Epilepsy

Complex MONDO:0005027 Pathograph 20 Show in embeddings browser Neurological Disease

Epilepsy is a chronic neurological disorder defined by an enduring predisposition to recurrent unprovoked seizures arising from abnormal, excessive, and synchronous neuronal activity. It encompasses focal and generalized syndromes (e.g., temporal lobe epilepsy, juvenile myoclonic epilepsy, childhood absence epilepsy). The core mechanism is an imbalance between neuronal excitation and inhibition producing hyperexcitability and hypersynchrony, driven by ion-channel, synaptic, and network dysfunction.

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Classifications

Harrison's Chapter

◆

Subtypes

Focal Epilepsy

Seizures originate from a localized brain region.

Generalized Epilepsy

Seizures involve both hemispheres from onset.

Temporal Lobe Epilepsy

Most common focal epilepsy, often with mesial temporal sclerosis.

Juvenile Myoclonic Epilepsy (JME) MONDO:0009696

A rare epilepsy syndrome characterized by adolescence/young adulthood onset of myoclonic with or without other generalized seizure types in an otherwise healthy individual. The EEG shows 3-5.5 Hz generalized spike-waves and polyspike-waves. Photosensitivity is common.

Show evidence (1 reference)

ORPHA:307 SUPPORT

"A rare epilepsy syndrome characterized by adolescence/young adulthood onset of myoclonic with or without other generalized seizure types in an otherwise healthy individual."

Orphanet definition of juvenile myoclonic epilepsy.

Childhood Absence Epilepsy

Frequent brief absence seizures beginning in childhood.

Juvenile Absence Epilepsy (JAE) MONDO:0800453

A genetic epilepsy with onset occurring around puberty, characterized by sporadic occurrence of absence seizures, frequently associated with generalized tonic-clonic seizures and sporadic myoclonic jerks.

Show evidence (1 reference)

ORPHA:1941 SUPPORT

"Juvenile absence epilepsy (JAE) is a genetic epilepsy with onset occurring around puberty."

Orphanet definition of juvenile absence epilepsy.

Epilepsy with Myoclonic-Atonic Seizures (Doose Syndrome) MONDO:0014633

A rare childhood onset epilepsy syndrome characterized by multiple seizure types including myoclonic-atonic seizures that occur usually in previously healthy children.

Show evidence (1 reference)

ORPHA:1942 SUPPORT

"A rare, childhood onset epilepsy syndrome characterized by multiple seizure types including myoclonic-atonic (MA) seizures that occur usually in previously healthy children."

Orphanet definition of epilepsy with myoclonic-atonic seizures.

Self-Limited Neonatal Epilepsy (BFNS) MONDO:0016027

A rare genetic epilepsy syndrome characterized by seizure onset typically in the first week of life, in otherwise healthy newborns, usually resolving within the first year of life. Autosomal dominant inheritance with KCNQ2 and KCNQ3 mutations.

Show evidence (1 reference)

ORPHA:1949 SUPPORT

"A rare genetic epilepsy syndrome characterized by seizures onset typically in the first week of life, in otherwise healthy newborns, and usually resolving within the first year of life."

Orphanet definition of self-limited neonatal epilepsy.

SYNGAP1-related Disorder (SRD) MONDO:0012960

A monogenic developmental and epileptic encephalopathy caused by SYNGAP1 haploinsufficiency. Presents with intellectual disability, generalized epilepsy, and autism spectrum-associated behavioral and sensory abnormalities. Individuals typically present in infancy with global developmental delay and hypotonia, with later-onset generalized epilepsy characterized by atypical absences, myoclonic and myoclonic-atonic seizures, and eyelid myoclonia with reflex triggers. Drug resistance is common, and developmental regression frequently coincides with seizure and EEG worsening. Nearly all individuals manifest moderate-to-severe intellectual disability with disproportionately severe expressive language impairment, autism spectrum features, ADHD-like symptoms, severe irritability, and marked sensory abnormalities.

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"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."

Comprehensive review establishing SRD clinical phenotype and characteristic seizure types.

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Pathophysiology

Neuronal Hyperexcitability

Imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmission leads to synchronized, excessive neuronal firing. Ion channel dysfunction is a common mechanism.

Pyramidal Neuron CL:0000598 GABAergic Interneuron CL:0000617

Synaptic Transmission GO:0007268

Blood-Brain Barrier Disruption

Loss of tight junction proteins (claudin-5) in brain endothelial cells leads to blood-brain barrier breakdown, allowing albumin extravasation and disruption of ionic homeostasis.

Endothelial Cell CL:0000115

Blood-Brain Barrier Maintenance GO:0035633

Downstream

Network Hyperexcitability BBB disruption causes albumin entry and altered ionic balance, increasing neuronal excitability.

Show evidence (4 references)

PMID:35422069 SUPPORT Human Clinical

"claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption."

Demonstrates that BBB dysfunction occurs in human epilepsy patients and is characterized by loss of tight junction proteins.

PMID:35422069 SUPPORT Model Organism

"targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption"

Shows that partial (heterozygous) loss of claudin-5 or focal hippocampal disruption worsens both chemically-induced seizures and BBB breakdown, indicating a dose-dependent contribution of tight-junction integrity to seizure susceptibility.

PMID:35422069 SUPPORT Model Organism

"inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality."

Establishes causal role of BBB dysfunction in seizure generation, showing that disruption of endothelial tight junctions is sufficient to trigger spontaneous seizures.

+ 1 more reference

Network Hyperexcitability

Abnormal synchronization of neuronal networks that can recruit adjacent or distant brain regions, leading to seizure propagation.

Neuronal Activity GO:0019226

Neuroinflammation and Gliosis

Activation of microglia and reactive astrocytes following brain injury or during seizures, releasing inflammatory mediators and undergoing morphological changes that alter the brain microenvironment.

Astrocyte CL:0000127 Microglia CL:0000129

Neuroinflammatory Response GO:0150076

Downstream

Lipoxygenase-Mediated Lipid Peroxidation and Eicosanoid Signaling Neuroinflammatory activation of phospholipase A2 releases arachidonic acid from membrane phospholipids, providing substrate for LOX-mediated eicosanoid generation (a positive-feedback arm of the neuroinflammatory cascade).

Complement System-Mediated Microglial Neuroinflammation Neuroinflammatory signals activate complement cascade and microglial synaptic pruning pathways.

Synaptic Reorganization Inflammatory mediators and glial activation alter synaptic structure and connectivity.

Lipoxygenase-Mediated Lipid Peroxidation and Eicosanoid Signaling

Lipoxygenase (LOX) enzymes, particularly 5-LOX and 12/15-LOX, catalyze the generation of bioactive lipid metabolites (eicosanoids including leukotrienes and lipoxins) from arachidonic acid. LOX-mediated lipid peroxidation contributes to oxidative stress and pro-inflammatory signaling, with dysregulation of LOX activity contributing to blood-brain barrier disruption, glial cell activation, cytokine release, immune cell infiltration, and neuronal hyperexcitability. These eicosanoid mediators propagate neuroinflammatory cascades that promote seizure susceptibility and drug-resistant epilepsy.

Microglia CL:0000129 Astrocyte CL:0000127 Endothelial Cell CL:0000115

Lipoxygenase Pathway GO:0019372 Inflammatory Response GO:0006954 Oxidative Stress GO:0006979

Downstream

Blood-Brain Barrier Disruption LOX-derived eicosanoids and oxidative stress compromise endothelial tight junction integrity (claudin-5) leading to BBB breakdown.

Neuroinflammation and Gliosis LOX-mediated lipid peroxidation activates microglia and astrocytes, propagating neuroinflammatory signaling.

Neuronal Hyperexcitability Eicosanoid mediators from LOX activity enhance neuronal excitability through altered ion channel function and synaptic transmission.

Show evidence (3 references)

PMID:42331232 SUPPORT Other

"lipoxygenase (LOX) enzymes play a pivotal role in mediating oxidative stress, lipid peroxidation, and pro-inflammatory signaling through the generation of bioactive lipid metabolites"

Review establishes LOX enzymes as central mediators of oxidative and inflammatory stress in epilepsy pathophysiology.

