RARE DISEASE
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Synonyms: Long QT interval-deafness syndrome, Long QT interval-hearing loss syndrome
Synonyms: Long QT interval-deafness syndrome, Long QT interval-hearing loss syndrome
Synonyms: Long QT interval-deafness syndrome, Long QT interval-hearing loss syndrome
Drug discovery
1
drug
With orphan designation
Overview
Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive disorder characterized by congenital bilateral sensorineural hearing loss and prolonged QT interval, predisposing to life-threatening ventricular arrhythmias and sudden cardiac death [1][6][13]. Caused by mutations in KCNQ1 (90% of cases) or KCNE1 genes, it disrupts potassium ion channels critical for cardiac repolarization and cochlear function [1][3][6].
Therapies
Cardiac management:
First-line β-blockers (nadolol/propranolol) to reduce arrhythmia risk [7][12].
Implantable cardioverter-defibrillators (ICDs) for high-risk patients [3][10][13].
Left cardiac sympathetic denervation (LCSD) in refractory cases [7][13].
Hearing interventions: Cochlear implants for profound deafness [3][13].
Lifestyle: Avoid triggers (exercise, stress) and electrolyte imbalances [3][6].
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare otorhinolaryngological diseases
Research Papers
1,381 drug discovery papers about Jervell and Lange-Nielsen syndrome, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,381 drug discovery papers about Jervell and Lange-Nielsen syndrome, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-12 | ERLAD-hERG axis and L-type calcium channel activation mediate cholesterol-induced acquired long QT syndrome-related cardiotoxicity.
High cholesterol is a key cardiovascular risk factor that can modulate cardiac electrophysiology and promote acquired long QT syndrome (acLQTS)-related cardiotoxicity, a potentially life-threatening condition associated with QT prolongation, torsade de pointes, and sudden cardiac death. This study investigated the effects of cholesterol overload on human Ether-à-go-go-Related Gene (hERG/Kv11.1; encoded by KCNH2) potassium channels and L-type calcium channels (LTCC; mainly Cav1.2/CACNA1C in cardiomyocytes), as well as the underlying mechanisms of acLQTS-related cardiotoxicity, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), whole-cell patch clamp, quantitative real-time PCR (qRT-PCR), Western blotting, immunoprecipitation, fluorescence imaging, and a high-cholesterol diet guinea pig model with rosuvastatin intervention combined with optical mapping. The results showed that transient cholesterol exposure inhibited hERG tail current amplitude and accelerated channel inactivation, with the effect showing a Y652-dependent component, while also enhancing LTCC activity. Mechanistically, cholesterol overload triggered endoplasmic reticulum (ER) stress, impaired hERG proteostasis, and promoted ER-to-lysosome-associated degradation (ERLAD) of hERG. This process was associated with CANX-mediated recognition of abnormal hERG and FAM134B-LC3B-related autophagic-lysosomal processing, contributing to reduced total hERG expression and membrane-localized mature hERG. FAM134B overexpression partially preserved hERG expression and attenuated cholesterol-induced ER stress/autophagy-related abnormalities. In vivo, rosuvastatin improved lipid profiles and cardiac remodeling in high-cholesterol guinea pigs but was associated with more pronounced action potential duration (APD) and QT interval prolongation under high-cholesterol conditions. These findings suggest that cholesterol overload may increase susceptibility to hERG-related repolarization abnormalities during rosuvastatin exposure and highlight the importance of cholesterol management and electrocardiographic (ECG) monitoring in hypercholesterolemic settings.
2026-07-20 | Effects of curcumin and nicorandil on nilotinib-induced QT interval prolongation in rats: A telemetry-based study.
