Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

Children, Journal Year: 2025, Volume and Issue: 12(4), P. 481 - 481

Published: April 8, 2025

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, neuromodulation, but often fail to address the underlying pathophysiology or improve outcomes. As genetic causes are identified in 30-40% of LGS cases, precision therapeutics targeting specific molecular mechanisms emerging as promising disease-modifying approaches. This narrative review explores therapeutic strategies for based pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, targeted pharmacotherapy, antisense oligonucleotides, gene repurposing existing with mechanism-specific effects. Early intervention may not only control could also potentially prevent progression susceptible populations. Future directions developing computable phenotypes accurate diagnosis, refining subgrouping, enhancing drug development, advancing gene-based therapies, personalizing implementing adaptive clinical trial designs, ensuring equitable access While significant challenges remain, integrating biological insights innovative offers new hope transforming treatment from symptomatic disease modification.

Language: Английский

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Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(23)

Published: May 29, 2024

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities convulsive in patients mouse models Dravet syndrome (DS), a developmental epileptic encephalopathy which hypoexcitability GABAergic neurons considered be the main dysfunction. analyzed EEGs from DS carrying SCN1A pathogenic variant, as well epidural electrocorticograms, hippocampal local field potentials, single-unit neuronal Scn1a +/− RH/+ mice. Strikingly, most had low-voltage-fast onset both mice, thought generated by hyperactivity interneurons, opposite mechanism DS. Analyzing recordings, we observed that temporal disorganization firing putative interneurons period immediately before seizure (preictal) precedes increase their activity at onset, together with entire network. Moreover, found early signatures preictal spectral features cortical potential mice patients’ EEG, are consistent dysfunctions single allowed prediction. Therefore, perturbed leads generalized seizures, similar those other epilepsies triggered neurons. Preictal may used predictive biomarkers.

Language: Английский

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Voltage‐gated sodium channels in genetic epilepsy: up and down of excitability

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 168(12), P. 3872 - 3890

Published: Aug. 31, 2023

Abstract The past two decades have witnessed a wide range of studies investigating genetic variants voltage‐gated sodium (Na V ) channels, which are involved in broad spectrum diseases, including several types epilepsy. We reviewed here phenotypes and pathological mechanisms epilepsies caused by Na α β subunits, as well some relevant interacting proteins ( FGF12/FHF1 , PRRT2, Ankyrin‐G). Notably, all these genes can induce either gain‐ or loss‐of‐function leading to neuronal hyperexcitability hypoexcitability. present the results functional obtained with different experimental models, highlighting that they should be interpreted considering features system used. These systems but allowed us better understand pathophysiological issues, ameliorate diagnostics, orientate counseling, select/develop therapies within precision medicine framework. also gain insights into physiological roles channels cells express them. Overall, our review shows progress has been made, need for further on aspects not yet clarified. Finally, we conclude significant themes general interest gleaned from work last decades. image

Language: Английский

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Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy

Human Molecular Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Abstract While de novo missense variants in the BTB domains of atypical RhoGTPase RHOBTB2 cause a severe developmental and epileptic encephalopathy, GTPase domain or bi-allelic truncating are associated with more variable neurodevelopmental seizure phenotypes. Apart from observation abundance resulting BTB-domain increased susceptibility Drosophila overexpressing RhoBTB, our knowledge on RHOBTB2-related pathomechanisms is limited. We now found enrichment for ion channels among differentially expressed genes RNA-Seq fly heads RhoBTB. Subsequent genetic interaction experiments confirmed functional link between RhoBTB paralytic, orthologue human sodium channels, including epilepsy SCN1A, vivo. then performed patch-clamp recordings mature neurons differentiated induced pluripotent stem cells either homozygous frameshifts patient-specific heterozygous domains. This revealed significantly altered neuronal activity excitability but not upon complete loss RHOBTB2. Our study indicates role deregulated pathogenesis encephalopathy points to specific underlying observed genotype–phenotype correlations regarding variant zygosity, location nature.

Language: Английский

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Aperiodic activity indexes neural hyperexcitability in generalized epilepsy