PMID:42331232 SUPPORT Other

"Dysregulation of LOX activity contributes to epileptogenic processes, such as blood-brain barrier disruption, glial activation, cytokine release, immune-cell infiltration, neuronal hyperexcitability, and neuronal death"

Comprehensive review documenting LOX dysregulation as a driver of multiple epileptogenic mechanisms including BBB disruption and glial activation.

PMID:42331232 SUPPORT Other

"LOX pathways, particularly those mediated by 5-LOX and 12/15-LOX, play a major role in the pathophysiology of epileptic seizures and may also contribute to neuropsychiatric comorbidities"

Review identifies 5-LOX and 12/15-LOX as principal contributors to both seizure pathophysiology and associated neuropsychiatric complications in epilepsy.

Complement System-Mediated Microglial Neuroinflammation

Complement cascade activation contributes to microglial-mediated neuroinflammation and synaptic remodeling in epilepsy. Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis as a potential driver rather than merely an epiphenomenon of neuroinflammation, promoting aberrant synaptic remodeling and progressive neuronal dysfunction underlying seizure susceptibility.

Microglia CL:0000129 Neuron CL:0000540

Complement Activation GO:0006956 ↑ INCREASED

Downstream

Synaptic Reorganization Complement-mediated synaptic pruning and microglial phagocytosis contribute to aberrant synaptic remodeling and loss of network connectivity.

Show evidence (2 references)

PMID:42269875 SUPPORT Model Organism

"Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis. This suggests that complement dysregulation is not merely an epiphenomenon of neuroinflammation but rather a potential driver of seizure development and progression."

Review synthesizes preclinical evidence that complement system dysregulation is a primary driver of epileptogenesis, not just a secondary consequence of inflammation.

PMID:42269875 SUPPORT Human Clinical

"This review summarizes current preclinical and clinical evidence on complement-mediated mechanisms in epilepsy, with a focus on neuroinflammation, synaptic remodeling, glial proliferation, biomarkers, and therapeutic targets."

Establishes that complement system activation is mechanistically linked to multiple pathophysiological processes in epilepsy including synaptic remodeling and glial activation.

Synaptic Reorganization

Aberrant sprouting, formation of new synaptic connections, and altered synaptic plasticity that promote recurrent excitatory circuits and seizure susceptibility.

Synaptic Plasticity GO:0048167

mTOR Pathway Hyperactivation

Constitutive activation of the mechanistic target of rapamycin (mTOR) signaling pathway, driving abnormal neuronal growth and development of dysmorphic neurons in focal cortical malformations.

mTOR Signaling GO:0031929

Downstream

Dysmorphic Neuron Generation Hyperactive mTOR signaling causes abnormal neuronal soma enlargement and cytoskeletal changes.

Show evidence (2 references)

PMID:31174205 SUPPORT Model Organism

"Treatment with the mTORC1 inhibitor rapamycin starting after 3 weeks of age significantly prolonged the survival of Depdc5cc+ mice and partially rescued the behavioral hyperactivity."

Demonstrates that mTORC1 pathway hyperactivation caused by DEPDC5 loss drives epilepsy pathogenesis and that mTOR inhibition can rescue the phenotype.

PMID:31174205 SUPPORT Model Organism

"Rapamycin decreased the enlarged brain size of Depdc5cc+ mice with corresponding decrease in neuronal soma size."

Shows that mTOR hyperactivation causes abnormal neuronal growth contributing to epileptogenesis, which can be reversed by mTOR inhibition.

Dysmorphic Neuron Generation

Formation of abnormally enlarged neurons with cytoskeletal disruption and cellular senescence markers, creating epileptogenic foci in cortical malformations.

Show evidence (2 references)

PMID:38710875 PARTIAL Human Clinical

"We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity."

Supports senescence signatures in pathological cells of mTOR-related FCD, but only partially supports all structural details in this descriptor.

PMID:38710875 PARTIAL Model Organism

"administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model"

Supports seizure reduction via senolytics in an mTOR-related model, but only partially supports this broader dysmorphic neuron descriptor.

SYNGAP1 Haploinsufficiency

Heterozygous loss-of-function variants in SYNGAP1 cause haploinsufficiency of the postsynaptic Ras GTPase-activating protein SynGAP, the proximal molecular lesion in SYNGAP1-related disorder.

Pyramidal Neuron CL:0000598

Synapse assembly GO:0007416 Glutamate receptor signaling pathway GO:0007215

Downstream

Ras/Rap-ERK Signaling Dysregulation Reduced SynGAP protein removes negative regulation of Ras/Rap-ERK signaling at the postsynaptic density.

GABAergic Interneuron Dysfunction Beyond glutamatergic pyramidal neurons, SynGAP haploinsufficiency also impairs the development and function of GABAergic inhibitory interneurons.

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused"

Identifies SYNGAP1 haploinsufficiency as the causal molecular lesion of SRD.

Ras/Rap-ERK Signaling Dysregulation

SynGAP normally inactivates Ras and Rap at the postsynaptic density; its loss produces excessive Ras/Rap-ERK signaling that perturbs downstream synaptic structural and functional plasticity.

Pyramidal Neuron CL:0000598

Ras/Rap-ERK signaling GO:0007265 ↑ INCREASED

Downstream

Accelerated Dendritic Spine Maturation Excess Ras/Rap-ERK signaling drives precocious dendritic spine structural maturation.

AMPA Receptor Trafficking Disruption Dysregulated Ras/Rap-ERK signaling alters trafficking of AMPA-type glutamate receptors at the synapse.

Postsynaptic Density Destabilization Persistent Ras/Rap-ERK signaling destabilizes the molecular architecture of the postsynaptic density.

Show evidence (1 reference)

PMID:42161154 SUPPORT Model Organism

"loss of the postsynaptic Ras GTPase-activating protein SynGAP disrupts Ras/Rap-ERK signaling"

Review of mouse and in vitro data establishing Ras/Rap-ERK dysregulation as the immediate signaling consequence of SynGAP loss.

Accelerated Dendritic Spine Maturation

Loss of SynGAP-mediated regulation drives premature structural maturation of dendritic spines on cortical pyramidal neurons, locking spines into mature morphologies earlier than the normal developmental timetable.

Pyramidal Neuron CL:0000598

Dendritic spine maturation GO:0060996 ↑ INCREASED

Downstream

Cortical Circuit Hard-Wiring Precocious spine maturation contributes to early lock-in of cortical circuit connectivity.

Show evidence (1 reference)

PMID:42161154 SUPPORT Model Organism

"accelerates dendritic spine maturation"

Review synthesis of animal-model evidence that SynGAP loss accelerates dendritic spine structural maturation.

AMPA Receptor Trafficking Disruption

SynGAP loss alters the trafficking of AMPA-type glutamate receptors to and from the postsynaptic membrane, perturbing excitatory synaptic transmission strength and plasticity.

Pyramidal Neuron CL:0000598

AMPA receptor trafficking GO:0099072

Downstream

Cortical Circuit Hard-Wiring Altered AMPA receptor trafficking contributes to aberrant excitatory synaptic strength underlying premature circuit consolidation.

Show evidence (1 reference)

PMID:42161154 SUPPORT Model Organism

"alters AMPA receptor trafficking"

Review synthesis of in vitro and animal-model evidence for altered AMPA receptor trafficking with SynGAP loss.

Postsynaptic Density Destabilization

SynGAP is a major scaffold component of the postsynaptic density; its haploinsufficiency destabilizes postsynaptic density architecture and scaffolding integrity at excitatory synapses.

Pyramidal Neuron CL:0000598

Postsynaptic density assembly GO:0097107 ↓ DECREASED

Downstream

Cortical Circuit Hard-Wiring Loss of PSD scaffolding integrity contributes to aberrant maturation and stabilization of cortical synapses.

Show evidence (1 reference)

PMID:42161154 SUPPORT Model Organism

"destabilizes postsynaptic density architecture"

Review synthesis of model-organism data on PSD architectural destabilization with SynGAP loss.

Cortical Circuit Hard-Wiring

Premature spine maturation, altered AMPA receptor trafficking, and PSD destabilization converge to lock cortical circuits into early, rigid connectivity patterns, with abnormal oscillatory dynamics and impaired synaptic plasticity at the network level.

