scholarly journals Somatostatin-positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy

2021 ◽  
Author(s):  
Eric R. Wengert ◽  
Kyle C.A. Wedgwood ◽  
Pravin K. Wagley ◽  
Samantha M. Strohm ◽  
Payal S. Panchal ◽  
...  
Keyword(s):  
Audiogenic Seizures ◽  
Epileptic Encephalopathy ◽  
Epilepsy Syndrome ◽  
Inhibitory Interneurons ◽  
Wild Type ◽  
Depolarization Block ◽  
Voltage Gated ◽  
Selective Expression ◽  
Electrographic Seizures ◽  
Potential Failure

AbstractSCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. We found that selective expression of the R1872W mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of wild-type SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A encephalopathy, but epilepsy in general.

Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage‐gated sodium channel function

Epilepsia ◽  
2021 ◽  
Author(s):  
Marcello Scala ◽  
Stephanie Efthymiou ◽  
Tipu Sultan ◽  
Jolien De Waele ◽  
Marta Panciroli ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epileptic Encephalopathy ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Channel Function

scholarly journals Engineering Gain-of-Function Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNaV1.7 Sodium Channel

Toxins ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 358 ◽  
Author(s):  
Yunxiao Zhang ◽  
Qiuchu Yang ◽  
Qingfeng Zhang ◽  
Dezheng Peng ◽  
Minzhi Chen ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Medical Condition ◽  
Human Life ◽  
Hydrophobic Surface ◽  
Well Being ◽  
Charged Surface ◽  
Multiple Site ◽  
Wild Type ◽  
Voltage Gated ◽  
Normal Human

Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. The voltage-gated sodium channel (VGSC) human NaV1.7 (hNaV1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of NaV-targeting spider toxin (NaSpTx) family 1, has shown negligible activity on mammalian VGSCs, including the hNaV1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNaV1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated an analogue E1G–N23S–D26H–L32W with >300-fold improved potency compared with wild-type HNTX-1 on hNaV1.7 (IC50 0.036 ± 0.007 µM). Structural simulation suggested that the charged surface and the hydrophobic surface of the modified peptide are responsible for binding affinity to the hNaV1.7 channel, while variable residues may determine pharmacological specificity. Therefore, this study provides a profile for drug design targeting the hNaV1.7 channel.

Identification of the target of gabapentinoid action in neuropathic pain

2018 ◽  
Author(s):  
Turo J. Nurmikko
Keyword(s):  
Neuropathic Pain ◽  
Scientific Community ◽  
Oral Absorption ◽  
Molecular Target ◽  
Wild Type ◽  
Seminal Paper ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

The landmark paper discussed in this chapter is ‘Identification of the α‎2-δ‎-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin’, published by Field et al. in 2006. In this seminal paper, Field et al. demonstrated that the anti-allodynic effect of pregabalin is related to its binding to the α‎2δ‎-1 subunit of the voltage-gated calcium channel. In transgenic mice lacking this subunit, pregabalin had no effect on allodynia induced by sciatic nerve ligation, whereas, in wild-type mice, there was a substantial anti-allodynic response. This discovery was well received by the scientific community and was considered to conclusively establish the mechanism of action of pregabalin, which has remarkably similar properties to gabapentin but with increased potency and oral absorption. This exciting result acted as an impetus for further studies on the role of the subunit in the development and maintenance of neuropathic pain.

scholarly journals Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

2019 ◽  
Vol 57 (2) ◽  
pp. 132-137 ◽  
Author(s):  
Edgard Verdura ◽  
Carme Fons ◽  
Agatha Schlüter ◽  
Montserrat Ruiz ◽  
Stéphane Fourcade ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dominant Mode ◽  
Wild Type ◽  
Adequate Treatment ◽  
Cellular Assays ◽  
Disease Spectrum ◽  
Whole Exome ◽  
Pore Domain ◽  
Mode Of Inheritance

BackgroundSince 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.MethodsA patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.ResultsWES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.ConclusionThis newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Extinguishing Febrile Infection-Related Epilepsy Syndrome: Pipe Dream or Reality?

2020 ◽  
Vol 40 (02) ◽  
pp. 263-272 ◽  
Author(s):  
Eric T. Payne ◽  
Sookyong Koh ◽  
Elaine C. Wirrell
Keyword(s):  
Interleukin 1 ◽  
Treatment Strategies ◽  
Febrile Illness ◽  
Epileptic Encephalopathy ◽  
Epilepsy Syndrome ◽  
Collaborative Studies ◽  
High Incidence ◽  
Neurocognitive Outcomes ◽  
Children And Young Adults ◽  
Pipe Dream

AbstractFebrile infection-related epilepsy syndrome (FIRES) is a rare and devastating epileptic encephalopathy with historically abysmal neurocognitive outcomes, including a high incidence of mortality. It tends to affect children and young adults and is characterized by superrefractory status epilepticus following a recent febrile illness. Growing evidence suggests a heterogeneous etiology resulting in fulminant nonantibody-mediated neuroinflammation. For some children with FIRES, this aberrant neuroinflammation appears secondary to a functional deficiency in the endogenous interleukin-1 receptor antagonist. A precise etiology has not been identified in all FIRES patients, and current treatments are not always successful. Limited treatment evidence exists to guide choice, dosing, and duration of therapies. However, the ketogenic diet and certain targeted immunomodulatory treatments, including anakinra, appear safe and have been associated with relatively excellent clinical outcomes in some FIRES patients. Future prospective multicenter collaborative studies are needed to further delineate the FIRES heterogeneous disease pathophysiology and to determine the safety and efficacy of treatment strategies through a robust measurement of neurocognitive outcomes.

