RARE DISEASE
SYNGAP1-related developmental and epileptic encephalopathy
SYNGAP1-related developmental and epileptic encephalopathy
SYNGAP1-related developmental and epileptic encephalopathy
Synonyms: SYNGAP1-related DEE
Synonyms: SYNGAP1-related DEE
Synonyms: SYNGAP1-related DEE
Drug discovery
2
drugs
With orphan designations
Overview
SYNGAP1-related developmental and epileptic encephalopathy (SYNGAP1-DEE) is a rare genetic disorder caused by pathogenic variants in the SYNGAP1 gene, leading to synaptic dysfunction. Key features include early-onset developmental delay, generalized epilepsy (often with eyelid myoclonia and myoclonic-atonic seizures), intellectual disability, autism spectrum disorder, and behavioral challenges. Most cases result from de novo mutations. Management involves antiseizure medications, ketogenic diet, and multidisciplinary therapies, but approximately 50% of patients have drug-resistant epilepsy [1][3][9].
Therapies
Antiseizure medications (e.g., valproate, lamotrigine, ethosuximide) and ketogenic diet for epilepsy [10][16].
Multidisciplinary support: physical, occupational, and speech therapies; behavioral interventions for ASD [2][3].
Emerging gene therapies targeting SYNGAP1 haploinsufficiency are in preclinical trials [6][14].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
18 drug discovery papers about SYNGAP1-related developmental and epileptic encephalopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
18 drug discovery papers about SYNGAP1-related developmental and epileptic encephalopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-02 | Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies.
Developmental and epileptic encephalopathies (DEEs) are severe neurological disorders characterized by childhood-onset seizures and significant developmental impairments. Seizures are often refractory to treatment with traditional antiseizure medications, which fail to address the underlying genetic and molecular mechanisms. This comprehensive review explores the evolving landscape of precision therapeutics for DEEs, focusing on mechanism-driven interventions across key pathophysiologic categories. Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies. For synaptic dysfunctions, innovative treatments such as chemical chaperones for STXBP1-related disorders and Ras-Raf-MEK-ERK inhibitors for SYNGAP1 pathologies are discussed. The review also examines precision interventions targeting cellular signaling pathways in tuberous sclerosis complex, epigenetic regulation in Rett syndrome, and metabolic interventions like ketogenic diets and targeted supplementation for specific genetic etiologies. Additionally, the importance of enhancing access to genetic testing, conducting robust natural history studies, and employing innovative clinical trial designs is emphasized. Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care.
2024-01-15 | Cannabinerol (CBNR) Influences Synaptic Genes Associated with Cytoskeleton and Ion Channels in NSC-34 Cell Line: A Transcriptomic Study
Cannabinoids are receiving great attention as a novel approach in the treatment of cognitive and motor disabilities, which characterize neurological disorders. To date, over 100 phytocannabinoids have been extracted from Cannabis sativa, and some of them have shown neuroprotective properties and the capacity to influence synaptic transmission. In this study, we investigated the effects of a less-known phytocannabinoid, cannabinerol (CBNR), on neuronal physiology. Using the NSC-34 motor-neuron-like cell line and next-generation sequencing analysis, we discovered that CBNR influences synaptic genes associated with synapse organization and specialization, including genes related to the cytoskeleton and ion channels. Specifically, the calcium, sodium, and potassium channel subunits (Cacna1b, Cacna1c, Cacnb1, Grin1, Scn8a, Kcnc1, Kcnj9) were upregulated, along with genes related to NMDAR (Agap3, Syngap1) and calcium (Cabp1, Camkv) signaling. Moreover, cytoskeletal and cytoskeleton-associated genes (Actn2, Ina, Trio, Marcks, Bsn, Rtn4, Dgkz, Htt) were also regulated by CBNR. These findings highlight the important role played by CBNR in the regulation of synaptogenesis and synaptic transmission, suggesting the need for further studies to evaluate the neuroprotective role of CBNR in the treatment of synaptic dysfunctions that characterize motor disabilities in many neurological disorders.