Pyramidal Neuron CL:0000598

Regulation of synaptic plasticity GO:0048167 ↓ DECREASED

Downstream

Neuronal Hyperexcitability Aberrant cortical circuit consolidation and impaired plasticity contribute to excitatory/inhibitory imbalance underlying SRD seizures.

Show evidence (1 reference)

PMID:42161154 SUPPORT Model Organism

"producing early "hard-wiring" of cortical circuits, abnormal oscillatory dynamics, and impaired plasticity."

Review synthesis describing the network-level developmental consequence of converging molecular and synaptic defects in SRD.

GABAergic Interneuron Dysfunction

SYNGAP1 is expressed in GABAergic inhibitory interneurons as well as glutamatergic pyramidal neurons. Haploinsufficiency in medial ganglionic eminence-derived parvalbumin and somatostatin interneurons impairs inhibitory circuit development and produces abnormal cortical oscillatory dynamics, reducing effective inhibitory tone and contributing to the excitatory/inhibitory imbalance that drives network hyperexcitability in SRD.

GABAergic Interneuron CL:0011005

GABAergic synaptic transmission GO:0051932 ↓ DECREASED

Downstream

Neuronal Hyperexcitability Reduced interneuron-mediated inhibition shifts the cortical excitatory/inhibitory balance toward hyperexcitability and seizure susceptibility.

Show evidence (2 references)

PMID:37558489 SUPPORT Model Organism

"SynGAP plays a critical role in the function of GABAergic inhibitory interneurons as well as glutamatergic pyramidal neurons in the neocortex"

Mouse study establishing that SynGAP function in inhibitory interneurons contributes to cortical circuit function, supporting an inhibitory-side mechanism distinct from the glutamatergic arm.

PMID:39406516 SUPPORT Model Organism

"Mice with prenatal-onset Syngap1 haploinsufficiency restricted to Nkx2.1-expressing neurons show abnormal cortical oscillations and increased entrainment induced by 40 Hz auditory stimulation but lack stimulus-specific adaptation"

Mouse study showing Syngap1 haploinsufficiency restricted to MGE-derived (Nkx2.1-expressing) interneurons produces abnormal cortical oscillations, linking interneuron dysfunction to network-level alterations in SRD.

Complement System Activation and Dysregulation

Aberrant activation of the complement cascade (C1q, C3, C5) leads to dysregulated complement-mediated signaling, driving both neuroinflammation and synaptic remodeling that directly contribute to seizure development and disease progression. Complement dysregulation is not merely an epiphenomenon of neuroinflammation but a potential driver of epileptogenesis.

Microglia CL:0000129 Neuron CL:0000540

Complement Activation GO:0006956 ↑ INCREASED Regulation of Complement Activation GO:0030449

Downstream

Neuroinflammation and Gliosis Complement dysregulation drives microglial C3 deposition and inflammatory mediator release, contributing to the neuroinflammatory cascade.

Synaptic Reorganization Complement-mediated C3b deposition and microglial-synaptic pruning alter synaptic structure, connectivity, and plasticity.

Show evidence (1 reference)

PMID:42269875 SUPPORT Other

"Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis"

Review synthesis establishing complement activation as a key driver of epileptogenesis, with focus on neuroinflammation, synaptic remodeling, and glial proliferation mechanisms.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Digestive 1

Feeding Difficulties Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:30789692 SUPPORT Human Clinical

"Feeding difficulties can be significant in some"

GeneReviews SYNGAP1-related intellectual disability chapter documents clinically significant feeding difficulties in a subset of affected individuals.

Musculoskeletal 1

Infantile Hypotonia FREQUENT Generalized hypotonia HP:0001290

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"most individuals present in infancy with global developmental delay, hypotonia"

Samanta 2026 review reports that most individuals with SRD present in infancy with global developmental delay and hypotonia, supporting hypotonia as a frequent early feature.

Nervous System 20

Seizures VERY_FREQUENT Seizure HP:0001250

Generalized Tonic-Clonic Seizures VERY_FREQUENT Bilateral tonic-clonic seizure HP:0002069

Show evidence (1 reference)

ORPHA:1941 SUPPORT

"HP:0002069 | Bilateral tonic-clonic seizure | Very frequent (99-80%)"

Orphanet phenotype data for juvenile absence epilepsy shows bilateral tonic-clonic seizures are very frequent.

Absence Seizures FREQUENT Generalized non-motor (absence) seizure HP:0002121

Show evidence (1 reference)

ORPHA:1941 SUPPORT

"HP:0002121 | Generalized non-motor (absence) seizure | Frequent (79-30%)"

Orphanet data shows absence seizures are frequent in juvenile absence epilepsy.

Focal-Onset Seizures VERY_FREQUENT Focal-onset seizure HP:0007359

Show evidence (1 reference)

ORPHA:1949 SUPPORT

"HP:0007359 | Focal-onset seizure | Very frequent (99-80%)"

Orphanet data shows focal-onset seizures are very frequent in self-limited neonatal epilepsy.

Febrile Seizures OCCASIONAL Febrile seizure (within the age range of 3 months to 6 years) HP:0002373

Show evidence (1 reference)

ORPHA:307 SUPPORT

"HP:0002373 | Febrile seizure (within the age range of 3 months to 6 years) | Occasional (29-5%)"

Orphanet data shows febrile seizures occur occasionally in JME patients.

EEG Abnormality VERY_FREQUENT EEG abnormality HP:0002353

Show evidence (2 references)

ORPHA:307 SUPPORT

"HP:0002392 | EEG with polyspike wave complexes | Very frequent (99-80%)"

Orphanet data shows polyspike-wave complexes on EEG are very frequent in JME.

ORPHA:1949 SUPPORT

"HP:0011188 | Focal EEG discharges with secondary generalization | Very frequent (99-80%)"

Orphanet data shows focal EEG discharges with secondary generalization are very frequent in self-limited neonatal epilepsy.

Postictal Confusion FREQUENT Confusion HP:0001289

Confusion following generalized or complex partial seizures

Aura FREQUENT Somatic sensory dysfunction HP:0003474

Warning symptoms before focal seizures including visual, somatosensory, olfactory, or psychic phenomena

Memory Impairment Memory impairment HP:0002354

Frequently reported in temporal lobe epilepsy; quantitative frequency data across all epilepsy subtypes is limited.

Intellectual Disability FREQUENT Intellectual disability HP:0001249

Show evidence (1 reference)

ORPHA:1942 SUPPORT

"HP:0001249 | Intellectual disability | Frequent (79-30%)"

Orphanet data shows intellectual disability is frequent in epilepsy with myoclonic-atonic seizures.

Attention Deficit Hyperactivity Disorder FREQUENT Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

ORPHA:1942 SUPPORT

"HP:0007018 | Attention deficit hyperactivity disorder | Frequent (79-30%)"

Orphanet data shows ADHD is frequent in epilepsy with myoclonic-atonic seizures.

Depression OCCASIONAL Depression HP:0000716

Show evidence (3 references)

PMID:23175727 SUPPORT Human Clinical

"overall prevalence of active (current or past-year) depression of 23.1%"

Systematic review and meta-analysis of 14 studies showing 23.1% prevalence of active depression in people with epilepsy.

PMID:23175727 SUPPORT Human Clinical

"overall OR of active depression of 2.77 (95% CI 2.09-3.67) in PWE"

People with epilepsy have 2.77 times higher odds of active depression compared to the general population.

PMID:26549780 SUPPORT Human Clinical

"Several mechanisms explain how epilepsy and comorbidities are associated, including shared risk factors and bidirectional relations."

Keezer et al. reviews the bidirectional relationship between epilepsy and depression, with shared pathophysiological mechanisms.

Anxiety OCCASIONAL Anxiety HP:0000739

Show evidence (2 references)

ORPHA:1941 SUPPORT

"HP:0000739 | Anxiety | Occasional (29-5%)"

Orphanet data shows anxiety is an occasional phenotype in juvenile absence epilepsy.

PMID:26549780 SUPPORT Human Clinical

"including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight times more common in people with epilepsy"

Keezer et al. Lancet Neurol review documents anxiety among the major comorbidities of epilepsy.

