The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.

AIMS: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. METHODS AND RESULTS: We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small IKs was readily recorded but the pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (µM) of moxifloxacin required to prolong APD90 100 msec was 237.4 [median, interquartile range (IQR) 100.6-391.6, n = 7] in population cells vs. 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 µM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs and markedly prolonged APD90. CONCLUSION: Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs.

Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family.

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams).

Cochlear Implantation in Congenital Long-QT Syndrome: A Comprehensive Study.

OBJECTIVES: Jervell and Lange-Nielsen syndrome is a rare autosomal recessive disease characterized by congenital sensorineural deafness and significant QT interval prolongation. Aims were to study the prevalence of long QT in congenital hearing loss, complications encountered, outcomes by Categories of auditory Performance (CAP) scores and Speech Intelligibility Rating (SIR) scores and to create an algorithm with precautions to be followed in Long QT children. MATERIALS AND METHODS: Study was done at Auditory implant center at a tertiary referral care ENT hospital which includes 41 paediatric patients who were diagnosed to have Long QT during preoperative assessment and underwent cochlear implantation. A standard Protocol was followed in all candidates which includes comprehensive targeted history and investigations, preoperative and intraoperative precautions, and the findings were recorded. RESULTS: Preoperative prophylactic Beta blockers, avoiding sympathetic stimulation and drugs prolonging QT interval with rational use of Magnesium Sulphate and standby of defibrillator were the standard precautions practised. Fatal Arrhythmias were encountered intra-operatively in five patients which was treated with cardiac pacing. Cardiac monitoring was done intraoperatively and during switch-on. Significant improvement in CAP and SIR scores were observed at 3 and 6 months when compared to their base line values. CONCLUSION: With special attention to preoperative evaluation, appropriate intraoperative precautions and monitoring, judicious surgical planning and post surgical follow-up cochlear implantation may be performed safely in patients with JLNS with good postoperative results allowing for improved audition.

[Jervell and Lange-Nielsen syndrome].

Summary Jervell and Lange-Nielsen syndrome（JLNS） is an autosomal recessive hereditary disease characterized by congenital severe sensorineural hearing loss in both ears and severe arrhythmias with QT interval prolongation. Children with JLNS often exhibit sensorineural hearing loss and are easily misdiagnosed as non-syndromic hearing loss before attack of cardiac event. When a cochlear implant is performed, a fatal arrhythmia is likely to occur during the perioperative period, which seriously threatens the life of the child. It is currently found that the pathogenic genes of JLNS are mainly KCNQ1 and KCNE1. This article reviews the clinical manifestations, pathogenic genes, diagnosis and differential diagnosis, intervention measures of JLNS to further draw the attention to the disease, reduce misdiagnosis, improve the survival rate and quality of life of children with JLNS.

The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?

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.

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study.

BACKGROUND: The aim of the study was to determine, whether electrocardiogram (ECG) screening could reduce the risk of sudden cardiac death in patients with hearing loss through the early diagnosis of Jervell and Lange-Nielsen syndrome and the introduction of the therapy. METHODS: One thousand and eighty patients with hearing loss (aged 21.8 ± 19.9 years) underwent ECG. Additionally, all subjects were asked to complete a 3-question survey. Those who met, at least, one of the high-risk criteria underwent further cardiac assessment and genetic testing. RESULTS: QTc assessment was possible in 1,027 patients. Mean QTc measured 422.8 ± 23.7 ms in 313 women, 414.9 ± 27.7 ms in 273 men and 421.1 ± 21.5 ms in 441 children (individuals younger than 14 years). Abnormal QTc was found in 13 (4.1%) women, 20 (7.3%) men, and 72 (16.3%) children. In the studied group, no recessive mutation of KNCQ1 or KCNE1 was found. In 6 patients, other mutations were found: in KCNQ1 (n = 1), in KCNH2 (n = 3) and in SCN5A (n = 1), which were pathogenic for long-QT-syndromes (LQTS), and 2 mutations of unknown clinical significance in SCN5A. Overall, out of these 6 patients LQTS was diagnosed in 3 asymptomatic patients, but with abnormal QTc and in 2 patients with normal QTc, but who were previously treated for epilepsy. CONCLUSIONS: Jervell and Lange-Nielsen syndrome is a very rare condition even in a population with hearing loss. In this population, the prevalence of prolonged QT interval is increased over the general population. Further investigations are necessary.

Vestibular dysfunction is a clinical feature of the Jervell and Lange-Nielsen Syndrome.