2023-08-17 | Case report: Off-label use of low-dose perampanel in a 25-month-old girl with a pathogenic SYNGAP1 variant
Introduction Preclinical studies in a mouse model have shown that SYNGAP1 haploinsufficiency results in an epilepsy phenotype with excessive GluA2-AMPA insertion specifically on the soma of fast-spiking parvalbumin-positive interneurons associated with significant dysfunction of cortical gamma homeostasis that was rescued by perampanel (PER), an AMPA receptor blocker. In this single case, we aimed to investigate the presence of dysregulated cortical gamma in a toddler with a pathogenic SYNGAP1 variant and report on the effect of low-dose PER on electroencephalogram (EEG) and clinical profile. Methods Clinical data from physician's clinic notes; genetic testing reports; developmental scores from occupational therapy, physical therapy, speech and language therapy evaluations; and applied behavioral analysis reports were reviewed. Developmental assessments and EEG analysis were done pre- and post-PER. Results Clinically, the patient showed improvements in the developmental profile and sleep quality post-PER. EEG spectral power analysis in our patient revealed a loss of gamma power modulation with behavioral-state transitions similar to what was observed in Syngap1 +/− mice. Furthermore, the administration of low-dose PER rescued the dysfunctional cortical gamma homeostasis, similar to the preclinical study. However, as in the epileptic mice, PER did not curb epileptiform discharges or clinical seizures. Conclusion Similar to the Syngap1 +/− mice, cortical gamma homeostasis was dysregulated in the patient. This dysfunction was rescued by PER. These encouraging results necessitate further validation of gamma dysregulation as a potential translational EEG biomarker in SYNAP1-DEE. Low-dose PER can be explored as a therapeutic option through clinical trials.
2023-02-03 | Perampanel as precision therapy in rare genetic epilepsies
Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity.Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.
2020-11-15 | GABAergic signaling promotes early-life seizures in epileptic SYNGAP1+/- mice
Abstract Objective SYNGAP1 encephalopathy is a developmental and epileptic encephalopathy caused by pathogenic loss of function variants. Syngap1 -heterozygous (Het +/- ) mice demonstrate progressive epilepsy with multiple seizure phenotypes in adulthood. Here, we investigate early-life seizures in Het +/- pups and explore of Syngap1 encephalopathy during development. Methods Post-natal day 7 (P7) and P12 mice were investigated by tethered video-electroencephalographic (vEEG). The effects of GABAergic drugs phenobarbital (PB) and pentylenetetrazol (PTZ) were investigated at P7 and P12, respectively. 24h tethered vEEG was performed at P24, and telemetric 24h vEEG with 6h sleep deprivation was performed at P35. The effect of perampanel (PMP), an AMPA receptor antagonist, was investigated at P24. Results Het +/- mice have spontaneous early-life seizures that lack an overt behavioral phenotype. These subclinical seizures are refractory to PB, but the GABA A receptor (GABA A R) antagonist PTZ significantly reduced seizure frequency suggesting that GABAergic signaling may promote seizure generation in Het +/- pups. At juvenile ages, Het +/- pups recapitulated the early emergence of high gamma (35-50Hz) during NREM and disruption of behavioral-state gamma homeostasis. This biomarker was significantly exacerbated in Het +/- pups after increasing sleep pressure with sleep deprivation. Significance Seizures during development have adverse effects on cognitive function. Therefore, an improved understanding of the SYNGAP1 epilepsy during developmental ages is necessary to delineate the deleterious interactions between aberrant synaptic function and recurrent seizures. The development of evidence-based therapies for early-life intervention will benefit from these insights.
gene therapies
2026-05-21 | SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches.
SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused bySYNGAP1haploinsufficiency, leading to a highly penetrant triad of intellectual disability, generalized epilepsy, and autism spectrum-associated behavioral and sensory abnormalities. At the molecular level, loss of the postsynaptic Ras GTPase-activating protein SynGAP disrupts Ras/Rap-ERK signaling, accelerates dendritic spine maturation, alters AMPA receptor trafficking, and destabilizes postsynaptic density architecture, producing early "hard-wiring" of cortical circuits, abnormal oscillatory dynamics, and impaired plasticity. Clinically, most individuals present in infancy with global developmental delay, hypotonia, and later-onset generalized epilepsy characterized by atypical absences, myoclonic and myoclonic-atonic seizures, and eyelid myoclonia, often with eye-closure, fixation-off, or eating-induced reflex triggers. Drug resistance is common, and developmental regression frequently coincides with seizure and EEG worsening. Nearly all individuals with SRD have moderate-to-severe intellectual disability, characterized by disproportionately severe expressive language impairment. Autism spectrum features, profound expressive language impairment, ADHD-like symptoms, severe irritability, self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities and major drivers of caregiver burden. MRI is usually normal or nonspecifically abnormal, whereas EEG shows slowed background, generalized and posterior-predominant spike-wave discharges, eye-closure/fixation-off sensitivity, and frequent sleep activation; quantitative EEG, digital eye-tracking, and gait metrics are emerging as scalable biomarkers. Current management is symptomatic, relying on broad-spectrum antiseizure medications (especially valproate and lamotrigine), ketogenic diet, neuromodulation, psychotropics, melatonin, and intensive rehabilitative and behavioral interventions. A rapidly advancing precision-therapy pipeline-including antisense oligonucleotides to upregulate the intact allele, AAV-based gene replacement, CRISPR-mediated transcriptional activation, epigenetic modulators, and rational pathway-targeted small molecules-offers realistic prospects for disease modification, supported by robust natural-history data, disease concept models, and platform biomarkers that will enable rational trial design and outcome measurement in SRD.
2026-03-02 | Research progress in SYNGAP1-related neurodevelopmental disorders: from pathogenesis to therapeutic strategies.
SYNGAP1-related neurodevelopmental disorder (SRD) is a monogenic inherited brain disorder caused by heterozygous loss-of-function mutations in the SYNGAP1 gene. The clinical presentation is complex, with core features including global developmental delay/intellectual disability, epilepsy, autism spectrum disorder, and various behavioral abnormalities. The SynGAP protein, encoded by the SYNGAP1 gene, is a key regulatory protein in the postsynaptic density of excitatory neurons. Through its GTPase-activating protein activity and structural scaffolding functions, it plays a central role in regulating the Ras/Rap signaling pathways, AMPA receptor trafficking, and maintaining the excitatory/inhibitory balance of neural networks. Haploinsufficiency of SynGAP leads to synaptic plasticity disruption and neural circuit imbalance, thereby triggering a series of neurophysiological and behavioral phenotypes. This article systematically reviews the molecular pathogenesis of SRDs, summarizes advances in treatment from conventional anti-seizure medications to emerging precision therapeutic strategies such as gene supplementation, antisense oligonucleotide-mediated splicing modulation, and translation-activating RNAs, and discusses current research challenges and future directions. Key concepts central to understanding SRDs include the critical developmental periods during which SynGAP exerts its primary influence on synaptic maturation, and cell-type specificity, referring to the differential expression and function of SynGAP in distinct neuronal populations (e.g., excitatory pyramidal neurons vs. parvalbumin-positive interneurons), which underlies circuit-level dysfunction. The aim is to provide a comprehensive perspective for an in-depth understanding of the disease and to support the development of effective therapies.
2025-09-24 | AAV delivery of full-length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders.
SYNGAP1-related disorders (SRDs) are rare neurodevelopmental conditions characterized by severe neurological symptoms, including epilepsy, motor impairment, and cognitive dysfunction. Current treatment options are limited, with patients relying on a cocktail of medications to manage the diverse symptoms but that do not address the underlying pathology. SRDs are primarily caused by haploinsufficiency of the SYNGAP1 gene, which encodes the synaptic scaffolding and signaling protein, SynGAP. We developed a gene supplementation strategy to deliver broad neuronal expression of human SYNGAP1 via an adeno-associated virus (AAV). Driven by the pan-neuronal SYNAPSIN I promoter, SYNGAP1 delivery alleviated several disease phenotypes in a Syngap1 heterozygous mouse model, including epileptiform activity, hyperactivity, and risk-taking behaviors. Notably, AAV-SYNGAP1 administration in juvenile mice, which corresponds to the typical age of diagnosis in humans, rescued behavioral deficits, highlighting its clinical relevance. Our findings provide the first evidence that AAV-mediated gene therapy can restore SYNGAP1 function and reverse key phenotypes, supporting its potential as a transformative therapeutic for SRD patients.
