scholarly journals Dravet syndrome associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors

2021 ◽  
Author(s):  
Ciria C Hernandez ◽  
XiaoJuan Tian ◽  
Ningning Hu ◽  
Wangzhen Shen ◽  
Mackenzie A Catron ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
First Year ◽  
Genes Encoding ◽  
Genetic Landscape ◽  
Clonic Seizures ◽  
Trafficking Defects ◽  
First Year Of Life

Abstract Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p.L215P; c.640C>T, p.R214C; c.859G>A; V287I; c.641G>A, p.R214H) and GABRG2 (c.269C>G, p.T90R; c.1025C>T, p.P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p.F331S; c.542A>T, p.Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p.T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.

scholarly journals Dravet Syndrome: Diagnosis and Long-Term Course

2016 ◽  
Vol 43 (S3) ◽  
pp. S3-S8 ◽  
Author(s):  
Mary B. Connolly
Keyword(s):  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
First Year ◽  
High Morbidity ◽  
Pathophysiological Mechanism ◽  
Neuronal Excitation ◽  
Clonic Seizures ◽  
First Year Of Life ◽  
Severe Epilepsy

AbstractDravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The “interneuron hypothesis” is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson’s symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.

scholarly journals Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death

2018 ◽  
Vol 115 (34) ◽  
pp. E8077-E8085 ◽  
Author(s):  
Kay L. Richards ◽  
Carol J. Milligan ◽  
Robert J. Richardson ◽  
Nikola Jancovski ◽  
Morten Grunnet ◽  
...  
Keyword(s):  
Disease Onset ◽  
Intractable Epilepsy ◽  
Premature Death ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
First Year ◽  
Inhibitory Interneurons ◽  
Loss Of Function ◽  
Intracerebroventricular Infusion ◽  
First Year Of Life

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.

scholarly journals Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

2022 ◽  
Vol 12 (1) ◽  
pp. 106-116
Author(s):  
Martyna Stefaniak ◽  
Zofia Pietrzak ◽  
Piotr Dzikowski ◽  
Emilia Nowicka ◽  
Michał Obel ◽  
...  
Keyword(s):  
Oral Solution ◽  
Dravet Syndrome ◽  
First Year ◽  
Efficacy And Safety ◽  
Anti Epileptic Drug ◽  
Drug Regimens ◽  
Pulmonary Arterial ◽  
First Year Of Life ◽  
Patients Experience ◽  
Oral Doses

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life

2011 ◽  
Vol 53 (4) ◽  
pp. 354-360 ◽  
Author(s):  
FEDERICO MELANI ◽  
DAVIDE MEI ◽  
TIZIANA PISANO ◽  
SALVATORE SAVASTA ◽  
EMILIO FRANZONI ◽  
...  
Keyword(s):  
Epileptic Encephalopathy ◽  
First Year ◽  
First Year Of Life

Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients

2020 ◽  
Vol 111 ◽  
pp. 107322 ◽  
Author(s):  
Matias Juanes ◽  
Gabriel Veneruzzo ◽  
Mariana Loos ◽  
Gabriela Reyes ◽  
Hilda Veronica Araoz ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Epileptic Encephalopathy ◽  
Gene Panel ◽  
First Year ◽  
First Year Of Life

scholarly journals Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jennifer C. Wong ◽  
Kameryn M. Butler ◽  
Lindsey Shapiro ◽  
Jacquelyn T. Thelin ◽  
Kari A. Mattison ◽  
...  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Seizure Susceptibility ◽  
Pore Region ◽  
Behavioral Abnormalities ◽  
Spontaneous Seizures ◽  
Genetic Landscape ◽  
Mouse Lines

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.

scholarly journals Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2039-2057 ◽  
Author(s):  
Ariadna Amador ◽  
Christopher D Bostick ◽  
Heather Olson ◽  
Jurrian Peters ◽  
Chad R Camp ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Neurodevelopmental Disorders ◽  
Time Course ◽  
De Novo ◽  
Hippocampal Slices ◽  
Epileptic Encephalopathy ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Limbic Seizures ◽  
Clonic Seizures

Abstract NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.

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