Untangling the dravet syndrome seizure network: the changing face of a rare genetic epilepsy.
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ABSTRACT:
SUBMITTER: Chopra R
PROVIDER: S-EPMC4010885 | biostudies-other | 2014 Mar
REPOSITORIES: biostudies-other
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Project description:Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that is mainly associated with variants in SCN1A. While drug-resistant epilepsy is the most notable feature of this syndrome, numerous symptoms are present that have significant impact on patients' quality of life. In spite of novel, third-generation anti-seizure treatment options becoming available over the last several years, seizure freedom is often not attained and non-seizure symptoms remain. Precision medicine now offers realistic hope for seizure freedom in DS patients, with several approaches demonstrating preclinical success. Therapeutic approaches such as antisense oligonucleotides (ASO) and adeno-associated virus (AAV)-delivered gene modulation have expanded the potential treatment options for DS, with some of these approaches now transitioning to clinical trials. Several of these treatments may risk the exacerbation of gain-of-function variants and may not be reversible, therefore emphasizing the need for functional testing of new pathogenic variants. The current absence of treatments that address the overall disease, in addition to seizures, exposes the urgent need for reliable, valid measures of the entire complement of symptoms as outcome measures to truly know the impact of treatments on DS. Additionally, with so many treatment options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.
| S-EPMC8608987 | biostudies-literature
Project description:Relatively few SCN1A mutations associated with genetic epilepsy with febrile seizures-plus (GEFS+) and Dravet syndrome (DS) have been functionally characterized. In contrast to GEFS+, many mutations detected in DS patients are predicted to have complete loss of function. However, functional consequences are not immediately apparent for DS missense mutations. Therefore, we performed a biophysical analysis of three SCN1A missense mutations (R865G, R946C and R946H) we detected in six patients with DS. Furthermore, we compared the functionality of the R865G DS mutation with that of a R859H mutation detected in a GEFS+ patient; the two mutations reside in the same voltage sensor domain of Na(v) 1.1. The four mutations were co-expressed with ?1 and ?2 subunits in tsA201 cells, and characterized using the whole-cell patch clamp technique. The two DS mutations, R946C and R946H, were nonfunctional. However, the novel voltage sensor mutants R859H (GEFS+) and R865G (DS) produced sodium current densities similar to those in wild-type channels. Both mutants had negative shifts in the voltage dependence of activation, slower recovery from inactivation, and increased persistent current. Only the GEFS+ mutant exhibited a loss of function in voltage-dependent channel availability. Our results suggest that the R859H mutation causes GEFS+ by a mixture of biophysical defects in Na(v) 1.1 gating. Interestingly, while loss of Na(v) 1.1 function is common in DS, the R865G mutation may cause DS by overall gain-of-function defects.
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Project description:Dravet Syndrome (DS) is a developmental epileptic encephalopathy characterized by drug-resistant seizures and other clinical features, including intellectual disability and behavioral, sleep, and gait problems. The pathogenesis is strongly connected to voltage-gated sodium channel dysfunction. The current consensus of seizure management in DS consists of a combination of conventional and recently approved drugs such as stiripentol, cannabidiol, and fenfluramine. Despite promising results in randomized clinical trials and extension studies, the prognosis of the developmental outcomes of patients with DS remains unfavorable. The article summarizes recent changes in the therapeutic approach to DS and discusses ongoing clinical research directions. Serotonergic agents under investigation show promising results and may replace less DS-specific medicines. The use of antisense nucleotides and gene therapy is focused not only on symptom relief but primarily addresses the underlying cause of the syndrome. Novel compounds, after expected safe and successful implementation in clinical practice, will open a new era for patients with DS. The main goal of causative treatment is to modify the natural course of the disease and provide the best neurodevelopmental outcome with minimum neurological deficit.
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Project description:Epilepsy is a common chronic neurological disease affecting almost 3 million people in the United States and 50 million people worldwide. Despite availability of more than two dozen FDA-approved anti-epileptic drugs (AEDs), one-third of patients fail to receive adequate seizure control. Specifically, pediatric genetic epilepsies are often the most severe, debilitating and pharmaco-resistant forms of epilepsy. Epileptic syndromes share a common symptom of unprovoked seizures. While some epilepsies/forms of epilepsy are the result of acquired insults such as head trauma, febrile seizure, or viral infection, others have a genetic basis. The discovery of epilepsy associated genes suggests varied underlying pathologies and opens the door for development of new "personalized" treatment options for each genetic epilepsy. Among these, Dravet syndrome (DS) has received substantial attention for both the pre-clinical and early clinical development of novel therapeutics. Despite these advances, there is no FDA-approved treatment for DS. Over 80% of patients diagnosed with DS carry a de novo mutation within the voltage-gated sodium channel gene SCN1A and these patients suffer with drug resistant and life-threatening seizures. Here we will review the preclinical animal models for DS featuring inactivation of SCN1A (including zebrafish and mice) with an emphasis on seizure phenotypes and behavioral comorbidities. Because many drugs fail somewhere between initial preclinical discovery and clinical trials, it is equally important that we understand how these models respond to known AEDs. As such, we will also review the available literature and recent drug screening efforts using these models with a focus on assay protocols and predictive pharmacological profiles. Validation of these preclinical models is a critical step in our efforts to efficiently discover new therapies for these patients. The behavioral and electrophysiological drug screening assays in zebrafish will be discussed in detail including specific examples from our laboratory using a zebrafish scn1 mutant and a summary of the nearly 3000 drugs screened to date. As the discovery and development phase rapidly moves from the lab-to-the-clinic for DS, it is hoped that this preclinical strategy offers a platform for how to approach any genetic epilepsy.