Headache Headache HP:0002315

Show evidence (1 reference)

PMID:26549780 SUPPORT Human Clinical

"including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight times more common in people with epilepsy"

Keezer et al. Lancet Neurol review documents migraine as a major comorbidity of epilepsy.

Moderate-to-Severe Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (2 references)

PMID:30789692 SUPPORT Human Clinical

"developmental delay (DD) or intellectual disability (ID) (100% of affected individuals)"

GeneReviews reports developmental delay or intellectual disability in 100% of individuals with SYNGAP1-related intellectual disability, establishing it as the defining near-universal feature and supporting the VERY_FREQUENT classification.

PMID:42161154 SUPPORT Human Clinical

"Nearly all individuals with SRD have moderate-to-severe intellectual disability"

Samanta 2026 review confirms that nearly all individuals with SRD have moderate-to-severe intellectual disability.

Autism Spectrum Features VERY_FREQUENT Autistic behavior HP:0000729

Show evidence (2 references)

PMID:42161154 SUPPORT Human Clinical

"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"

Samanta 2026 review identifies autism spectrum features as part of the cluster of almost-universal SRD comorbidities, substantiating the VERY_FREQUENT classification.

PMID:30789692 PARTIAL Human Clinical

"autism spectrum disorder (ASD) and other behavioral abnormalities (≤50%)"

GeneReviews quantifies formal ASD diagnosis at ≤50% prevalence, which on its own supports FREQUENT rather than VERY_FREQUENT. Marked PARTIAL because Samanta 2026 uses the broader "autism spectrum features" construct (almost universal); the GeneReviews figure refers to the narrower formal ASD diagnosis.

SRD-Associated Insomnia VERY_FREQUENT Insomnia HP:0100785

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"

Samanta 2026 review identifies sleep-onset and maintenance insomnia among the cluster of almost-universal SRD comorbidities, substantiating the VERY_FREQUENT classification.

ADHD-like Features VERY_FREQUENT Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"ADHD-like symptoms, severe irritability, self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"

Samanta 2026 review lists ADHD-like symptoms among the almost-universal SRD behavioral comorbidities, supporting the VERY_FREQUENT classification.

Severe Irritability VERY_FREQUENT Irritability HP:0000737

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"severe irritability, self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"

Samanta 2026 review lists severe irritability among the almost-universal SRD behavioral comorbidities, supporting the VERY_FREQUENT classification.

Self-Injurious Behavior VERY_FREQUENT Self-injurious behavior HP:0100716

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"

Samanta 2026 review lists self-injury among the almost-universal SRD behavioral comorbidities, supporting the VERY_FREQUENT classification.

Other 7

Myoclonic Seizures VERY_FREQUENT Myoclonic seizure HP:0032794

Show evidence (1 reference)

ORPHA:307 SUPPORT

"HP:0007000 | Morning myoclonic jerks | Very frequent (99-80%)"

Orphanet cites HP:0007000 (Morning myoclonic jerks), a more specific child term of HP:0032794 (Myoclonic seizure). The broader term is used here as it applies across epilepsy subtypes, not just JME.

Myoclonic-Atonic Seizures VERY_FREQUENT Generalized myoclonic-atonic seizure HP:0011170

Show evidence (1 reference)

ORPHA:1942 SUPPORT

"HP:0011170 | Myoclonic atonic seizures | Very frequent (99-80%)"

Orphanet data shows myoclonic-atonic seizures are very frequent in Doose syndrome.

Status Epilepticus VERY_RARE Status epilepticus HP:0002133

Show evidence (1 reference)

ORPHA:307 SUPPORT

"HP:0002133 | Status epilepticus | Very rare (<4-1%)"

Orphanet data shows status epilepticus is very rare in JME.

Automatisms FREQUENT Focal automatism seizure HP:0032898

Profound Expressive Language Impairment VERY_FREQUENT Expressive language delay HP:0002474

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"Nearly all individuals with SRD have moderate-to-severe intellectual disability, characterized by disproportionately severe expressive language impairment."

Samanta 2026 review identifies disproportionately severe expressive language impairment as a near-universal, clinically distinctive SRD feature.

Reflex Seizures FREQUENT Reflex seizure HP:0020207

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"eye-closure, fixation-off, or eating-induced reflex triggers"

Samanta 2026 review documents the characteristic eye-closure, fixation-off, and eating-induced reflex seizure triggers in SRD.

Sensory Behavioral Abnormality VERY_FREQUENT Sensory behavioral abnormality HP:5200046

Show evidence (1 reference)

PMID:42161154 SUPPORT Human Clinical

"marked sensory abnormalities are almost universal comorbidities"

Samanta 2026 review identifies marked sensory abnormalities as a near-universal SRD comorbidity.

🧬

Genetic Associations

SCN1A (Causative)

Show evidence (3 references)

ORPHA:1942 SUPPORT

"SCN1A | sodium voltage-gated channel alpha subunit 1 | hgnc:10585 | Disease-causing germline mutation(s) in"

Orphanet confirms SCN1A as disease-causing in epilepsy with myoclonic-atonic seizures.

PMID:37812819 SUPPORT Human Clinical

"It is caused by haploinsufficiency of SCN1A gene encoding for the α-subunit of the voltage-gated sodium channel Nav1.1."

Establishes SCN1A haploinsufficiency as the genetic cause of Dravet syndrome epileptic encephalopathy.

PMID:37812819 SUPPORT Model Organism

"Induction of heterozygous Nav1.1 mutation at P30 and P60 elicited susceptibility to the development of both spontaneous and hyperthermia-induced seizures and SUDEP rates comparable to P2-induced mice, with symptom onset accompanied by the characteristic GABAergic interneuron dysfunction."

Demonstrates that SCN1A haploinsufficiency causes seizures through GABAergic interneuron dysfunction, and this mechanism is active throughout life, not just during development.

SCN2A (Causative)

Show evidence (2 references)

PMID:31205438 SUPPORT

"The voltage-gated sodium channel neuronal type 2 alpha subunit (Navα1.2) encoded by the SCN2A gene causes early infantile epileptic encephalopathy (EIEE) inherited in an autosomal dominant manner."

Establishes SCN2A mutations as a cause of early infantile epileptic encephalopathy.

PMID:31205438 SUPPORT Human Clinical

"Clinically, it has variable presentations, ranging from benign familial infantile seizures (BFIS) to severe EIEE"

Documents the broad SCN2A phenotypic spectrum, from self-limiting benign familial infantile seizures at the mild end to severe early infantile epileptic encephalopathy, reflecting the allelic gain- versus loss-of-function heterogeneity of SCN2A-related epilepsy.

KCNQ2 (Causative)

Show evidence (2 references)

PMID:17675531 SUPPORT

"Benign familial neonatal seizures are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half of which lead to protein truncation."

Establishes KCNQ2 as the most common genetic cause of benign familial neonatal seizures.

ORPHA:1949 SUPPORT

"KCNQ2 | potassium voltage-gated channel subfamily Q member 2 | hgnc:6296 | Disease-causing germline mutation(s) in"

Orphanet confirms KCNQ2 as disease-causing in self-limited neonatal epilepsy.

KCNQ3 (Causative)

Show evidence (2 references)

ORPHA:1949 SUPPORT

"KCNQ3 | potassium voltage-gated channel subfamily Q member 3 | hgnc:6297 | Disease-causing germline mutation(s) in"

Orphanet data shows KCNQ3 as disease-causing in self-limited neonatal epilepsy.

ORPHA:307 SUPPORT

"KCNQ3 | potassium voltage-gated channel subfamily Q member 3 | hgnc:6297 | Major susceptibility factor in"

Orphanet data shows KCNQ3 as a major susceptibility factor in juvenile myoclonic epilepsy.

EFHC1 (Susceptibility)

Show evidence (2 references)

ORPHA:307 SUPPORT

"EFHC1 | EF-hand domain containing 1 | hgnc:16406 | Major susceptibility factor in"

Orphanet data identifies EFHC1 as a major susceptibility factor in JME.

ORPHA:1941 SUPPORT

"EFHC1 | EF-hand domain containing 1 | hgnc:16406 | Major susceptibility factor in"

Orphanet data identifies EFHC1 as a major susceptibility factor in juvenile absence epilepsy.