2025-01-14 | Roadmap to advance therapeutics for SYNGAP1-related disorder: a patient organization perspective from SynGAP Research Fund.
SYNGAP1-related disorder (SRD) is a developmental and epileptic encephalopathy caused by a disruption of the SYNGAP1 gene. At the beginning of 2024, it is one of many rare monogenic brain disorders without disease-modifying treatments, but that is changing. This article chronicles the last 5 years, beginning when treatments for SRD were not publicly in development, to the start of 2024 when many SRD-specific treatments are advancing. We discuss the progress across many realms that have brought SRD to the forefront of drug development and highlight how Patient Advocacy Groups (PAGs) have had direct roles in accelerating the route to meaningful treatments for our children. We start with a summary of why SRD is an attractive pharmaceutical target. Second, we introduce the disease, the clinical features, and the number of patients. Next, we describe our PAG, our international partners and cite examples of the broad range of activities we believe are accelerating our pace toward treatments. We summarize the current SYNGAP1 pipeline and the status of each public project. Finally, we discuss two open questions that urgently need to be addressed in advance of clinical trials for SRD.
2022-08-01 | Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway
Introduction Developmental and epileptic encephalopathies (DEE) is a group of epilepsies where the epileptic activity, seizures and the underlying neurobiology contributes to cognitive and behavioral impairments. Uncovering the causes of DEE is important in order to develop guidelines for treatment and follow-up. The aim of the present study was to describe the clinical picture and to identify genetic causes in a patient cohort with DEE without known etiology, from a Norwegian regional hospital. Methods Systematic searches of medical records were performed at Drammen Hospital, Vestre Viken Health Trust, to identify patients with epilepsy in the period 1999–2018. Medical records were reviewed to identify patients with DEE of unknown cause. In 2018, patients were also recruited consecutively from treating physicians. All patients underwent thorough clinical evaluation and updated genetic diagnostic analyses. Results Fifty-five of 2,225 patients with epilepsy had DEE of unknown etiology. Disease-causing genetic variants were found in 15/33 (45%) included patients. Three had potentially treatable metabolic disorders ( SLC2A1, COQ4 and SLC6A8 ). Developmental comorbidity was higher in the group with a genetic diagnosis, compared to those who remained undiagnosed. Five novel variants in known genes were found, and the patient phenotypes are described. Conclusion The results from this study illustrate the importance of performing updated genetic investigations and/or analyses in patients with DEE of unknown etiology. A genetic cause was identified in 45% of the patients, and three of these patients had potentially treatable conditions where available targeted therapy may improve patient outcome.
small molecules
2026-07-02 | Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies.
Developmental and epileptic encephalopathies (DEEs) are severe neurological disorders characterized by childhood-onset seizures and significant developmental impairments. Seizures are often refractory to treatment with traditional antiseizure medications, which fail to address the underlying genetic and molecular mechanisms. This comprehensive review explores the evolving landscape of precision therapeutics for DEEs, focusing on mechanism-driven interventions across key pathophysiologic categories. Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies. For synaptic dysfunctions, innovative treatments such as chemical chaperones for STXBP1-related disorders and Ras-Raf-MEK-ERK inhibitors for SYNGAP1 pathologies are discussed. The review also examines precision interventions targeting cellular signaling pathways in tuberous sclerosis complex, epigenetic regulation in Rett syndrome, and metabolic interventions like ketogenic diets and targeted supplementation for specific genetic etiologies. Additionally, the importance of enhancing access to genetic testing, conducting robust natural history studies, and employing innovative clinical trial designs is emphasized. Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care.