OBJECTIVES: To investigate the possible association between Jervell and Lange-Nielsen Syndrome (JLNS) genotype and vestibular dysfunction. DESIGN: In 15 cases with JLNS, clinical data obtained from a semi-structured interview and full medical records were reviewed and post-rotatory nystagmus testing was performed. RESULTS: All genotyped cases (n = 14) had double KCNQ1 mutations. Symptoms of impaired balance were reported in 14/14 deaf JLNS cases. Gross motor developmental delay (not walking without support at 18 months of age) was seen in 11/12 cases with available data (mean age for walking: 24 months). A pathologic post-rotatory test was seen in 9/9 tested subjects, and in 3 subjects clinical testing had been performed showing complete lack of vestibular function. Vestibular dysfunction was seen in deaf JLNS cases with (n = 5) and without (n = 9) cochlear implants, including subjective symptoms (5/5 vs. 9/9) and gross motor developmental delay (5/5 vs. 6/8). CONCLUSIONS: We identified a high frequency of symptoms and signs associated with vestibular dysfunction in deaf JLNS cases, irrespective of previous cochlear implantation. Disruption of endolymph homeostasis in the inner ear, including cochlea and vestibular system, by profound KCNQ1 function loss is the proposed mechanism.

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.

Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and ß subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation.

Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families.

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.

Síndrome de Jervell y Lange-Nielsen / Jervell and Lange-Nielsen Syndrome

El síndrome de Jervell y Lange-Nielsen es una forma poco frecuente de síndrome de QT largo. Su herencia es autosómica recesiva y se manifiesta con sordera neurosensorial. Revisamos el caso de una niña de 7 años implantada coclear bilateral. Tras un episodio sincopal se realiza el diagnóstico de síndrome de QT largo, el estudio genético confirma el diagnóstico. Recomendamos realizar electrocardiograma a todos los niños con hipoacusia severa con el objeto de descartar este síndrome.

The Jervell and Lange-Nielsen (JLNS) is an uncommon form of long QT syndrome. His inheritance is autosomal recessive and manifests as a sensorineural deafness. We review the case of a 7 year old girl bilateral cochlear implanted. After a syncope episode, a long QT syndrome was confirmed by genetic study. We recommend electrocardiogram (ECG) to all children with severe hearing loss in order to rule out this syndrome.

Jervell and Lange-Nielsen syndrome in a father and daughter from a large highly inbred family: a 16-year follow-up of 59 living members.

OBJECTIVE: To report the autosomal dominant inheritance of the Jervell and Lange-Nielsen syndrome in a highly inbred family, the initiation of Torsades de Pointes, and the natural history of the syndrome based on a 16-year follow-up of the kindred. METHOD: A family tree was constructed that included 66 blood relatives from three successive generations. Electrocardiograms were obtained from 59 living members including the proband, four members from a nuclear family, and 54 from the extended family. Evoked response audiometry was recorded for the proband and the nuclear family. All 59 family members were followed up regularly for 16 years. RESULTS: A total of 24 living members were affected--QTc: 480-680 ms. The proband had long QTc, bilateral high-tone sensorineural deafness, recurrent syncope, and Torsades de Pointes. The asymptomatic father had long QTc and unilateral high-tone sensorineural deafness that involved specifically the left ear. One asymptomatic sibling of the proband had long QTc and normal hearing. The mother and another sibling were asymptomatic; QTc and hearing were normal in both. A total of 21 affected members from the extended family had only long QTc, and all were asymptomatic. There were three congenitally deaf first cousins who had recurrent syncope and adrenergic-triggered sudden death. In all, seven of 10 parents had consanguineous marriage to a first cousin. Each affected offspring had at least one affected parent. The severely symptomatic proband who received only ß-blocker therapy and the 23 affected members without antiadrenergic therapy, all remained asymptomatic throughout the 16-year follow-up period. CONCLUSION: Jervell and Lange-Nielsen syndrome was inherited as autosomal dominant in this kindred. The majority of the affected members had a mild phenotype. The severity of auditory and cardiac phenotypes corresponded.

Videoscopic left cardiac sympathetic denervation for patients with recurrent ventricular fibrillation/malignant ventricular arrhythmia syndromes besides congenital long-QT syndrome.

BACKGROUND: Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non-long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting. METHODS AND RESULTS: In this institutional review board-approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and ß-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event. CONCLUSIONS: LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.

Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome.

