Left cardiac sympathetic denervation in children with Jervell Lange-Nielsen syndrome and drug refractory torsades - A case series.

INTRODUCTION: Long QT syndrome is an inherited malignant channelopathy which leads to life-threatening arrhythmia, with multiple genotypes. Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive subtype of this disease, characterized by congenital sensorineural deafness and a high incidence of sudden cardiac death (SCD). METHODOLOGY: We prospectively followed up six children who underwent left cardiac sympathetic denervation (LCSD) for JLNS in view of high-risk features despite being on maximally tolerated doses of oral propranolol. RESULTS: Mean age at diagnosis was 2.75 ± 0.39 years, with a significant delay between onset of symptoms and diagnosis (mean 7.2 ± 3.5 months). All had sensorineural hearing loss, conforming to the JLNS phenotype. Mean QTc interval was 603 ± 93 ms, with T wave alternans (TWA) seen in all cases. All were started on propranolol and subsequently subjected to LCSD, and 3 underwent AAI permanent pacemaker implantation. Over a mean follow-up of 20 months, there was a significant reduction in QTc (603 ± 93 ms to 501 ± 33 ms, p = .04), which was persistent on follow-up (525 ± 41 ms) and only two out of six had persistent T wave alternans on ECG (p < .01). None of these children had presyncope, syncope, seizures, torsades de pointes, cardiac arrest or death on follow up following LCSD. CONCLUSION: Jervell Lange-Nielsen syndrome is a subtype of LQTS with high-risk features. LCSD, an effective therapeutic option for those having symptoms despite being on propranolol, results in significant reduction of QTc interval and amelioration of symptoms.

Autosomal Recessive Long QT Syndrome: Clinical Aspects and Therapy.

The autosomal recessive (AR) form of Long QT Syndrome (LQTS) is described both associated with deafness known as Jervell and Lange-Nielsen (JLN) syndrome, and without deafness (WD). The aim of the study is to report the characteristics of AR LQTS patients and the efficacy of the therapy. Data of all children with AR LQTS referred to the Bambino Gesù Children's Hospital IRCCS from September 2012 to September 2021were included. Three (30%) patients had compound heterozygosity and 7 (70%) had homozygous variants of the KCNQ1 gene, the latter showing deafness. Four patients (40%) presented aborted sudden cardiac death (aSCD): three with previous episodes of syncope (75%), the other without previous symptoms (16.6% of asymptomatic patients). An episode of aSCD occurred in 2/3 (66.7%) of WD and heterozygous patients, while in 2/7 (28%) JLN and homozygous patients and in 2/2 patients with QTC > 600 ms. All patients were treated with Nadolol. In 5 Mexiletine was added, shortening QTc and obtaining the disappearance of the T-wave alternance (TWA) in 3/3. Episodes of aSCD seem to be more frequent in LQTS patients with compound heterozygous variants and WD than in those with JLN and homozygous variants. Episodes of aSCD also appear more frequent in children with syncope or with QTc value > 600 ms, even on beta-blocker therapy, than in patients without syncope or with Qtc < 600 ms. However, our descriptive results should be confirmed by larger studies. Moreover, Mexiletine addition reduced QTc value and eliminated TWA.

Novel combinations of variations in KCNQ1 were associated with patients with long QT syndrome or Jervell and Lange-Nielsen syndrome.

OBJECTIVES: Long QT syndrome (LQTS) is one of the primary causes of sudden cardiac death (SCD) in youth. Studies have identified mutations in ion channel genes as key players in the pathogenesis of LQTS. However, the specific etiology in individual families remains unknown. METHODS: Three unrelated Chinese pedigrees diagnosed with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) were recruited clinically. Whole exome sequencing (WES) was performed and further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. RESULTS: All of the probands in our study experienced syncope episodes and featured typically prolonged QTc-intervals. Two probands also presented with congenital hearing loss and iron-deficiency anemia and thus were diagnosed with JLNS. A total of five different variants in KCNQ1, encoding a subunit of the voltage-gated potassium channel, were identified in 3 probands. The heterozygous variants, KCNQ1 c.749T > C was responsible for LQTS in Case 1, transmitting in an autosomal dominant pattern. Two patterns of compound heterozygous variants were responsible for JLNS, including a large deletion causing loss of the exon 16 and missense variant c.1663 C > T in Case 2, and splicing variant c.605-2 A > G and frame-shift variant c.1265del in Case 3. To our knowledge, the compound heterozygous mutations containing a large deletion and missense variant were first reported in patients with JLNS. CONCLUSION: Our study expanded the LQTS genetic spectrum, thus favoring disease screening and diagnosis, personalized treatment, and genetic consultation.