2024-01-15 | Cannabinerol (CBNR) Influences Synaptic Genes Associated with Cytoskeleton and Ion Channels in NSC-34 Cell Line: A Transcriptomic Study
Cannabinoids are receiving great attention as a novel approach in the treatment of cognitive and motor disabilities, which characterize neurological disorders. To date, over 100 phytocannabinoids have been extracted from Cannabis sativa, and some of them have shown neuroprotective properties and the capacity to influence synaptic transmission. In this study, we investigated the effects of a less-known phytocannabinoid, cannabinerol (CBNR), on neuronal physiology. Using the NSC-34 motor-neuron-like cell line and next-generation sequencing analysis, we discovered that CBNR influences synaptic genes associated with synapse organization and specialization, including genes related to the cytoskeleton and ion channels. Specifically, the calcium, sodium, and potassium channel subunits (Cacna1b, Cacna1c, Cacnb1, Grin1, Scn8a, Kcnc1, Kcnj9) were upregulated, along with genes related to NMDAR (Agap3, Syngap1) and calcium (Cabp1, Camkv) signaling. Moreover, cytoskeletal and cytoskeleton-associated genes (Actn2, Ina, Trio, Marcks, Bsn, Rtn4, Dgkz, Htt) were also regulated by CBNR. These findings highlight the important role played by CBNR in the regulation of synaptogenesis and synaptic transmission, suggesting the need for further studies to evaluate the neuroprotective role of CBNR in the treatment of synaptic dysfunctions that characterize motor disabilities in many neurological disorders.
2023-08-17 | Case report: Off-label use of low-dose perampanel in a 25-month-old girl with a pathogenic SYNGAP1 variant
Introduction Preclinical studies in a mouse model have shown that SYNGAP1 haploinsufficiency results in an epilepsy phenotype with excessive GluA2-AMPA insertion specifically on the soma of fast-spiking parvalbumin-positive interneurons associated with significant dysfunction of cortical gamma homeostasis that was rescued by perampanel (PER), an AMPA receptor blocker. In this single case, we aimed to investigate the presence of dysregulated cortical gamma in a toddler with a pathogenic SYNGAP1 variant and report on the effect of low-dose PER on electroencephalogram (EEG) and clinical profile. Methods Clinical data from physician's clinic notes; genetic testing reports; developmental scores from occupational therapy, physical therapy, speech and language therapy evaluations; and applied behavioral analysis reports were reviewed. Developmental assessments and EEG analysis were done pre- and post-PER. Results Clinically, the patient showed improvements in the developmental profile and sleep quality post-PER. EEG spectral power analysis in our patient revealed a loss of gamma power modulation with behavioral-state transitions similar to what was observed in Syngap1 +/− mice. Furthermore, the administration of low-dose PER rescued the dysfunctional cortical gamma homeostasis, similar to the preclinical study. However, as in the epileptic mice, PER did not curb epileptiform discharges or clinical seizures. Conclusion Similar to the Syngap1 +/− mice, cortical gamma homeostasis was dysregulated in the patient. This dysfunction was rescued by PER. These encouraging results necessitate further validation of gamma dysregulation as a potential translational EEG biomarker in SYNAP1-DEE. Low-dose PER can be explored as a therapeutic option through clinical trials.
2023-02-03 | Perampanel as precision therapy in rare genetic epilepsies
Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity.Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.
2020-11-15 | GABAergic signaling promotes early-life seizures in epileptic SYNGAP1+/- mice
Abstract Objective SYNGAP1 encephalopathy is a developmental and epileptic encephalopathy caused by pathogenic loss of function variants. Syngap1 -heterozygous (Het +/- ) mice demonstrate progressive epilepsy with multiple seizure phenotypes in adulthood. Here, we investigate early-life seizures in Het +/- pups and explore of Syngap1 encephalopathy during development. Methods Post-natal day 7 (P7) and P12 mice were investigated by tethered video-electroencephalographic (vEEG). The effects of GABAergic drugs phenobarbital (PB) and pentylenetetrazol (PTZ) were investigated at P7 and P12, respectively. 24h tethered vEEG was performed at P24, and telemetric 24h vEEG with 6h sleep deprivation was performed at P35. The effect of perampanel (PMP), an AMPA receptor antagonist, was investigated at P24. Results Het +/- mice have spontaneous early-life seizures that lack an overt behavioral phenotype. These subclinical seizures are refractory to PB, but the GABA A receptor (GABA A R) antagonist PTZ significantly reduced seizure frequency suggesting that GABAergic signaling may promote seizure generation in Het +/- pups. At juvenile ages, Het +/- pups recapitulated the early emergence of high gamma (35-50Hz) during NREM and disruption of behavioral-state gamma homeostasis. This biomarker was significantly exacerbated in Het +/- pups after increasing sleep pressure with sleep deprivation. Significance Seizures during development have adverse effects on cognitive function. Therefore, an improved understanding of the SYNGAP1 epilepsy during developmental ages is necessary to delineate the deleterious interactions between aberrant synaptic function and recurrent seizures. The development of evidence-based therapies for early-life intervention will benefit from these insights.
gene therapies
2026-05-21 | SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches.
SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused bySYNGAP1haploinsufficiency, leading to a highly penetrant triad of intellectual disability, generalized epilepsy, and autism spectrum-associated behavioral and sensory abnormalities. At the molecular level, loss of the postsynaptic Ras GTPase-activating protein SynGAP disrupts Ras/Rap-ERK signaling, accelerates dendritic spine maturation, alters AMPA receptor trafficking, and destabilizes postsynaptic density architecture, producing early "hard-wiring" of cortical circuits, abnormal oscillatory dynamics, and impaired plasticity. Clinically, most individuals present in infancy with global developmental delay, hypotonia, and later-onset generalized epilepsy characterized by atypical absences, myoclonic and myoclonic-atonic seizures, and eyelid myoclonia, often with eye-closure, fixation-off, or eating-induced reflex triggers. Drug resistance is common, and developmental regression frequently coincides with seizure and EEG worsening. Nearly all individuals with SRD have moderate-to-severe intellectual disability, characterized by disproportionately severe expressive language impairment. Autism spectrum features, profound expressive language impairment, ADHD-like symptoms, severe irritability, self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities and major drivers of caregiver burden. MRI is usually normal or nonspecifically abnormal, whereas EEG shows slowed background, generalized and posterior-predominant spike-wave discharges, eye-closure/fixation-off sensitivity, and frequent sleep activation; quantitative EEG, digital eye-tracking, and gait metrics are emerging as scalable biomarkers. Current management is symptomatic, relying on broad-spectrum antiseizure medications (especially valproate and lamotrigine), ketogenic diet, neuromodulation, psychotropics, melatonin, and intensive rehabilitative and behavioral interventions. A rapidly advancing precision-therapy pipeline-including antisense oligonucleotides to upregulate the intact allele, AAV-based gene replacement, CRISPR-mediated transcriptional activation, epigenetic modulators, and rational pathway-targeted small molecules-offers realistic prospects for disease modification, supported by robust natural-history data, disease concept models, and platform biomarkers that will enable rational trial design and outcome measurement in SRD.
2026-03-02 | Research progress in SYNGAP1-related neurodevelopmental disorders: from pathogenesis to therapeutic strategies.
SYNGAP1-related neurodevelopmental disorder (SRD) is a monogenic inherited brain disorder caused by heterozygous loss-of-function mutations in the SYNGAP1 gene. The clinical presentation is complex, with core features including global developmental delay/intellectual disability, epilepsy, autism spectrum disorder, and various behavioral abnormalities. The SynGAP protein, encoded by the SYNGAP1 gene, is a key regulatory protein in the postsynaptic density of excitatory neurons. Through its GTPase-activating protein activity and structural scaffolding functions, it plays a central role in regulating the Ras/Rap signaling pathways, AMPA receptor trafficking, and maintaining the excitatory/inhibitory balance of neural networks. Haploinsufficiency of SynGAP leads to synaptic plasticity disruption and neural circuit imbalance, thereby triggering a series of neurophysiological and behavioral phenotypes. This article systematically reviews the molecular pathogenesis of SRDs, summarizes advances in treatment from conventional anti-seizure medications to emerging precision therapeutic strategies such as gene supplementation, antisense oligonucleotide-mediated splicing modulation, and translation-activating RNAs, and discusses current research challenges and future directions. Key concepts central to understanding SRDs include the critical developmental periods during which SynGAP exerts its primary influence on synaptic maturation, and cell-type specificity, referring to the differential expression and function of SynGAP in distinct neuronal populations (e.g., excitatory pyramidal neurons vs. parvalbumin-positive interneurons), which underlies circuit-level dysfunction. The aim is to provide a comprehensive perspective for an in-depth understanding of the disease and to support the development of effective therapies.
2025-09-24 | AAV delivery of full-length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders.