Mutations in the KCNQ1 gene account for more than 90% of the individuals with Jervell and Lange-Nielsen syndrome (JLNS). In this study, we identified and characterized two novel KCNQ1 mutations that caused JLNS. A 6-year-old deaf girl suffering from recurrent syncope had a documented electrocardiogram with polymorphic ventricular fibrillation since the age of 4 years. The baseline electrocardiogram showed a significantly prolonged corrected QT interval (524 msec). Genetic analysis revealed that the proband carried two heterozygous mutations of T2C and 1149insT in the KCNQ1 gene on separate alleles. Patch-clamp analysis demonstrated that the T2C mutation resulted in significant reduction in the slowly activated delayed rectifier current (IKs). Furthermore, western blot analysis and confocal imaging revealed that the T2C mutation produced a truncated protein with trafficking defects. In contrast, the 1149insT mutation failed to generate any measurable current, consistent with no protein expression in both the cell membrane and cytoplasm. Moreover, co-expression of the T2C and 1149insT mutations significantly reduced the peak tail current density to 8.27% of the wild-type (WT) current value, while co-transfected WT channels with either T2C or 1149insT mutant channels produced comparable current and channel kinetics to that of WT channels. Our study demonstrates that the compound heterozygous mutations T2C and 1149insT cause the 'loss-of-function' of the IKs that may account for the clinical phenotype of the proband. Multiple mechanisms have been involved in the pathogenesis of 'loss-of-function' of IKs.

Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome.

Enhanced dispersion of repolarization has been proposed as an important mechanism in long QT related arrhythmias. Dispersion can be dynamic and can be augmented with the occurrence of spatially out-of-phase action potential duration (APD) alternans (discordant alternans; DA). We investigated the role of tissue heterogeneity in generating DA using a novel transgenic rabbit model of type 2 long QT syndrome (LQT2). Littermate control (LMC) and LQT2 rabbit hearts (n = 5 for each) were retrogradely perfused and action potentials were mapped from the epicardial surface using di-4-ANEPPS and a high speed CMOS camera. Spatial dispersion (Delta APD and Delta slope of APD restitution) were both increased in LQT2 compared to LMC (Delta APD: 34 +/- 7 ms vs. 23 +/- 6 ms; Delta slope: 1.14 +/- 0.23 vs. 0.59 +/- 0.19). Onset of DA under a ramp stimulation protocol was seen at longer pacing cycle length (CL) in LQT2 compared to LMC hearts (206 +/- 24 ms vs. 156 +/- 5 ms). Nodal lines between regions with APD alternans out of phase from each other were correlated with conduction velocity (CV) alternation in LMC but not in LQT2 hearts. In LQT2 hearts, larger APD dispersion was associated with onset of DA at longer pacing CL. At shorter CLs, closer to ventricular fibrillation induction (VF), nodal lines in LQT2 (n = 2 out of 5) showed persistent complex beat-to-beat changes in nodal line formation of DA associated with competing contribution from CV restitution and tissue spatial heterogeneity, increasing vulnerability to conduction block. In conclusion, tissue heterogeneity plays a significant role in providing substrate for ventricular arrhythmia in LQT2 rabbits by facilitating DA onset and contributing to unstable nodal lines prone to reentry formation.

Empirical correlation of triggered activity and spatial and temporal re-entrant substrates with arrhythmogenicity in a murine model for Jervell and Lange-Nielsen syndrome.

KCNE1 encodes the beta-subunit of the slow component of the delayed rectifier K(+) current. The Jervell and Lange-Nielsen syndrome is characterized by sensorineural deafness, prolonged QT intervals, and ventricular arrhythmogenicity. Loss-of-function mutations in KCNE1 are implicated in the JLN2 subtype. We recorded left ventricular epicardial and endocardial monophasic action potentials (MAPs) in intact, Langendorff-perfused mouse hearts. KCNE1 (-/-) but not wild-type (WT) hearts showed not only triggered activity and spontaneous ventricular tachycardia (VT), but also VT provoked by programmed electrical stimulation. The presence or absence of VT was related to the following set of criteria for re-entrant excitation for the first time in KCNE1 (-/-) hearts: Quantification of APD(90), the MAP duration at 90% repolarization, demonstrated alterations in (1) the difference, APD(90), between endocardial and epicardial APD(90) and (2) critical intervals for local re-excitation, given by differences between APD(90) and ventricular effective refractory period, reflecting spatial re-entrant substrate. Temporal re-entrant substrate was reflected in (3) increased APD(90) alternans, through a range of pacing rates, and (4) steeper epicardial and endocardial APD(90) restitution curves determined with a dynamic pacing protocol. (5) Nicorandil (20 microM) rescued spontaneous and provoked arrhythmogenic phenomena in KCNE1 (-/-) hearts. WTs remained nonarrhythmogenic. Nicorandil correspondingly restored parameters representing re-entrant criteria in KCNE1 (-/-) hearts toward values found in untreated WTs. It shifted such values in WT hearts in similar directions. Together, these findings directly implicate triggered electrical activity and spatial and temporal re-entrant mechanisms in the arrhythmogenesis observed in KCNE1 (-/-) hearts.