The purpose of this study was to evaluate the safety and effect of pacing in addition to beta-blocker treatment in children with JLNS. METHODS: All genetically confirmed patients with JLNS born since 1999 in Norway were included in the study. Data on history of long QT syndrome-related symptoms, QT interval, and beta-blocker and pacemaker treatment were recorded. RESULTS: A total of 9 patients with QT intervals ranging from 510 to 660 ms were identified. Eight patients developed long QT syndrome-related symptoms, and 1 patient died before diagnosis. The survivors received beta-blocker medication. Seven patients also received a pacemaker; 1 had a ventricular lead and 6 had atrial leads. The patient with the ventricular lead died during follow-up. The 6 patients with atrial leads survived without events at a mean follow-up of 6.9 years after pacemaker implantation. Two patients received prophylactic upgrade to a 2-chamber ICD. CONCLUSION: No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up. If confirmed in additional patients, this treatment strategy may prevent life-threatening arrhythmias in this high-risk patient group and may act as a bridge to insertion of a 2-chamber ICD when left cardiac sympathetic denervation is not available.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Arritmias Cardíacas , Estimulación Cardíaca Artificial/métodos , Síndrome de Jervell-Lange Nielsen , Canal de Potasio KCNQ1/genética , Simpatectomía/métodos , Adolescente , Arritmias Cardíacas/genética , Arritmias Cardíacas/prevención & control , Niño , Preescolar , Implantación Coclear/métodos , Sordera/congénito , Sordera/cirugía , Desfibriladores Implantables , Relación Dosis-Respuesta a Droga , Electrocardiografía/métodos , Femenino , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Lactante , Síndrome de Jervell-Lange Nielsen/complicaciones , Síndrome de Jervell-Lange Nielsen/epidemiología , Síndrome de Jervell-Lange Nielsen/fisiopatología , Síndrome de Jervell-Lange Nielsen/terapia , Masculino , Mutación , Noruega/epidemiología , Evaluación de Procesos y Resultados en Atención de SaludRESUMEN
Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1(-/-) mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0-P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner's membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1(-/-) mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss.
Asunto(s)
Conducto Coclear/fisiología , Sordera/genética , Sordera/terapia , Terapia Genética/métodos , Síndrome de Jervell-Lange Nielsen/genética , Síndrome de Jervell-Lange Nielsen/terapia , Canal de Potasio KCNQ1/genética , Animales , Sordera/congénito , Dependovirus/genética , Modelos Animales de Enfermedad , Expresión Génica , Ratones , Ratones Noqueados , Transducción Genética , Transgenes , Resultado del TratamientoAsunto(s)
Remoción de Dispositivos/métodos , Síndrome de Jervell-Lange Nielsen/diagnóstico , Síndrome de Jervell-Lange Nielsen/terapia , Procedimientos Innecesarios , Adolescente , Desfibriladores Implantables/efectos adversos , Estudios de Seguimiento , Humanos , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , Masculino , Nadolol/uso terapéutico , Marcapaso Artificial/efectos adversos , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p.R518X mutation. METHODS: The study included 19 Swedish p.R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software). RESULTS: Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000). CONCLUSIONS: R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.
Asunto(s)
Síndrome de Jervell-Lange Nielsen/genética , Canal de Potasio KCNQ1/genética , Biología Molecular , Mutación , Adulto , Análisis Mutacional de ADN , Electrocardiografía , Femenino , Efecto Fundador , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Paro Cardíaco/epidemiología , Paro Cardíaco/genética , Herencia , Heterocigoto , Humanos , Síndrome de Jervell-Lange Nielsen/diagnóstico , Síndrome de Jervell-Lange Nielsen/epidemiología , Síndrome de Jervell-Lange Nielsen/fisiopatología , Síndrome de Jervell-Lange Nielsen/terapia , Masculino , Linaje , Fenotipo , Pronóstico , Factores de Riesgo , Índice de Severidad de la Enfermedad , Suecia/epidemiología , Factores de Tiempo , Adulto JovenAsunto(s)
Causas de Muerte , Implantación Coclear/efectos adversos , Síndrome de Jervell-Lange Nielsen/mortalidad , Síndrome de Jervell-Lange Nielsen/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Preescolar , Implantación Coclear/métodos , Desfibriladores Implantables , Electrocardiografía , Femenino , Pérdida Auditiva Sensorineural/congénito , Pérdida Auditiva Sensorineural/cirugía , Humanos , Síndrome de Jervell-Lange Nielsen/diagnóstico , Masculino , Estudios Retrospectivos , Medición de Riesgo , Administración de la Seguridad , Muestreo , Tasa de SupervivenciaAsunto(s)