SLC6A1 (Causative)

Show evidence (1 reference)

ORPHA:1942 SUPPORT

"SLC6A1 | solute carrier family 6 member 1 | hgnc:11042 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet data shows SLC6A1 loss-of-function mutations as disease-causing in epilepsy with myoclonic-atonic seizures.

SYNGAP1 (Causative)

Gene: SYNGAP1 hgnc:11497

Show evidence (2 references)

ORPHA:1942 SUPPORT

"SYNGAP1 | synaptic Ras GTPase activating protein 1 | hgnc:11497 | Disease-causing germline mutation(s) in"

Orphanet data shows SYNGAP1 mutations as disease-causing in epilepsy with myoclonic-atonic seizures.

PMID:42161154 SUPPORT Human Clinical

"SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused"

Comprehensive review establishing SYNGAP1 haploinsufficiency as the molecular cause of SRD.

GABRA1 (Susceptibility)

Show evidence (3 references)

PMID:11992121 SUPPORT

"We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy."

Establishes GABRA1 mutations as a cause of juvenile myoclonic epilepsy through GABA receptor dysfunction.

ORPHA:307 SUPPORT

"GABRA1 | gamma-aminobutyric acid type A receptor subunit alpha1 | hgnc:4075 | Major susceptibility factor in"

Orphanet confirms GABRA1 as a major susceptibility factor in JME.

CGGV:assertion_60478d36-384e-4246-ba8a-730755d6f216-2024-09-03T170000.000Z SUPPORT Other

ClinGen classifies the GABRA1-epilepsy gene-disease relationship as definitive with autosomal dominant inheritance.

CDKL5 (Causative)

Show evidence (1 reference)

PMID:20493745 SUPPORT

"Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype."

Establishes CDKL5 mutations as a cause of early-onset epileptic encephalopathy.

DEPDC5 (Causative)

Show evidence (2 references)

PMID:31174205 SUPPORT Model Organism

"DEPDC5 is now recognized as one of the genes most often implicated in familial/inherited focal epilepsy and brain malformations."

Background statement in a mouse model study establishing DEPDC5 as a major gene in familial focal epilepsy.

PMID:31174205 SUPPORT Model Organism

"Individuals with pathogenic variants in DEPDC5 are at risk for epilepsy, associated neuropsychiatric comorbidities and sudden unexplained death in epilepsy."

Background statement documenting the clinical spectrum of DEPDC5-related epilepsy including SUDEP risk.

GABRD (Pathogenic Variants)

Gene: GABRD hgnc:4084

Show evidence (1 reference)

CGGV:assertion_64f743b4-408d-40d6-855b-ef9d67fc172e-2023-07-18T190000.000Z SUPPORT Other

ClinGen classifies the GABRD-epilepsy gene-disease relationship as limited with autosomal dominant inheritance.

GABRG2 (Pathogenic Variants)

Gene: GABRG2 hgnc:4087

Show evidence (1 reference)

CGGV:assertion_3a3176e9-ac0c-41fe-ae40-0750726c33d8-2020-01-21T170000.000Z SUPPORT Other

ClinGen classifies the GABRG2-epilepsy gene-disease relationship as definitive with autosomal dominant inheritance.

KPNA7 (Pathogenic Variants)

Gene: KPNA7 hgnc:21839

Show evidence (1 reference)

CGGV:assertion_9aa05adf-d315-4a06-b4f2-c5a5f6a23700-2025-10-07T160000.000Z SUPPORT Other

ClinGen classifies the KPNA7-epilepsy gene-disease relationship as limited with autosomal recessive inheritance.

PRIMA1 (Pathogenic Variants)

Gene: PRIMA1 hgnc:18319

Show evidence (1 reference)

CGGV:assertion_2247fe32-492c-4a1b-8e1c-5ee13bae944a-2025-01-07T180000.000Z SUPPORT Other

ClinGen classifies the PRIMA1-epilepsy gene-disease relationship as limited with autosomal recessive inheritance.

💊

Medical Actions

Antiseizure Medications

First-line treatment - levetiracetam, lamotrigine, valproate, carbamazepine.

Show evidence (1 reference)

PMID:30587993 SUPPORT

"Meta-analysis of the included RCTs indicated that LEV was as effective as carbamazepine (CBZ; treatment for 6 months: 58.9% vs 64.8%, OR=0.76, 95% CI: 0.50-1.16; 12 months: 54.9% vs 55.5%, OR=1.24, 95% CI: 0.79-1.93), oxcarbazepine (57.7% vs 59.8%, OR=1.34, 95% CI: 0.34-5.23), phenobarbital..."

Meta-analysis demonstrates comparable efficacy of levetiracetam with other first-line antiseizure medications.

Ketogenic Diet

High-fat, low-carbohydrate diet effective for drug-resistant epilepsy.

Show evidence (1 reference)

PMID:18456557 SUPPORT

"28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls"

Landmark RCT demonstrating significant seizure reduction with ketogenic diet in drug-resistant childhood epilepsy.

Vagus Nerve Stimulation

Implanted device for drug-resistant epilepsy.

Show evidence (1 reference)

PMID:21838505 SUPPORT

"After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy."

Meta-analysis of 74 studies with 3321 patients demonstrates VNS efficacy in medically refractory epilepsy.

Epilepsy Surgery

Resection of seizure focus for drug-resistant focal epilepsy.

Show evidence (1 reference)

PMID:11484687 SUPPORT

"At one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58 percent in the surgical group and 8 percent in the medical group (P<0.001)."

Landmark RCT in NEJM demonstrating surgery is superior to prolonged medical therapy for temporal-lobe epilepsy.

Responsive Neurostimulation

Closed-loop brain stimulation for focal epilepsy.

Show evidence (1 reference)

PMID:32690786 SUPPORT

"At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency."

Nine-year prospective study demonstrates sustained efficacy and safety of brain-responsive neurostimulation.

Deep Brain Stimulation

Anterior thalamic stimulation for drug-resistant epilepsy.

Show evidence (1 reference)

PMID:25663221 SUPPORT

"The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years."

SANTE trial 5-year follow-up demonstrates sustained efficacy of anterior thalamic deep brain stimulation.

SYNGAP1 Allele-Upregulating Antisense Oligonucleotide

Action: antisense oligonucleotide therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: antisense oligonucleotide NCIT:C1291

Allele-upregulating antisense oligonucleotides aim to compensate for SYNGAP1 haploinsufficiency by increasing translation from the intact wild-type allele, rather than replacing or correcting the mutant transcript. ASO programs targeting SRD are in preclinical and early translational development as part of the SRD precision-therapy pipeline.

Mechanism Target:

RESTORES SYNGAP1 Haploinsufficiency — Allele-upregulating ASOs increase translation from the intact SYNGAP1 allele, partially compensating for the haploinsufficient lesion that drives downstream SynGAP loss.

Show evidence (1 reference)

PMID:42161154 SUPPORT Other

"antisense oligonucleotides to upregulate the intact allele"

Samanta 2026 review identifies allele-upregulating ASOs as a precision-therapy approach in development for SRD.

AAV-Based SYNGAP1 Gene Replacement

Action: AAV gene replacement therapy Ontology label: gene therapy MAXO:0001001

Adeno-associated virus (AAV)-mediated delivery of a functional SYNGAP1 transgene aims to restore SynGAP protein expression in target neurons. AAV gene replacement is a precision-therapy strategy in preclinical development for SRD.

Mechanism Target:

RESTORES SYNGAP1 Haploinsufficiency — AAV-delivered SYNGAP1 transgene restores SynGAP protein levels in target neurons, directly addressing the haploinsufficient molecular lesion.

Show evidence (1 reference)

PMID:42161154 SUPPORT Other

"AAV-based gene replacement"

Samanta 2026 review identifies AAV-based gene replacement among precision-therapy strategies in development for SRD.

CRISPR-Mediated SYNGAP1 Transcriptional Activation

Action: CRISPR transcriptional activation therapy Ontology label: gene therapy MAXO:0001001

CRISPR activation (CRISPRa) using a catalytically inactive Cas9 fused to transcriptional activators is being developed to upregulate the intact SYNGAP1 allele in neurons. This complements ASO-based allele upregulation by acting at the transcriptional rather than translational level.

