Precision Therapeutics for Monogenic Epilepsies: From Molecular Mechanisms to Disease Modification in Developmental and Epileptic Encephalopathies and Neurodevelopmental Disorders with Epilepsy
- 1Division of Child Neurology, Department of Pediatrics, University of Arkansas for Medical Sciences, 1 Children’s Way, Little Rock, AR 72202, USA
Abstract
Background: Developmental and epileptic encephalopathies (DEEs) and neurodevelopmental disorders with epilepsy (NDD-E) are etiologically heterogeneous conditions historically treated with syndrome-based, symptomatic approaches. Advances in genomic sequencing have identified monogenic causes across more than 900 genes, creating opportunities for mechanism-informed and disease-modifying precision therapies. Methods: For this narrative review, PubMed/MEDLINE and ClinicalTrials.gov were searched through September 2026 using disorder-, gene-, mechanism-, and therapeutic-modality-specific terms to identify mechanism-informed and disease-modifying therapies for monogenic DEEs and NDD-E. Results: Pathogenic mechanisms include gain- or loss-of-function ion-channel abnormalities, altered neurotransmitter receptor/transporter function, impaired synaptic signaling, dysregulated intracellular pathways, metabolic deficiencies, protein misfolding, and transcriptional or epigenetic dysregulation. Across genes such as SCN1A, SCN2A, SCN8A, KCNQ2, KCNT1, KCNA2, CACNA1A, GABA-receptor subunits, SLC6A1, GRIN genes, SYNGAP1, STXBP1, DNM1, SHANK3, TSC1/TSC2, GNAO1, UBE3A, MECP2, and TCF4, therapeutic strategies range from repurposed and mechanism-targeted pharmacologic agents (e.g., sodium- and potassium-channel modulators, mTOR inhibitors) to antisense oligonucleotides, RNA interference, gene replacement or augmentation, transcriptional activation, and genome editing. Several programs have advanced from preclinical proof of concept into early- and late-phase human trials, with variant-specific functional classification increasingly guiding therapy selection, particularly distinguishing gain-of-function from loss-of-function disease. Conclusions: Precision therapeutics are shifting the treatment paradigm for monogenic DEEs and NDD-E from empiric seizure control toward mechanism-based targeting of dysregulated molecular pathways and gene-based disease-modifying therapies. Realizing this potential will require functional variant classification, delivery technologies capable of durable and cell-appropriate target engagement, and trial designs incorporating developmental and biomarker outcomes beyond seizure frequency alone to demonstrate genuine disease modification.
Related
- Caregiver perceptions of telemedicine in developmental and epileptic encephalopathies: a nationwide Spanish survey
- Genetic developmental and epileptic encephalopathies in adulthood: Gaps in evidence and care.
- Beyond seizures: the hidden burden of developmental epileptic encephalopathies
- Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies
- Functional characterization and pharmacochaperone rescue of a novel SLC6A1 variant associated with developmental epileptic encephalopathies
BibTeX
@article{samanta2026precision,
title = {{Precision Therapeutics for Monogenic Epilepsies: From Molecular Mechanisms to Disease Modification in Developmental and Epileptic Encephalopathies and Neurodevelopmental Disorders with Epilepsy}},
author = {Debopam Samanta},
journal = {Journal of Clinical Medicine},
year = {2026},
month = oct,
doi = {10.3390/jcm15207886},
url = {https://www.mdpi.com/2077-0383/15/20/7886},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Precision Therapeutics for Monogenic Epilepsies: From Molecular Mechanisms to Disease Modification in Developmental and Epileptic Encephalopathies and Neurodevelopmental Disorders with Epilepsy
AU - Debopam Samanta
PY - 2026
DA - 2026/10/13
JO - Journal of Clinical Medicine
DO - 10.3390/jcm15207886
UR - https://www.mdpi.com/2077-0383/15/20/7886
AB - Background: Developmental and epileptic encephalopathies (DEEs) and neurodevelopmental disorders with epilepsy (NDD-E) are etiologically heterogeneous conditions historically treated with syndrome-based, symptomatic approaches. Advances in genomic sequencing have identified monogenic causes across more than 900 genes, creating opportunities for mechanism-informed and disease-modifying precision therapies. Methods: For this narrative review, PubMed/MEDLINE and ClinicalTrials.gov were searched through September 2026 using disorder-, gene-, mechanism-, and therapeutic-modality-specific terms to identify mechanism-informed and disease-modifying therapies for monogenic DEEs and NDD-E. Results: Pathogenic mechanisms include gain- or loss-of-function ion-channel abnormalities, altered neurotransmitter receptor/transporter function, impaired synaptic signaling, dysregulated intracellular pathways, metabolic deficiencies, protein misfolding, and transcriptional or epigenetic dysregulation. Across genes such as SCN1A, SCN2A, SCN8A, KCNQ2, KCNT1, KCNA2, CACNA1A, GABA-receptor subunits, SLC6A1, GRIN genes, SYNGAP1, STXBP1, DNM1, SHANK3, TSC1/TSC2, GNAO1, UBE3A, MECP2, and TCF4, therapeutic strategies range from repurposed and mechanism-targeted pharmacologic agents (e.g., sodium- and potassium-channel modulators, mTOR inhibitors) to antisense oligonucleotides, RNA interference, gene replacement or augmentation, transcriptional activation, and genome editing. Several programs have advanced from preclinical proof of concept into early- and late-phase human trials, with variant-specific functional classification increasingly guiding therapy selection, particularly distinguishing gain-of-function from loss-of-function disease. Conclusions: Precision therapeutics are shifting the treatment paradigm for monogenic DEEs and NDD-E from empiric seizure control toward mechanism-based targeting of dysregulated molecular pathways and gene-based disease-modifying therapies. Realizing this potential will require functional variant classification, delivery technologies capable of durable and cell-appropriate target engagement, and trial designs incorporating developmental and biomarker outcomes beyond seizure frequency alone to demonstrate genuine disease modification.
SN - 2077-0383
ER -