eNeuro, Journal Year: 2024, Volume and Issue: unknown, P. ENEURO.0242 - 24.2024

Published: Aug. 13, 2024

Generalized epilepsy (GE) encompasses a heterogenous group of hyperexcitability disorders that clinically manifest as seizures. At the whole-brain level, distinct seizure patterns well interictal epileptic discharges (IEDs) reflect key signatures in magneto- and electroencephalographic (M/EEG) recordings. Moreover, it had been suggested aperiodic activity, specifically slope 1/ƒ x decay function power spectrum, might index neural excitability. However, remained unclear if encountered at cellular level directly translates to putative large-scale excitability signatures, amenable M/EEG. In order test whether spectrum is altered hyperexcitable states, we recorded resting state MEG from male female GE patients (n = 51; 29 females; 28.82 ± 12.18 years; mean SD) age-matched healthy controls 49; 22 32.10 12.09 years). We parametrized spectra using FOOOF separate oscillatory activity systematically patients. further identified IEDs quantify temporal dynamics around overt activity. The results demonstrate indexes especially during epochs when no were present (p 0.0130, d 0.52). Upon IEDs, circuits transiently shifted less excitable network 0.001, 0.68). sum, these uncover background based on current brain does not rely presence waveforms. Significance Statement It long suspected electric disorders, such epilepsy. To date, how pathologic can be quantified. Kopf et al. hyperexcitability, absent; hence, providing novel non-invasively biomarker possibly reflects

Language: Английский

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Preface: Special issue: “Ion channels and genetic epilepsy”

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 168(12), P. 3829 - 3830

Published: May 9, 2024

This preface introduces the Journal of Neurochemistry Special Issue on Advances in Epilepsy Research. is a devastating disease characterized by recurrent seizures. Despite addition numerous therapeutics over last few decades epilepsy patients resistant to standard care treatments remains stubbornly high. highlights clear unmet clinical need and importance new research into this disease. One major advance two has been recognition that genetic factors play significant role underlying pathogenesis epilepsy. Much our insights pathogenic mechanisms come from genes encode ion channels. In issue, there are up-to-date reviews discussing caused variation HCN channels, voltage-dependent sodium calcium GABA

Language: Английский

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Voltage-gated ion channels in epilepsies: circuit dysfunctions and treatments

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(11), P. 1018 - 1032

Published: Oct. 14, 2024

Language: Английский

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GABAergic neurons can facilitate the propagation of cortical spreading depolarization: experiments in mouse neocortical slices and a novel neural field computational model

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 24, 2024

Abstract Cortical spreading depolarization (CSD) is a wave of with local onset and extended propagation implicated in several pathological conditions. Its mechanisms have been extensively investigated, including our recent studies showing experimental computational approaches that the hyperactivity GABAergic neurons can initiate migraine-related CSD because spiking-generated extracellular potassium (K + ) build-up. However, less known about role played by propagation. Here we studied propagation, focusing on neurons, experiments performed mouse brain slices new spatially neural field model. Experimentally, induced applying brief puffs chloride (KCl) somatosensory cortex from wild type VGAT-ChR2-tdtomato mice, which specifically express excitatory opsin channelrhodopsin (ChR2) neurons. We evaluated modulating their activity optogenetic illumination synaptic connections pharmacological tools. developed model to obtain realistic simulations both initiation CSD. It includes large populations interconnected inhibitory as well effect ion concentrations features. found decrease enhance reduction weight, whereas spiking K upload. differently for initiation, latter normally hidden action transmission. A transmission, be observed states, reveal potentiating upload activation. The implemented generate accurate CSD, providing testable hypotheses mechanisms, also used modeling other (patho)-physiological activities neuronal networks.

Language: Английский

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Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to Low-Voltage-Fast onset seizures in Dravet syndrome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 22, 2023

Abstract Epilepsies have numerous specific mechanisms. Understanding neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing targeted therapeutic approaches. We investigated electrographic activities convulsive in patients mouse models of Dravet syndrome (DS), a developmental epileptic encephalopathy which hypoexcitability GABAergic neurons considered be the main dysfunction. analyzed EEGs from DS carrying SCN1A pathogenic variant, as well epidural electrocorticograms, hippocampal local field potentials single-unit neuronal Scn1a +/- knock-out RH/+ knock-in mice. Strikingly, most had low-voltage-fast onset both mice, thought generated by hyperactivity interneurons, opposite mechanism DS. Analyzing single unit recordings, we observed that temporal disorganization firing putative interneurons period immediately before seizure (preictal period) precedes increase their activity at onset, together with entire network. Moreover, found early signatures preictal spectral features cortical potential mice patients’ EEG, are consistent dysfunctions neurons. Therefore, perturbed leads generalized seizures, similar those other epilepsies triggered Spectral may used predictive biomarker. Significance statement (DS) caused mutations Na V 1.1 sodium channel ( gene) interneurons. instead disclosed pattern period), rebound onset. Consistently, signal showed decrease fast oscillations period. Thus, interneurons’ activity, DS, induces exploited prediction.

Language: Английский

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Editorial: Epilepsy syndromes: pathophysiology and managements

Frontiers in Neurology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 13, 2023

EDITORIAL article Front. Neurol., 13 November 2023Sec. Epilepsy Volume 14 - 2023 | https://doi.org/10.3389/fneur.2023.1325553

Language: Английский

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