Mechanism Target:

RESTORES SYNGAP1 Haploinsufficiency — CRISPRa machinery recruits transcriptional activators to the wild-type SYNGAP1 locus, boosting transcription of the intact allele to compensate for haploinsufficiency.

Show evidence (1 reference)

PMID:42161154 SUPPORT Other

"CRISPR-mediated transcriptional activation"

Samanta 2026 review identifies CRISPR-mediated transcriptional activation as a precision-therapy strategy under development for SRD.

🌍

Environmental Factors

Traumatic Brain Injury

Major cause of acquired epilepsy

CNS Infections

Meningitis, encephalitis

Stroke

Leading cause in older adults

Brain Tumors

Can cause focal epilepsy

Perinatal Injury

Hypoxic-ischemic encephalopathy

🔬

Clinical Trials

NCT06555965 NOT_APPLICABLE RECRUITING

Prospective natural history study of STXBP1- and SYNGAP1-related disorders enrolling participants for detailed developmental, seizure, and quality-of-life assessments. Establishes baseline clinical-spectrum data intended to support upcoming SYNGAP1-targeted treatment trials referenced in the SRD precision-therapy block of this entry.

Target Phenotypes: Seizure HP:0001250 Intellectual disability HP:0001249 Autistic behavior HP:0000729

Show evidence (1 reference)

clinicaltrials:NCT06555965 SUPPORT

"The primary objective of the study is to better define and outline the clinical spectrum of STXBP1 and SYNGAP1 through detailed developmental, seizure, and quality of life assessments"

SRD-specific natural history study capturing developmental, seizure, and quality-of-life trajectory needed to support the upcoming SYNGAP1 treatment trials referenced in this entry's SRD precision-therapy block.

