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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Genetic Screening of Tuberous Sclerosis Complex in Sicily with a Focus on Neurological Manifestations

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder characterized by widespread hamartomas in multiple organs and significant neurological involvement. TSC caused pathogenic variants TSC1 or TSC2 genes, leading to hyperactivation of the mTOR pathway consequent dysregulation cell growth. These tumor suppressor genes encode hamartin tuberin, proteins critical for regulating proliferation, neuronal excitability synaptogenesis. In this retrospective study, we analyzed clinical, genetic radiological features 81 patients from Sicily, focusing on genotype-phenotype correlations intergroup comparisons. mutations were more common than (61.7% vs. 38.3%). Patients with tended exhibit a higher frequency weekly seizures, prevalence infantile spasms hypsarrhythmia compared those mutations, consistent severe phenotype. Interestingly, exhibited incidence radial bands, while harbored larger average size tubers subependymal nodules. Cognitive behavioral disorders similarly distributed, although had rates normal borderline cognitive function, neuropsychiatric profiles TSC1. Additionally, present four novel potential correlations. To our knowledge, these first comprehensive mutational analysis correlation study carried out large cohort Sicilian affected TSC. Our findings contribute regional global data TSC, emphasizing utility genotype-informed management strategies.

Language: Английский

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Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies

Pediatric Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Behavioral analyses in rodent models of tuberous sclerosis complex

Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 165, P. 110313 - 110313

Published: Feb. 19, 2025

Language: Английский

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Tuberous Sclerosis Complex: An updated in the treatment of epilepsy for early careers

Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 167, P. 110396 - 110396

Published: April 3, 2025

Language: Английский

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