Long QT syndrome (LQTS) is characterized by QT prolongation, ventricular arrhythmias and sudden death. Nilotinib (Nilo), a tyrosine kinase inhibitor used in chronic myeloid leukemia, prolongs QTc mainly through hERG (IKr) channel inhibition. Curcumin (Curc), often co-administered, modulates cardiac ion channels, whereas nicorandil (Nico) acts as a KATP channel opener. This study evaluated the effects of Curc and Nico on Nilo-induced QTc prolongation. Male Sprague-Dawley rats implanted with radiotelemetry transmitters received 10 mg/kg nilotinib (selected as the minimal effective dose based on preliminary dose-finding studies at 10, 30 and 50 mg/kg), 100 mg/kg curcumin, or 10 mg/kg nicorandil, as previously described. Animals were allocated into seven groups: Control, Nilo, Curc, Nico, Nilo+Curc, Nilo+Nico and Nilo+Curc+Nico. ECG, biochemical and histopathological analyses were performed. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test. Nilotinib caused dose-dependent QTc prolongation, with 10 mg/kg as the minimal effective dose (p<0.001). Curcumin further exacerbated QTc prolongation, whereas nicorandil co-administration mitigated this effect. (p<0.001). Nilo also elevated TNF-α and TAS, which were attenuated in combination groups. Nilotinib-induced dose-dependent QTc prolongation was aggravated by curcumin, whereas nicorandil demonstrated a potential protective effect on drug-induced LQTS.
2026-07-17 | Late INa as a Therapeutic Target: New Strategies, Computational Modelling, Drug Development, and Clinical Translation.
The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.
2026-07-16 | Multimodality Risk Stratification in Athletes With Long QT Syndrome.
Long QT syndrome has traditionally led to exercise restriction due to concerns for exertion-triggered arrhythmia and sudden cardiac death. Emerging data, however, support individualized participation guided by genotype and physiologic risk markers. We describe 3 young athletes with distinct genotypes (KCNE1 D85N [long QT syndrome type 5-Lite], KCNQ1 R555H [long QT syndrome type 1], and KCNH2 p.T613M [long QT syndrome type 2]) evaluated through electrocardiography, exercise testing, and echocardiographic assessment of the electromechanical window. The electromechanical window ranged from mildly to severely negative (-11 to -103 ms) and corresponded with phenotypic severity. Personalized management, including selective β-blockade, mexiletine, and device therapy, enabled safe continuation of sports participation in all cases. This case series underscores the role of genotype-specific, multimodality assessment in risk stratifying athletes with long QT syndrome. Integration of individualized therapy, shared decision making, and structured emergency preparedness supports safe athletic participation while maintaining arrhythmic protection and quality of life. Individualized risk assessment including resting and stress electrocardiography, genotype analysis, and electromechanical window measurement provides a more accurate estimate of arrhythmic risk than does resting QTc interval alone. Genotype-guided therapy and structured sports counseling allow most patients with LQTS to safely engage in exercise and even competitive athletics under expert supervision. Shared decision making and emergency preparedness, including automated external defibrillator access and multidisciplinary collaboration, are essential to balancing athletic participation with long-term safety in patients with LQTS.
2026-07-13 | Electro-Mechanical Uncoupling of KV7.1 Voltage Sensor and Pore by 1,4-Benzodiazepines Is Modulated by Decoration of Position 1.
The voltage-gated potassium channel KV7.1 (KCNQ1) is essential for cardiac repolarization. Loss-of-function mutations prolong the action potential and cause long QT syndrome 1, predisposing to malignant arrhythmias. Pharmacological activators of KV7.1 are therefore of therapeutic interest. Among them, the 1,4-benzodiazepine derivative (R)-L3 is a potent activator that not only increases current amplitude but also slows activation and deactivation kinetics and abolishes inactivation by uncoupling the voltage sensor from the pore. To explore the structure-activity relationships (SAR) of (R)-L3, we synthesized and functionally characterized a series of novel 1,4-benzodiazepine derivatives and examined their effects on KV7.1 gating. Human KV7.1 channels were heterologously expressed in Xenopus laevis oocytes. Two-electrode voltage clamp recordings were performed to assess current amplitude and kinetic parameters of activation, deactivation, and inactivation. 1,4-Benzodiazepines modified at 1-position reproduced the canonical effects of (R)-L3, including increased current amplitude and suppression of inactivation to varying degrees. Some derivatives displayed completely altered profiles: Modulation of activation, altered (de-)activation kinetics or exerting attenuated effects on inactivation could be uncoupled. These differences suggest that modifications of the 1,4-benzodiazepine scaffold at 1-position shift the interaction between pore binding and voltage sensor-pore uncoupling to isolate kinetic effects. Our data demonstrates that (R)-L3 analogues can differentially modulate KV7.1 gating. By identifying structural determinants of efficacy, this study provides a framework for rational design of next-generation KV7.1 activators. Such compounds may serve as pharmacological tools for dissecting electromechanical coupling in KV7.1 and hold promise as candidates for antiarrhythmic therapy in long QT syndrome.