{ }

Source YAML

click to show

name: Epilepsy
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-05-01T12:00:00Z'
description: >-
  Epilepsy is a chronic neurological disorder defined by an enduring predisposition
  to recurrent unprovoked seizures arising from abnormal, excessive, and
  synchronous neuronal activity. It encompasses focal and generalized syndromes
  (e.g., temporal lobe epilepsy, juvenile myoclonic epilepsy, childhood absence
  epilepsy). The core mechanism is an imbalance between neuronal excitation and
  inhibition producing hyperexcitability and hypersynchrony, driven by ion-channel,
  synaptic, and network dysfunction.
category: Complex
parents:
- Neurological Disease
disease_term:
  preferred_term: epilepsy
  term:
    id: MONDO:0005027
    label: epilepsy
prevalence:
- population: Global
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 638.0
  percentage: 6.38 per 1,000 (active epilepsy)
  evidence:
  - reference: PMID:27986877
    reference_title: "Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The point prevalence of active epilepsy was 6.38 per 1,000 persons"
    explanation: Systematic review and meta-analysis of 222 studies providing the most comprehensive global prevalence estimate for active epilepsy.
- population: Drug-Resistant Epilepsy
  percentage: 30% of epilepsy patients
  evidence:
  - reference: PMID:30426482
    reference_title: "The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pooled prevalence proportion of DRE among epilepsy patients was 0.30"
    explanation: Meta-analysis of 35 studies showing approximately 30% of epilepsy patients develop drug resistance.
- population: Juvenile Myoclonic Epilepsy (Norway)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 56.0
  percentage: 5.6 per 10,000
  evidence:
  - reference: PMID:27861775
    reference_title: "Prevalence of juvenile myoclonic epilepsy in people <30 years of age-A population-based study in Norway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The point prevalence was estimated at 5.6/10,000. JME constituted 9.3% of all epilepsies in the age group we investigated."
    explanation: Population-based study providing JME-specific prevalence in Norway.
has_subtypes:
- name: Focal Epilepsy
  description: Seizures originate from a localized brain region.
- name: Generalized Epilepsy
  description: Seizures involve both hemispheres from onset.
- name: Temporal Lobe Epilepsy
  description: Most common focal epilepsy, often with mesial temporal sclerosis.
- name: Juvenile Myoclonic Epilepsy
  display_name: Juvenile Myoclonic Epilepsy (JME)
  subtype_term:
    preferred_term: juvenile myoclonic epilepsy
    term:
      id: MONDO:0009696
      label: juvenile myoclonic epilepsy
  description: >
    A rare epilepsy syndrome characterized by adolescence/young adulthood onset of myoclonic
    with or without other generalized seizure types in an otherwise healthy individual.
    The EEG shows 3-5.5 Hz generalized spike-waves and polyspike-waves. Photosensitivity is common.
  evidence:
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "A rare epilepsy syndrome characterized by adolescence/young adulthood onset of myoclonic with or without other generalized seizure types in an otherwise healthy individual."
    explanation: Orphanet definition of juvenile myoclonic epilepsy.
- name: Childhood Absence Epilepsy
  description: Frequent brief absence seizures beginning in childhood.
- name: Juvenile Absence Epilepsy
  display_name: Juvenile Absence Epilepsy (JAE)
  subtype_term:
    preferred_term: juvenile absence epilepsy
    term:
      id: MONDO:0800453
      label: juvenile absence epilepsy
  description: >
    A genetic epilepsy with onset occurring around puberty, characterized by sporadic
    occurrence of absence seizures, frequently associated with generalized tonic-clonic
    seizures and sporadic myoclonic jerks.
  evidence:
  - reference: ORPHA:1941
    reference_title: "Juvenile absence epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "Juvenile absence epilepsy (JAE) is a genetic epilepsy with onset occurring around puberty."
    explanation: Orphanet definition of juvenile absence epilepsy.
- name: Epilepsy with Myoclonic-Atonic Seizures
  display_name: Epilepsy with Myoclonic-Atonic Seizures (Doose Syndrome)
  subtype_term:
    preferred_term: epilepsy with myoclonic atonic seizures
    term:
      id: MONDO:0014633
      label: epilepsy with myoclonic atonic seizures
  description: >
    A rare childhood onset epilepsy syndrome characterized by multiple seizure types
    including myoclonic-atonic seizures that occur usually in previously healthy children.
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "A rare, childhood onset epilepsy syndrome characterized by multiple seizure types including myoclonic-atonic (MA) seizures that occur usually in previously healthy children."
    explanation: Orphanet definition of epilepsy with myoclonic-atonic seizures.
- name: Self-Limited Neonatal Epilepsy
  display_name: Self-Limited Neonatal Epilepsy (BFNS)
  subtype_term:
    preferred_term: self-limited neonatal epilepsy
    term:
      id: MONDO:0016027
      label: benign neonatal seizures
  description: >
    A rare genetic epilepsy syndrome characterized by seizure onset typically in the first
    week of life, in otherwise healthy newborns, usually resolving within the first year of life.
    Autosomal dominant inheritance with KCNQ2 and KCNQ3 mutations.
  evidence:
  - reference: ORPHA:1949
    reference_title: "Self-limited neonatal epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "A rare genetic epilepsy syndrome characterized by seizures onset typically in the first week of life, in otherwise healthy newborns, and usually resolving within the first year of life."
    explanation: Orphanet definition of self-limited neonatal epilepsy.
- name: SYNGAP1-related Disorder
  display_name: SYNGAP1-related Disorder (SRD)
  subtype_term:
    preferred_term: SYNGAP1-related developmental and epileptic encephalopathy
    term:
      id: MONDO:0012960
      label: intellectual disability, autosomal dominant 5
  description: >
    A monogenic developmental and epileptic encephalopathy caused by SYNGAP1 haploinsufficiency.
    Presents with intellectual disability, generalized epilepsy, and autism spectrum-associated
    behavioral and sensory abnormalities. Individuals typically present in infancy with global
    developmental delay and hypotonia, with later-onset generalized epilepsy characterized by
    atypical absences, myoclonic and myoclonic-atonic seizures, and eyelid myoclonia with reflex
    triggers. Drug resistance is common, and developmental regression frequently coincides with
    seizure and EEG worsening. Nearly all individuals manifest moderate-to-severe intellectual
    disability with disproportionately severe expressive language impairment, autism spectrum
    features, ADHD-like symptoms, severe irritability, and marked sensory abnormalities.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Comprehensive review establishing SRD clinical phenotype and characteristic seizure types.
pathophysiology:
- name: Neuronal Hyperexcitability
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
  description: >
    Imbalance between excitatory (glutamate) and inhibitory (GABA)
    neurotransmission leads to synchronized, excessive neuronal firing.
    Ion channel dysfunction is a common mechanism.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: GABAergic Interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: Synaptic Transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
- name: Blood-Brain Barrier Disruption
  description: >
    Loss of tight junction proteins (claudin-5) in brain endothelial cells
    leads to blood-brain barrier breakdown, allowing albumin extravasation
    and disruption of ionic homeostasis.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Blood-Brain Barrier Maintenance
    term:
      id: GO:0035633
      label: maintenance of blood-brain barrier
  downstream:
  - target: Network Hyperexcitability
    description: BBB disruption causes albumin entry and altered ionic balance, increasing neuronal excitability.
  evidence:
  - reference: PMID:35422069
    reference_title: "Microvascular stabilization via blood-brain barrier regulation prevents seizure activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption."
    explanation: Demonstrates that BBB dysfunction occurs in human epilepsy patients and is characterized by loss of tight junction proteins.
  - reference: PMID:35422069
    reference_title: "Microvascular stabilization via blood-brain barrier regulation prevents seizure activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption"
    explanation: Shows that partial (heterozygous) loss of claudin-5 or focal hippocampal disruption worsens both chemically-induced seizures and BBB breakdown, indicating a dose-dependent contribution of tight-junction integrity to seizure susceptibility.
  - reference: PMID:35422069
    reference_title: "Microvascular stabilization via blood-brain barrier regulation prevents seizure activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality."
    explanation: Establishes causal role of BBB dysfunction in seizure generation, showing that disruption of endothelial tight junctions is sufficient to trigger spontaneous seizures.
  - reference: PMID:35422069
    reference_title: "Microvascular stabilization via blood-brain barrier regulation prevents seizure activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy."
    explanation: Provides proof-of-concept that stabilizing the BBB through claudin-5 upregulation can prevent seizures, supporting BBB as a therapeutic target.
- name: Network Hyperexcitability
  description: >
    Abnormal synchronization of neuronal networks that can recruit
    adjacent or distant brain regions, leading to seizure propagation.
  biological_processes:
  - preferred_term: Neuronal Activity
    term:
      id: GO:0019226
      label: transmission of nerve impulse
- name: Neuroinflammation and Gliosis
  description: >
    Activation of microglia and reactive astrocytes following brain injury
    or during seizures, releasing inflammatory mediators and undergoing
    morphological changes that alter the brain microenvironment.
  cell_types:
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: Microglia
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: Neuroinflammatory Response
    term:
      id: GO:0150076
      label: neuroinflammatory response
  downstream:
  - target: Lipoxygenase-Mediated Lipid Peroxidation and Eicosanoid Signaling
    description: Neuroinflammatory activation of phospholipase A2 releases arachidonic acid from membrane phospholipids, providing substrate for LOX-mediated eicosanoid generation (a positive-feedback arm of the neuroinflammatory cascade).
  - target: Complement System-Mediated Microglial Neuroinflammation
    description: Neuroinflammatory signals activate complement cascade and microglial synaptic pruning pathways.
  - target: Synaptic Reorganization
    description: Inflammatory mediators and glial activation alter synaptic structure and connectivity.
- name: Lipoxygenase-Mediated Lipid Peroxidation and Eicosanoid Signaling
  description: >
    Lipoxygenase (LOX) enzymes, particularly 5-LOX and 12/15-LOX, catalyze the generation of bioactive
    lipid metabolites (eicosanoids including leukotrienes and lipoxins) from arachidonic acid. LOX-mediated
    lipid peroxidation contributes to oxidative stress and pro-inflammatory signaling, with dysregulation
    of LOX activity contributing to blood-brain barrier disruption, glial cell activation, cytokine release,
    immune cell infiltration, and neuronal hyperexcitability. These eicosanoid mediators propagate
    neuroinflammatory cascades that promote seizure susceptibility and drug-resistant epilepsy.
  cell_types:
  - preferred_term: Microglia
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Lipoxygenase Pathway
    term:
      id: GO:0019372
      label: lipoxygenase pathway
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: Oxidative Stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Blood-Brain Barrier Disruption
    description: LOX-derived eicosanoids and oxidative stress compromise endothelial tight junction integrity (claudin-5) leading to BBB breakdown.
  - target: Neuroinflammation and Gliosis
    description: LOX-mediated lipid peroxidation activates microglia and astrocytes, propagating neuroinflammatory signaling.
  - target: Neuronal Hyperexcitability
    description: Eicosanoid mediators from LOX activity enhance neuronal excitability through altered ion channel function and synaptic transmission.
  evidence:
  - reference: PMID:42331232
    reference_title: "Lipoxygenase (LOX) signaling in epilepsy: Pathophysiology and therapeutic prospects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "lipoxygenase (LOX) enzymes play a pivotal role in mediating oxidative stress, lipid peroxidation, and pro-inflammatory signaling through the generation of bioactive lipid metabolites"