| S-EPMC5994396 | biostudies-literature
Project description:OBJECTIVE:Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage-gated sodium channel Na(v) 1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that decreased Na(v) 1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient-specific neurons. METHODS:Here we derive forebrain-like pyramidal- and bipolar-shaped neurons from 2 DS subjects and 3 human controls by iPSC reprogramming of fibroblasts. DS and control iPSC-derived neurons are compared using whole-cell patch clamp recordings. Sodium current density and intrinsic neuronal excitability are examined. RESULTS:Neural progenitors from DS and human control iPSCs display a forebrain identity and differentiate into bipolar- and pyramidal-shaped neurons. DS patient-derived neurons show increased sodium currents in both bipolar- and pyramidal-shaped neurons. Consistent with increased sodium currents, both types of patient-derived neurons show spontaneous bursting and other evidence of hyperexcitability. Sodium channel transcripts are not elevated, consistent with a post-translational mechanism. INTERPRETATION:These data demonstrate that epilepsy patient-specific iPSC-derived neurons are useful for modeling epileptic-like hyperactivity. Our findings reveal a previously unrecognized cell-autonomous epilepsy mechanism potentially underlying DS, and offer a platform for screening new antiepileptic therapies.
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Project description:UnlabelledClassic Dravet syndrome is also termed severe myoclonic epilepsy of infancy (SMEI). There are subtle phenotypic variants of Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the group of severe infantile onset epilepsies (OMIM #607208, #182389, #604403) associated with mutations in SCN1A (OMIM *182389). SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. SCN1A testing can be done through bi-directional DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) for: 1) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types - several seizure types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or 2) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy.DisclaimerThis summary is based on a UK Genetic Testing Network (UKGTN) approved Gene Dossier application.
| S-EPMC3644298 | biostudies-literature
Project description:Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.
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Project description:Takotsubo cardiomyopathy (TC) is increasingly recognized in neurocritical care population especially in postmenopausal females. We are presenting a 61-year-old African American female with past medical history of epilepsy, bipolar disorder, and hypertension who presented with multiple episodes of seizures due to noncompliance with antiepileptic medications. She was on telemetry which showed ST alarm. Electrocardiogram (ECG) was ordered and showed ST elevation in anterolateral leads and troponins were positive. Subsequently Takotsubo cardiomyopathy was diagnosed by left ventriculography findings and absence of angiographic evidence of obstructive coronary artery disease. Echocardiogram showed apical hypokinesia, ejection fraction of 40%, and systolic anterior motion of mitral valve with hyperdynamic left ventricle, in the absence of intracoronary thrombus formation in the angiogram. Electroencephalography showed evidence of generalized tonic-clonic seizure. She was treated with supportive therapy. This case illustrates importance of ECG in all patients with seizure irrespective of cardiac symptoms as TC could be the cause of Sudden Unexpected Death in Epilepsy (SUDEP) and may be underdiagnosed and so undertreated.
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Project description:There is a substantial body of evidence that spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially the familial forms that have an early onset. In transgenic mice that simulate these genetic forms of AD, seizures or reduced seizure threshold have also been reported. Mechanisms underlying the seizures or reduced seizure threshold in these mice are not yet clear and are likely to be complex, because the synthesis of amyloid β (Aβ) involves many peptides and proteases that influence excitability. Based on transgenic mouse models of AD where Aβ and its precursor are elevated, it has been suggested that seizures are caused by the downregulation of the Nav1.1 sodium channel in a subset of GABAergic interneurons, leading to a reduction in GABAergic inhibition. Another mechanism of hyperexcitability appears to involve tau, because deletion of tau reduces seizures in some of the same transgenic mouse models of AD. Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles-especially for the familial forms of AD.
| S-EPMC3482723 | biostudies-other
Project description:Dravet syndrome is considered to be one of the most severe types of genetic epilepsy. Mutations in SCN1A gene have been found to be responsible for at least 80% of patients with Dravet syndrome, and 90% of these mutations arise de novo. The variable clinical phenotype is commonly observed among these patients with SCN1A mutations, suggesting that genetic modifiers may influence the phenotypic expression of Dravet syndrome. In the present study, we described the clinical, pathological, and molecular characteristics of 13 Han Chinese pedigrees clinically diagnosed with Dravet syndrome. By targeted-exome sequencing, bioinformatics analysis and Sanger sequencing verification, 11 variants were identified in SCN1A gene among 11 pedigrees including 7 missense mutations, 2 splice site mutations, and 2 frameshift mutations (9 novel variants and 2 reported mutations). Particularly, 2 of these Dravet syndrome patients with SCN1A variants also harbored SCN9A, KCNQ2, or SLC6A8 variants. In addition, 2 subjects were failed to detect any pathogenic mutations in SCN1A and other epilepsy-related genes. These data suggested that SCN1A variants account for about 84.6% of Dravet syndrome in our cohort. This study expanded the mutational spectrum for the SCN1A gene, and also provided clinical and genetic evidence for the hypothesis that genetic modifiers may contribute to the variable manifestation of Dravet syndrome patients with SCN1A mutations. Thus, targeted-exome sequencing will make it possible to detect the interactions of epilepsy-related genes and reveal their modification on the severity of SCN1A mutation-related Dravet syndrome.
| S-EPMC6320057 | biostudies-literature