2026-08-12 | ERLAD-hERG axis and L-type calcium channel activation mediate cholesterol-induced acquired long QT syndrome-related cardiotoxicity.
High cholesterol is a key cardiovascular risk factor that can modulate cardiac electrophysiology and promote acquired long QT syndrome (acLQTS)-related cardiotoxicity, a potentially life-threatening condition associated with QT prolongation, torsade de pointes, and sudden cardiac death. This study investigated the effects of cholesterol overload on human Ether-à-go-go-Related Gene (hERG/Kv11.1; encoded by KCNH2) potassium channels and L-type calcium channels (LTCC; mainly Cav1.2/CACNA1C in cardiomyocytes), as well as the underlying mechanisms of acLQTS-related cardiotoxicity, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), whole-cell patch clamp, quantitative real-time PCR (qRT-PCR), Western blotting, immunoprecipitation, fluorescence imaging, and a high-cholesterol diet guinea pig model with rosuvastatin intervention combined with optical mapping. The results showed that transient cholesterol exposure inhibited hERG tail current amplitude and accelerated channel inactivation, with the effect showing a Y652-dependent component, while also enhancing LTCC activity. Mechanistically, cholesterol overload triggered endoplasmic reticulum (ER) stress, impaired hERG proteostasis, and promoted ER-to-lysosome-associated degradation (ERLAD) of hERG. This process was associated with CANX-mediated recognition of abnormal hERG and FAM134B-LC3B-related autophagic-lysosomal processing, contributing to reduced total hERG expression and membrane-localized mature hERG. FAM134B overexpression partially preserved hERG expression and attenuated cholesterol-induced ER stress/autophagy-related abnormalities. In vivo, rosuvastatin improved lipid profiles and cardiac remodeling in high-cholesterol guinea pigs but was associated with more pronounced action potential duration (APD) and QT interval prolongation under high-cholesterol conditions. These findings suggest that cholesterol overload may increase susceptibility to hERG-related repolarization abnormalities during rosuvastatin exposure and highlight the importance of cholesterol management and electrocardiographic (ECG) monitoring in hypercholesterolemic settings.
2026-07-20 | Effects of curcumin and nicorandil on nilotinib-induced QT interval prolongation in rats: A telemetry-based study.
Long QT syndrome (LQTS) is characterized by QT prolongation, ventricular arrhythmias and sudden death. Nilotinib (Nilo), a tyrosine kinase inhibitor used in chronic myeloid leukemia, prolongs QTc mainly through hERG (IKr) channel inhibition. Curcumin (Curc), often co-administered, modulates cardiac ion channels, whereas nicorandil (Nico) acts as a KATP channel opener. This study evaluated the effects of Curc and Nico on Nilo-induced QTc prolongation. Male Sprague-Dawley rats implanted with radiotelemetry transmitters received 10 mg/kg nilotinib (selected as the minimal effective dose based on preliminary dose-finding studies at 10, 30 and 50 mg/kg), 100 mg/kg curcumin, or 10 mg/kg nicorandil, as previously described. Animals were allocated into seven groups: Control, Nilo, Curc, Nico, Nilo+Curc, Nilo+Nico and Nilo+Curc+Nico. ECG, biochemical and histopathological analyses were performed. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test. Nilotinib caused dose-dependent QTc prolongation, with 10 mg/kg as the minimal effective dose (p<0.001). Curcumin further exacerbated QTc prolongation, whereas nicorandil co-administration mitigated this effect. (p<0.001). Nilo also elevated TNF-α and TAS, which were attenuated in combination groups. Nilotinib-induced dose-dependent QTc prolongation was aggravated by curcumin, whereas nicorandil demonstrated a potential protective effect on drug-induced LQTS.