Computational Study on Effect of KCNQ1 P535T Mutation in a Cardiac Ventricular Tissue.

Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange-Nielsen syndrome (JLNS), and Romano-Ward syndrome (RWS).

Clinical and functional characterisation of a recurrent KCNQ1 variant in the Belgian population.

BACKGROUND: The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant. RESULTS: Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele. CONCLUSIONS: The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded.

Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants.

The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.

Genetic testing hearing loss: The challenge of non syndromic mimics.

Congenital hearing loss is a common cause of morbidity in early childhood. There are multiple reasons for congenital hearing impairment, with genetic contribution becoming increasingly recognized. Sensorineural hearing loss has classically been viewed as either syndromic or non-syndromic. With the advent of DNA sequencing technology such as NextGen sequencing, a subcategory has arisen, that of non-syndromic mimics (NSM)s. NSMs present initially as isolated hearing loss but as the patient ages other phenotypes become evident. Early diagnosis of these conditions is imperative as patients may suffer significant morbidity and mortality from complications from their hearing loss syndrome. An example is QT prolongation in Jervell and Lange-Nielsen Syndrome. The need for genetic testing and proper genetic counseling is necessary for patients with hearing loss and testing should be done as early in life as possible.

Prevalence of Jervell-Lange Nielsen syndrome in children with congenital bilateral sensorineural hearing loss.

OBJECTIVE: Long QT syndrome (LQTS) is an inherited cardiac ion channel disorder (channelopathy) that is characterized by prolonged QT intervals on the electrocardiography (ECG) and possess the risk of sudden cardiac death (SCD). Jervell-Lange Nielsen syndrome (JLNS) is a specific subtype of LQTS that is accompanied by congenital sensorineural hearing loss, inherited autosomal recessively, and higher risk of SCD. In this study, we aimed to investigate JLNS prevalence in deaf children attending special schools for hearing loss, located in our province. METHODS: An ECG screening program was conducted in 6 special schools for children with hearing loss in Istanbul and a total of 440 students between 6 and 18 years old were included. Corrected QT interval (QTc) was calculated using the Bazett formula. Notably, 51 students, detected with any abnormal finding on ECG, were invited to our center for a comprehensive examination. RESULTS: A total of 8 patients were found with a prolonged QT interval. JLNS was diagnosed in 4 (0.9%) patients. In addition, 2 students had already been diagnosed with JLNS at another center earlier. The other 2 students, being siblings, were newly diagnosed with JLNS; and appropriate treatment was initiated. Genetic testing revealed a pathological homozygous mutation in KCNQ1 gene. The younger sibling (Case 1), who possessed a QTc of greater than 500 ms and a history of syncope, which was very suspicious for SCD, was implanted an implantable cardioverter-defibrillator. Propranolol treatment was initiated for both siblings. CONCLUSION: JLNS should be carefully considered and screened, especially in patients with a history of congenital deafness.

Establishment of iPSC line from a Chinese infant (XACHi012-A) with Jervell and Lange-Nielsen syndrome carrying combined KCNQ1 frameshift c.431delC(p.I145Sfs*92) and nonsense c.1175G > A (p.W392X) variants and two iPSC lines from the parents (XACHi013-A, XACHi014-A).

Induced pluripotent stem cell lines (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of a two month-old boy and the parents. Jervell and Lange-Nielsen syndrome (JLNS) was diagnosed in the boy carrying combined KCNQ1 frameshift c.431delC (p.I145Sfs*92) and nonsense c.1175G > A(p.W392X) variants inherited from his mother and father respectively. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. IPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carrying identified KCNQ1 variants with corresponding PBMC, and have a normal karyotype. Thus we established three iPSC lines as useful tools for studying the pathophysiological mechanism of JLNS and drug testing.

Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2.

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.

Treatment on arrhythmia electric storm in a Jervell and Lange-Nielsen syndrome patient by ablation of the triggering premature ventricular contraction: a case report.

Jervell and Lange-Nielsen syndrome (JLNS) is a subtype of congenital long QT syndrome (LQTS), which is a potentially life-threatening ion channelopathy characterized by delayed myocardial repolarization that leads to QT prolongation. Since JLNS is a rare disease, there have been few in-depth studies on this disease since yet. Previous studies have found that the pathogenesis of JLNS is related to KCNQ1 or KCNE1 gene mutation. There are a relatively small number of studies reporting the successful ablation treatment on JLNS patient due to the extremely low incidence rate. We report a 51-year-old female patient diagnosed with JLNS through gene detection. The patient has A to G missense mutation in KCNE1 gene, and a subunit with abnormal structure, which is the basis for congenital deafness. The main clinical manifestation of this patient is frequent fatal ventricular arrhythmia triggered by premature ventricular contraction (PVC). Ablation was successfully performed to eliminate the triggering PVC. The patient was not able to have implantable cardioverter defibrillator (ICD) implantation due to economic reasons. During the 12-month follow-up, no syncope or fatal arrhythmia was found in this patient. Our case showed that radiofrequency catheter ablation (RFCA) was an effective way to treat fatal arrhythmia in JLNS patient.