scholarly journals Corticosteroids versus clobazam in epileptic encephalopathy with ESES: a European multicentre randomised controlled clinical trial (RESCUE ESES*)

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Bart van den Munckhof ◽  
◽  
Alexis Arzimanoglou ◽  
Emilio Perucca ◽  
Heleen C. van Teeseling ◽  
...  
Keyword(s):  
Cognitive Functioning ◽  
Treatment Response ◽  
Controlled Trial ◽  
Epileptic Encephalopathy ◽  
Cognitive Outcome ◽  
Controlled Study ◽  
Controlled Clinical Trial ◽  
Epilepsy Syndrome ◽  
Eeg Abnormalities ◽  
Randomised Controlled

Abstract Background Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is an epilepsy syndrome occurring almost exclusively in children, usually at an age between 4 and 12 years. It is characterised by abundant sleep-induced epileptic activity in the electroencephalogram (EEG) and by acquired cognitive and behavioural deficits. The goal of treatment is to prevent further decline or even improve cognitive functioning. Based on mostly small and retrospective studies, corticosteroids and clobazam are regarded by many clinicians as the most effective pharmacological treatments. This European multicentre randomised controlled trial is designed to compare the effects of corticosteroids and clobazam on cognitive functioning after 6 months. Secondary outcomes include cognitive functioning after 18 months, EEG abnormalities in sleep, safety and tolerability, and seizure frequency. We also aimed at investigating whether treatment response in epileptic encephalopathy with ESES can be predicted by measurement of inflammatory mediators and autoantibodies in serum. Methods The pragmatic study will be performed in centres with expertise in the treatment of rare paediatric epilepsy syndromes across Europe. A total of 130 patients, 2 to 12 years of age, with epileptic encephalopathy with ESES will be enrolled and randomised in a 1:1 ratio to receive either corticosteroids (monthly intravenous methylprednisolone pulses or daily oral prednisolone) or oral clobazam for 6 months according to an open-label parallel-group design. Follow-up visits with clinical assessment, EEGs, and neuropsychological testing are scheduled for up to 18 months. Blood samples for cytokine and autoantibody testing are obtained before treatment and 8 months after treatment initiation. Discussion The treatment of epileptic encephalopathy with ESES aims at improving cognitive outcome. This randomised controlled study will compare the most frequently used treatments, i.e. corticosteroids and clobazam. If the study proves superiority of one treatment over the other or identifies biomarkers of treatment response, results will guide clinicians in the early treatment of this severe epilepsy syndrome. Trial registration ISRCTN, ISRCTN42686094. Registered on 24 May 2013.

Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy

2013 ◽  
Vol 50 (2) ◽  
pp. 118-123 ◽  
Author(s):  
Simon Edvardson ◽  
Shimrit Oz ◽  
Fida Aziz Abulhijaa ◽  
Flora Barghouthi Taher ◽  
Avraham Shaag ◽  
...  
Keyword(s):  
High Voltage ◽  
Epileptic Encephalopathy ◽  
Voltage Gated ◽  
Calcium Channelopathy

Epileptic encephalopathy after HHV6 post-transplant acute limbic encephalitis in children: Confirmation of a new epilepsy syndrome

2013 ◽  
Vol 105 (3) ◽  
pp. 419-422 ◽  
Author(s):  
Miquel Raspall-Chaure ◽  
Thaís Armangué ◽  
Izaskun Elorza ◽  
Àngel Sanchez-Montanez ◽  
Mònica Vicente-Rasoamalala ◽  
...  
Keyword(s):  
Limbic Encephalitis ◽  
Epileptic Encephalopathy ◽  
Epilepsy Syndrome ◽  
Post Transplant

Sequence of the voltage-gated sodium channel β1-subunit in wild-type and in quivering mice

1996 ◽  
Vol 42 (2) ◽  
pp. 222-226 ◽  
Author(s):  
Christie L.S. Grosson ◽  
Stephen C. Cannon ◽  
David P. Corey ◽  
James F. Gusella
Keyword(s):  
Sodium Channel ◽  
Wild Type ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

scholarly journals Proteolytic maturation of α2δ controls the probability of synaptic vesicular release

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Laurent Ferron ◽  
Ivan Kadurin ◽  
Annette C Dolphin
Keyword(s):  
Calcium Channels ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Voltage Gated ◽  
Synaptic Release ◽  
Voltage Gated Calcium Channels ◽  
Vesicular Release ◽  
Active Zones ◽  
Asynchronous Release

Auxiliary α2δ subunits are important proteins for trafficking of voltage-gated calcium channels (CaV) at the active zones of synapses. We have previously shown that the post-translational proteolytic cleavage of α2δ is essential for their modulatory effects on the trafficking of N-type (CaV2.2) calcium channels (Kadurin et al., 2016). We extend these results here by showing that the probability of presynaptic vesicular release is reduced when an uncleaved α2δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α2δ is restored. We also show that asynchronous release is influenced by the maturation of α2δ−1, highlighting the role of CaV channels in this component of vesicular release. We present additional evidence that CaV2.2 co-immunoprecipitates preferentially with cleaved wild-type α2δ. Our data indicate that the proteolytic maturation increases the association of α2δ−1 with CaV channel complex and is essential for its function on synaptic release.

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