Síndrome de Jervell-Lange Nielsen/fisiopatología , Síndrome de Jervell-Lange Nielsen/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Desfibriladores Implantables , Humanos , Síndrome de Jervell-Lange Nielsen/mortalidad , Síndrome de QT Prolongado/mortalidad , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/terapia , Factores de RiesgoRESUMEN
INTRODUCTION: Data regarding risk factors and clinical course of patients affected with Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recessive form of the congenital long-QT syndrome (LQTS), are limited to several reported cases and a retrospective analysis. METHODS AND RESULTS: We prospectively followed-up 44 JLNS patients from the U.S. portion of the International LQTS Registry and compared their clinical course with 2,174 patients with the phenotypically determined dominant form of LQTS (Romano-Ward syndrome [RWS]) and a subgroup of 285 patients with type 1 LQTS (LQT1). Mean (+/-SD) corrected QT interval (QTc) in the JLNS, RWS, and LQT1 groups were 548 +/- 73, 500 +/- 48, and 502 +/- 46 msec, respectively (P < 0.001). The cumulative rates of cardiac events from birth through age 40 among JLNS and RWS patients were 93% (mean [+/-SD] age: 5.0 +/- 7.0 years) and 54% (mean [+/-SD] age: 14.2 +/- 9.3 years), respectively (P < 0.001). The JLNS:RWS and JLNS:LQT1 adjusted hazard ratios (HR) for cardiac events were highest among patients with a baseline QTc > or = 550 msec (HR = 15.83 [P < 0.001] and 13.80 [P < 0.001], respectively). Among JLNS patients treated with beta-blockers, the cumulative probability of LQTS-related death was 35%; defibrillator therapy was associated with a 0% mortality rate during a mean (+/-SD) follow-up period of 4.9 +/- 3.4 years. CONCLUSIONS: Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy. Defibrillator therapy appears to improve outcome in this high-risk population, although longer follow-up is needed to establish its long-term efficacy.
Asunto(s)
Síndrome de Jervell-Lange Nielsen/fisiopatología , Síndrome de Jervell-Lange Nielsen/terapia , Adolescente , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Niño , Preescolar , Desfibriladores Implantables , Femenino , Estudios de Seguimiento , Humanos , Lactante , Síndrome de Jervell-Lange Nielsen/genética , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/terapia , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
A child with Jervell-Lange Nielsen syndrome is presented from Kolkata. Family study showed that the other family members are suffering from long QT syndrome. The child had frequent syncopal attack and very prolonged QT interval requiring left cardiac sympathetic denervation and beta-blocker therapy as patient could not afford implantable defibrillator and cardiac pacing.
Asunto(s)
Síndrome de Jervell-Lange Nielsen/diagnóstico , Síndrome de Jervell-Lange Nielsen/terapia , Simpatectomía/métodos , Antagonistas Adrenérgicos beta/uso terapéutico , Niño , Corazón/inervación , Humanos , MasculinoRESUMEN
BACKGROUND: Data on the Jervell and Lange-Nielsen syndrome (J-LN), 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 I(Ks) current, are still based largely on case reports. METHODS AND RESULTS: We analyzed data from 186 J-LN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events, and 50% were already symptomatic 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) (hazard ratio, 0.54; 95% CI, 0.34 to 0.88; P=0.01). 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; 51% of the patients had events despite therapy and 27% had CA/SD. CONCLUSIONS: J-LN syndrome is a most severe variant of LQTS, with a very early onset and major QTc prolongation, and in which beta-blockers have limited efficacy. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc < or =550 ms, those without events in the first year of life, and those with mutations on KCNE1. Early therapy with implanted cardioverter/defibrillators must be considered.
Asunto(s)
Síndrome de Jervell-Lange Nielsen , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Recolección de Datos , Salud de la Familia , Femenino , Genotipo , Humanos , Lactante , Síndrome de Jervell-Lange Nielsen/etiología , Síndrome de Jervell-Lange Nielsen/genética , Síndrome de Jervell-Lange Nielsen/mortalidad , Síndrome de Jervell-Lange Nielsen/terapia , Canal de Potasio KCNQ1/genética , Masculino , Persona de Mediana Edad , Canales de Potasio con Entrada de Voltaje/genética , Factores Sexuales , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We report a case of a child with familial long QT syndrome (Jervell Lange-Nielsen) who had multiple electrical storms in the presence of b blocker and implantable cardioverter device (ICD) therapy. Discontinuation of ICD therapy and addition of oral amiodarone to b blockade therapy resulted in freedom from electrical storms.