Propranolol syrup to tablets change triggers electrical storm in Jervell-Lange-Nielsen syndrome.

A 10-year-old girl with genetically confirmed Jervell-Lange-Nielsen syndrome treated with beta-blocker and developed electrical storm after changing propranolol syrup to tablets. Jervell-Lange-Nielsen is characterised by long QT and congenital sensorineural deafness, with high risk of malignant arrhythmias at early ages. Gastric involvement and achlorhydria may be present, with subsequent alteration of medication bioavailability which can trigger severe arrhythmic complications.

Outcomes of Cochlear Implantation in Patients with Jervell and Lange-Nielsen Syndrome: A Systematic Review and Narrative Synthesis.

Establish outcomes following cochlear implantation (CI) in patients with Jervell and Lange-Nielsen Syndrome (JLNS). Methods Systematic review and narrative synthesis. Databases searched on Medline, Pubmed, Embase, Web of Science, Cochrane Collection and ClinicalTrials.gov. No limits placed on language or year of publication. Review conducted in accordance with the PRISMA statement. Searches identified 63 abstracts and 19 full texts. Of these, 9 studies met inclusion criteria reporting outcomes in 66 patients with at least 72 implants. Hearing outcomes were generally good. Mortality secondary to cardiac complications within the follow up period occurred in at least five cases (7.6%), though three of these were thought to be unrelated to surgery. Potentially dangerous arrhythmias without associated morbidity were also noted in at least five patients. The methodological quality of included studies was modest, predominantly consisting of case reports and non-controlled case series with small numbers of patients. All studies were OCEBM grade IV. One study contributed 41/66 patients (62%). Hearing outcomes following CI in JLNS are generally good with the majority of patients experiencing useful hearing improvement. Significant peri-operative cardiac risks exist and should be discussed with the patient and family during pre-operative counselling and prompt thorough investigation, pre-operative optimisation and peri-operative monitoring.

The combined novel KCNQ1 frameshift I145Sfs*92 and nonsense W392X variants caused Jervell and Lange-Nielsen syndrome in a Chinese infant presenting with sustained foetal bradycardia.

AIMS: We report clinical and molecular analysis of an infant presenting with foetal bradycardia and clinical outcome of Jervell and Lange-Nielsen syndrome (JLNS). METHODS AND RESULTS: Clinical, electrocardiogram (ECG), and echocardiographic data were collected from members in a three-generation family. Whole exomes were amplified and sequenced for proband. The identified variants were verified in the remaining members. The pathogenicity of candidate variants was predicted using multiple software programmes. A 28-year-old non-consanguineous Chinese woman at 23 weeks' gestation presenting with sustained foetal bradycardia of 100 b.p.m. Immunological disorders and infection were excluded. The infant was delivered at 37 weeks' gestation with 2700-g birthweight. QTc was prolonged in both ECG and Holter recording. Hearing tests confirmed bilateral sensorineural hearing loss. Genetic testing demonstrated that the infant carried a novel frameshift c.431delC (p.I145Sfs*92) and a novel nonsense c.1175G>A (p.W392X) compound variants of KCNQ1 inherited from mother and father, respectively, in autosomal recessive inheritance. Only relative II-5 carrying heterozygous KCNQ1-I145Sfs*92 variant had prolonged QTc, while the other carriers did not have prolonged QT, suggesting an autosomal dominant inheritance of LQT1 phenotype with incomplete penetrance in the family. CONCLUSION: We report the novel frameshift KCNQ1-I145Sfs*92 and nonsense KCNQ1-W392X compound variants in autosomal recessive inheritance that caused JLNS presenting as sustained foetal bradycardia for the first time. Meanwhile, KCNQ1-I145Sfs*92 heterozygous variant demonstrated LQT1 phenotype in autosomal dominant inheritance with incomplete penetrance.

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.

Replacement of an Implantable Cardioverter-Defibrillator (ICD) with a New Standard Subcutaneous ICD System in a Patient with Jervell and Lange-Nielsen Syndrome.

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.

[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.