SYNGAP1-related disorders (SRDs) are rare neurodevelopmental conditions characterized by severe neurological symptoms, including epilepsy, motor impairment, and cognitive dysfunction. Current treatment options are limited, with patients relying on a cocktail of medications to manage the diverse symptoms but that do not address the underlying pathology. SRDs are primarily caused by haploinsufficiency of the SYNGAP1 gene, which encodes the synaptic scaffolding and signaling protein, SynGAP. We developed a gene supplementation strategy to deliver broad neuronal expression of human SYNGAP1 via an adeno-associated virus (AAV). Driven by the pan-neuronal SYNAPSIN I promoter, SYNGAP1 delivery alleviated several disease phenotypes in a Syngap1 heterozygous mouse model, including epileptiform activity, hyperactivity, and risk-taking behaviors. Notably, AAV-SYNGAP1 administration in juvenile mice, which corresponds to the typical age of diagnosis in humans, rescued behavioral deficits, highlighting its clinical relevance. Our findings provide the first evidence that AAV-mediated gene therapy can restore SYNGAP1 function and reverse key phenotypes, supporting its potential as a transformative therapeutic for SRD patients.
2025-01-14 | Roadmap to advance therapeutics for SYNGAP1-related disorder: a patient organization perspective from SynGAP Research Fund.
SYNGAP1-related disorder (SRD) is a developmental and epileptic encephalopathy caused by a disruption of the SYNGAP1 gene. At the beginning of 2024, it is one of many rare monogenic brain disorders without disease-modifying treatments, but that is changing. This article chronicles the last 5 years, beginning when treatments for SRD were not publicly in development, to the start of 2024 when many SRD-specific treatments are advancing. We discuss the progress across many realms that have brought SRD to the forefront of drug development and highlight how Patient Advocacy Groups (PAGs) have had direct roles in accelerating the route to meaningful treatments for our children. We start with a summary of why SRD is an attractive pharmaceutical target. Second, we introduce the disease, the clinical features, and the number of patients. Next, we describe our PAG, our international partners and cite examples of the broad range of activities we believe are accelerating our pace toward treatments. We summarize the current SYNGAP1 pipeline and the status of each public project. Finally, we discuss two open questions that urgently need to be addressed in advance of clinical trials for SRD.
2022-08-01 | Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway
Introduction Developmental and epileptic encephalopathies (DEE) is a group of epilepsies where the epileptic activity, seizures and the underlying neurobiology contributes to cognitive and behavioral impairments. Uncovering the causes of DEE is important in order to develop guidelines for treatment and follow-up. The aim of the present study was to describe the clinical picture and to identify genetic causes in a patient cohort with DEE without known etiology, from a Norwegian regional hospital. Methods Systematic searches of medical records were performed at Drammen Hospital, Vestre Viken Health Trust, to identify patients with epilepsy in the period 1999–2018. Medical records were reviewed to identify patients with DEE of unknown cause. In 2018, patients were also recruited consecutively from treating physicians. All patients underwent thorough clinical evaluation and updated genetic diagnostic analyses. Results Fifty-five of 2,225 patients with epilepsy had DEE of unknown etiology. Disease-causing genetic variants were found in 15/33 (45%) included patients. Three had potentially treatable metabolic disorders ( SLC2A1, COQ4 and SLC6A8 ). Developmental comorbidity was higher in the group with a genetic diagnosis, compared to those who remained undiagnosed. Five novel variants in known genes were found, and the patient phenotypes are described. Conclusion The results from this study illustrate the importance of performing updated genetic investigations and/or analyses in patients with DEE of unknown etiology. A genetic cause was identified in 45% of the patients, and three of these patients had potentially treatable conditions where available targeted therapy may improve patient outcome.
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Drug Discovery Landscape
2 orphan drug designations for SYNGAP1-related developmental and epileptic encephalopathy.
2 orphan drug designations for SYNGAP1-related developmental and epileptic encephalopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Antisense oligonucleotide against SYNGAP1 regulatory RNA | oligonucleotides | EMA | 2026-04-20 | — | Orphix Consulting GmbH |
Recombinant AAV9 viral vector containing the transgene encoding the human WW domain-containing oxidoreductase (WWOX) protein, under the control of a human Synapsin I promoter | — | FDA | 2023-12-05 | — | Mahzi Therapeutics |
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