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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Hypotheses of pathophysiological mechanisms in epileptic encephalopathies: A review

Brain and Development, Journal Year: 2025, Volume and Issue: 47(1), P. 104318 - 104318

Published: Jan. 8, 2025

Language: Английский

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Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention

Progress in Neurobiology, Journal Year: 2025, Volume and Issue: 249, P. 102770 - 102770

Published: April 19, 2025

Language: Английский

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Regulatory Mechanism of CRTC1 on Autophagy and GluA2 Expression in Epilepsy

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: May 10, 2025

The objective of this study was to elucidate the molecular mechanisms by which cAMP-regulated transcription coactivator1 (CRTC1) regulates autophagy and GluA2 expression in patients with epilepsy. We initially established a magnesium-free epilepsy cell model recorded cellular discharges using whole-cell patch clamp technique. Next, we experimentally activated identified effective methods for silencing CRTC1 gene RNA interference technology. Furthermore, developed an animal models status epilepticus employed immunofluorescence Western Blot CRTC1's role regulating autophagy-related genes observed mouse hippocampal neurons under extracellular conditions. Treatment activator decreased expression; however, not dephosphorylated. siRNA suppressed LC3 PSD95 expression, whereas intervention restored expression. indirectly influences synaptic-related proteins directly modulating during pathological process findings reveal novel targets treatment

Language: Английский

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Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Aug. 14, 2024

Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the changes in brain activity at each time point remain unclear, as does potential molecular mechanisms temporal characteristics of TLE. Resting-state magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data then used to conduct HMM analysis on rs-fMRI from an HC group order explore intricate dynamics cognitive impairment (TLE-CI). Additionally, we aim examine gene expression profiles modular using Allen Human Brain Atlas (AHBA) database. Five states were identified this study. Compared HCs, TLE-CI exhibited distinct dynamics, including fractional occupancy, lifetimes, mean dwell switch rate. Furthermore, transition probability across significantly different between (p < 0.05). reconfiguration several networks (including high-order default mode network (DMN), subcortical (SCN), cerebellum (CN). a total 1580 genes revealed be TLE, mainly enriched neuronal signaling synaptic function. This study provides new insights into characterizing neural defined by may deepen our understanding neurobiological underpinnings TLE-CI, indicating linkage configuration

Language: Английский

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Molecular Mechanisms Underlying the Generation of Absence Seizures: Identification of Potential Targets for Therapeutic Intervention

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 9821 - 9821

Published: Sept. 11, 2024

Understanding the molecular mechanisms underlying generation of absence seizures is crucial for developing effective, patient-specific treatments childhood epilepsy (CAE). Currently, one-third patients remain refractive to antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining precise cellular directly responsible causing this type has proven challenging as they appear be complex multifactorial with different genetic backgrounds. Aberrant neuronal activity CAE may caused by several that are not fully understood. Thus, dissecting causal factors could targeted development precision medicines without remains a high priority ultimate goal field research. The aim review highlight our current understanding potential causative seizure generation, based on latest research using cutting-edge technologies. This information will important identifying targets future therapeutic intervention.

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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H- and m-channel overexpression promotes seizure-like events by impairing the ability of inhibitory neurons to process correlated inputs

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

Published: Nov. 25, 2024

Abstract Channelopathies affecting h- and m-channels present a paradox in epilepsy research: while both over- underexpression of these channels can be epileptogenic, channel overexpression does not appear to increase the excitatory-inhibitory (E-I) balance as caused by underexpression. We here derive viable mechanism for ictogenesis driven m-channel from analysis an silico spiking neuronal microcircuit exhibiting spontaneous seizure-like events (SLEs). Such SLEs are dependent upon sufficiently strong gain two adaptation terms phenomenologically modeling channels’ effects: voltage homeostasis (h-current) spike-frequency (m-current). Excessive interferes with circuit’s processing highly correlated input, promoting sequence network-level that collectively provoke SLE. Importantly, changes do cause increased excitability isolated neurons, nor this cascade require change amplitude external input circuit, suggesting ictogenic pathway independent classical E-I balance. The viability SLE onset is strengthened host experimentally-characterized features seizure produced model reliant presence terms, including irregular initiation termination time-varying peak frequency oscillations during such (i.e., chirps). Moreover, cell-type effects delineated our analyses, represent experimentally-testable predictions future study m-channelopathies. These computational results provide vital new insights into epileptogenic nature currently absent experimental literature.

Language: Английский

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Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Backgroud Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the changes in brain activity at each time point remain unclear, as does potential molecular mechanisms temporal characteristics of TLE. Methods Resting-state magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data then used to conduct HMM analysis on rs-fMRI from an HC group order explore intricate dynamics cognitive impairment (TLE-CI). Additionally, we aim examine gene expression profiles modular using Allen Human Brain Atlas (AHBA) database. Results Five states were identified this study. Compared HCs, TLE-CI exhibited distinct dynamics, including fractional occupancy, lifetimes, mean dwell switch rate. Furthermore, transition probability across significantly different between (p < 0.05). reconfiguration several networks (including high-order default mode network (DMN), subcortical (SCN), cerebellum (CN). a total 1580 genes revealed be TLE, mainly enriched neuronal signaling synaptic function. Conclusions This study provides new insights into characterizing neural defined by may deepen our understanding neurobiological underpinnings TLE-CI, indicating linkage configuration

Language: Английский

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