2026-07-17 | Late INa as a Therapeutic Target: New Strategies, Computational Modelling, Drug Development, and Clinical Translation.
The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.
2026-07-16 | Multimodality Risk Stratification in Athletes With Long QT Syndrome.
Long QT syndrome has traditionally led to exercise restriction due to concerns for exertion-triggered arrhythmia and sudden cardiac death. Emerging data, however, support individualized participation guided by genotype and physiologic risk markers. We describe 3 young athletes with distinct genotypes (KCNE1 D85N [long QT syndrome type 5-Lite], KCNQ1 R555H [long QT syndrome type 1], and KCNH2 p.T613M [long QT syndrome type 2]) evaluated through electrocardiography, exercise testing, and echocardiographic assessment of the electromechanical window. The electromechanical window ranged from mildly to severely negative (-11 to -103 ms) and corresponded with phenotypic severity. Personalized management, including selective β-blockade, mexiletine, and device therapy, enabled safe continuation of sports participation in all cases. This case series underscores the role of genotype-specific, multimodality assessment in risk stratifying athletes with long QT syndrome. Integration of individualized therapy, shared decision making, and structured emergency preparedness supports safe athletic participation while maintaining arrhythmic protection and quality of life. Individualized risk assessment including resting and stress electrocardiography, genotype analysis, and electromechanical window measurement provides a more accurate estimate of arrhythmic risk than does resting QTc interval alone. Genotype-guided therapy and structured sports counseling allow most patients with LQTS to safely engage in exercise and even competitive athletics under expert supervision. Shared decision making and emergency preparedness, including automated external defibrillator access and multidisciplinary collaboration, are essential to balancing athletic participation with long-term safety in patients with LQTS.
2026-07-13 | Electro-Mechanical Uncoupling of KV7.1 Voltage Sensor and Pore by 1,4-Benzodiazepines Is Modulated by Decoration of Position 1.
The voltage-gated potassium channel KV7.1 (KCNQ1) is essential for cardiac repolarization. Loss-of-function mutations prolong the action potential and cause long QT syndrome 1, predisposing to malignant arrhythmias. Pharmacological activators of KV7.1 are therefore of therapeutic interest. Among them, the 1,4-benzodiazepine derivative (R)-L3 is a potent activator that not only increases current amplitude but also slows activation and deactivation kinetics and abolishes inactivation by uncoupling the voltage sensor from the pore. To explore the structure-activity relationships (SAR) of (R)-L3, we synthesized and functionally characterized a series of novel 1,4-benzodiazepine derivatives and examined their effects on KV7.1 gating. Human KV7.1 channels were heterologously expressed in Xenopus laevis oocytes. Two-electrode voltage clamp recordings were performed to assess current amplitude and kinetic parameters of activation, deactivation, and inactivation. 1,4-Benzodiazepines modified at 1-position reproduced the canonical effects of (R)-L3, including increased current amplitude and suppression of inactivation to varying degrees. Some derivatives displayed completely altered profiles: Modulation of activation, altered (de-)activation kinetics or exerting attenuated effects on inactivation could be uncoupled. These differences suggest that modifications of the 1,4-benzodiazepine scaffold at 1-position shift the interaction between pore binding and voltage sensor-pore uncoupling to isolate kinetic effects. Our data demonstrates that (R)-L3 analogues can differentially modulate KV7.1 gating. By identifying structural determinants of efficacy, this study provides a framework for rational design of next-generation KV7.1 activators. Such compounds may serve as pharmacological tools for dissecting electromechanical coupling in KV7.1 and hold promise as candidates for antiarrhythmic therapy in long QT syndrome.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Jervell and Lange-Nielsen syndrome, including 1 approved therapy.
1 orphan drug designation for Jervell and Lange-Nielsen syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Amiodarone HCl [Cordarone] | small molecules | FDA | 1994-03-16 | 1995-08-03 | Wyeth-Ayerst Laboratories |
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