    explanation: Review establishes LOX enzymes as central mediators of oxidative and inflammatory stress in epilepsy pathophysiology.
  - reference: PMID:42331232
    reference_title: "Lipoxygenase (LOX) signaling in epilepsy: Pathophysiology and therapeutic prospects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dysregulation of LOX activity contributes to epileptogenic processes, such as blood-brain barrier disruption, glial activation, cytokine release, immune-cell infiltration, neuronal hyperexcitability, and neuronal death"
    explanation: Comprehensive review documenting LOX dysregulation as a driver of multiple epileptogenic mechanisms including BBB disruption and glial activation.
  - reference: PMID:42331232
    reference_title: "Lipoxygenase (LOX) signaling in epilepsy: Pathophysiology and therapeutic prospects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LOX pathways, particularly those mediated by 5-LOX and 12/15-LOX, play a major role in the pathophysiology of epileptic seizures and may also contribute to neuropsychiatric comorbidities"
    explanation: Review identifies 5-LOX and 12/15-LOX as principal contributors to both seizure pathophysiology and associated neuropsychiatric complications in epilepsy.
- name: Complement System-Mediated Microglial Neuroinflammation
  description: >
    Complement cascade activation contributes to microglial-mediated
    neuroinflammation and synaptic remodeling in epilepsy. Accumulating preclinical
    evidence indicates that abnormal complement activation contributes to
    epileptogenesis as a potential driver rather than merely an epiphenomenon of
    neuroinflammation, promoting aberrant synaptic remodeling and progressive
    neuronal dysfunction underlying seizure susceptibility.
  cell_types:
  - preferred_term: Microglia
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  downstream:
  - target: Synaptic Reorganization
    description: Complement-mediated synaptic pruning and microglial phagocytosis contribute to aberrant synaptic remodeling and loss of network connectivity.
  evidence:
  - reference: PMID:42269875
    reference_title: "Complement System-Mediated Immunomodulation in Epilepsy: From Pathogenesis to Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis. This suggests that complement dysregulation is not merely an epiphenomenon of neuroinflammation but rather a potential driver of seizure development and progression."
    explanation: Review synthesizes preclinical evidence that complement system dysregulation is a primary driver of epileptogenesis, not just a secondary consequence of inflammation.
  - reference: PMID:42269875
    reference_title: "Complement System-Mediated Immunomodulation in Epilepsy: From Pathogenesis to Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review summarizes current preclinical and clinical evidence on complement-mediated mechanisms in epilepsy, with a focus on neuroinflammation, synaptic remodeling, glial proliferation, biomarkers, and therapeutic targets."
    explanation: Establishes that complement system activation is mechanistically linked to multiple pathophysiological processes in epilepsy including synaptic remodeling and glial activation.
- name: Synaptic Reorganization
  description: >
    Aberrant sprouting, formation of new synaptic connections, and
    altered synaptic plasticity that promote recurrent excitatory circuits
    and seizure susceptibility.
  biological_processes:
  - preferred_term: Synaptic Plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
- name: mTOR Pathway Hyperactivation
  description: >
    Constitutive activation of the mechanistic target of rapamycin (mTOR)
    signaling pathway, driving abnormal neuronal growth and development
    of dysmorphic neurons in focal cortical malformations.
  biological_processes:
  - preferred_term: mTOR Signaling
    term:
      id: GO:0031929
      label: TOR signaling
  downstream:
  - target: Dysmorphic Neuron Generation
    description: Hyperactive mTOR signaling causes abnormal neuronal soma enlargement and cytoskeletal changes.
  evidence:
  - reference: PMID:31174205
    reference_title: "Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treatment with the mTORC1 inhibitor rapamycin starting after 3 weeks of age significantly prolonged the survival of Depdc5cc+ mice and partially rescued the behavioral hyperactivity."
    explanation: Demonstrates that mTORC1 pathway hyperactivation caused by DEPDC5 loss drives epilepsy pathogenesis and that mTOR inhibition can rescue the phenotype.
  - reference: PMID:31174205
    reference_title: "Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rapamycin decreased the enlarged brain size of Depdc5cc+ mice with corresponding decrease in neuronal soma size."
    explanation: Shows that mTOR hyperactivation causes abnormal neuronal growth contributing to epileptogenesis, which can be reversed by mTOR inhibition.
- name: Dysmorphic Neuron Generation
  description: >
    Formation of abnormally enlarged neurons with cytoskeletal disruption
    and cellular senescence markers, creating epileptogenic foci in
    cortical malformations.
  evidence:
  - reference: PMID:38710875
    reference_title: "Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity."
    explanation: Supports senescence signatures in pathological cells of mTOR-related FCD, but only partially supports all structural details in this descriptor.
  - reference: PMID:38710875
    reference_title: "Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model"
    explanation: Supports seizure reduction via senolytics in an mTOR-related model, but only partially supports this broader dysmorphic neuron descriptor.
- name: SYNGAP1 Haploinsufficiency
  conforms_to: "excitatory_synapse_scaffold_disruption#Postsynaptic Scaffold Disruption"
  description: >
    Heterozygous loss-of-function variants in SYNGAP1 cause haploinsufficiency of the
    postsynaptic Ras GTPase-activating protein SynGAP, the proximal molecular lesion
    in SYNGAP1-related disorder.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Synapse assembly
    term:
      id: GO:0007416
      label: synapse assembly
  - preferred_term: Glutamate receptor signaling pathway
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  downstream:
  - target: Ras/Rap-ERK Signaling Dysregulation
    description: Reduced SynGAP protein removes negative regulation of Ras/Rap-ERK signaling at the postsynaptic density.
  - target: GABAergic Interneuron Dysfunction
    description: Beyond glutamatergic pyramidal neurons, SynGAP haploinsufficiency also impairs the development and function of GABAergic inhibitory interneurons.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused"
    explanation: Identifies SYNGAP1 haploinsufficiency as the causal molecular lesion of SRD.
- name: Ras/Rap-ERK Signaling Dysregulation
  description: >
    SynGAP normally inactivates Ras and Rap at the postsynaptic density; its loss
    produces excessive Ras/Rap-ERK signaling that perturbs downstream synaptic
    structural and functional plasticity.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Ras/Rap-ERK signaling
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: INCREASED
  downstream:
  - target: Accelerated Dendritic Spine Maturation
    description: Excess Ras/Rap-ERK signaling drives precocious dendritic spine structural maturation.
  - target: AMPA Receptor Trafficking Disruption
    description: Dysregulated Ras/Rap-ERK signaling alters trafficking of AMPA-type glutamate receptors at the synapse.
  - target: Postsynaptic Density Destabilization
    description: Persistent Ras/Rap-ERK signaling destabilizes the molecular architecture of the postsynaptic density.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of the postsynaptic Ras GTPase-activating protein SynGAP disrupts Ras/Rap-ERK signaling"
    explanation: Review of mouse and in vitro data establishing Ras/Rap-ERK dysregulation as the immediate signaling consequence of SynGAP loss.
- name: Accelerated Dendritic Spine Maturation
  description: >
    Loss of SynGAP-mediated regulation drives premature structural maturation of
    dendritic spines on cortical pyramidal neurons, locking spines into mature
    morphologies earlier than the normal developmental timetable.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Dendritic spine maturation
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: INCREASED
  downstream:
  - target: Cortical Circuit Hard-Wiring
    description: Precocious spine maturation contributes to early lock-in of cortical circuit connectivity.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "accelerates dendritic spine maturation"
    explanation: Review synthesis of animal-model evidence that SynGAP loss accelerates dendritic spine structural maturation.
- name: AMPA Receptor Trafficking Disruption
  description: >
    SynGAP loss alters the trafficking of AMPA-type glutamate receptors to and
    from the postsynaptic membrane, perturbing excitatory synaptic transmission
    strength and plasticity.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: AMPA receptor trafficking
    term:
      id: GO:0099072
      label: regulation of postsynaptic membrane neurotransmitter receptor levels
  downstream:
  - target: Cortical Circuit Hard-Wiring
    description: Altered AMPA receptor trafficking contributes to aberrant excitatory synaptic strength underlying premature circuit consolidation.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "alters AMPA receptor trafficking"
    explanation: Review synthesis of in vitro and animal-model evidence for altered AMPA receptor trafficking with SynGAP loss.
- name: Postsynaptic Density Destabilization
  conforms_to: "excitatory_synapse_scaffold_disruption#Excitatory Postsynaptic Structural Deficit"
  description: >
    SynGAP is a major scaffold component of the postsynaptic density; its
    haploinsufficiency destabilizes postsynaptic density architecture and
    scaffolding integrity at excitatory synapses.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Postsynaptic density assembly
    term:
      id: GO:0097107
      label: postsynaptic density assembly
    modifier: DECREASED
  downstream:
  - target: Cortical Circuit Hard-Wiring
    description: Loss of PSD scaffolding integrity contributes to aberrant maturation and stabilization of cortical synapses.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "destabilizes postsynaptic density architecture"
    explanation: Review synthesis of model-organism data on PSD architectural destabilization with SynGAP loss.
- name: Cortical Circuit Hard-Wiring
  conforms_to: "excitatory_synapse_scaffold_disruption#Circuit-Level Dysfunction"
  description: >
    Premature spine maturation, altered AMPA receptor trafficking, and PSD
    destabilization converge to lock cortical circuits into early, rigid
    connectivity patterns, with abnormal oscillatory dynamics and impaired
    synaptic plasticity at the network level.
  cell_types:
  - preferred_term: Pyramidal Neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: DECREASED
  downstream:
  - target: Neuronal Hyperexcitability
    description: Aberrant cortical circuit consolidation and impaired plasticity contribute to excitatory/inhibitory imbalance underlying SRD seizures.
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "producing early \"hard-wiring\" of cortical circuits, abnormal oscillatory dynamics, and impaired plasticity."
    explanation: Review synthesis describing the network-level developmental consequence of converging molecular and synaptic defects in SRD.
- name: GABAergic Interneuron Dysfunction
  description: >
    SYNGAP1 is expressed in GABAergic inhibitory interneurons as well as
    glutamatergic pyramidal neurons. Haploinsufficiency in medial ganglionic
    eminence-derived parvalbumin and somatostatin interneurons impairs inhibitory
    circuit development and produces abnormal cortical oscillatory dynamics,
    reducing effective inhibitory tone and contributing to the excitatory/inhibitory
    imbalance that drives network hyperexcitability in SRD.
  cell_types:
  - preferred_term: GABAergic Interneuron
    term:
      id: CL:0011005
      label: GABAergic interneuron
  biological_processes:
  - preferred_term: GABAergic synaptic transmission
    term:
      id: GO:0051932
      label: synaptic transmission, GABAergic
    modifier: DECREASED
  downstream:
  - target: Neuronal Hyperexcitability
    description: Reduced interneuron-mediated inhibition shifts the cortical excitatory/inhibitory balance toward hyperexcitability and seizure susceptibility.
  evidence:
  - reference: PMID:37558489
    reference_title: "Interneuron-Targeted Disruption of SYNGAP1 Alters Sensory Representations in the Neocortex and Impairs Sensory Learning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SynGAP plays a critical role in the function of GABAergic inhibitory interneurons as well as glutamatergic pyramidal neurons in the neocortex"
    explanation: Mouse study establishing that SynGAP function in inhibitory interneurons contributes to cortical circuit function, supporting an inhibitory-side mechanism distinct from the glutamatergic arm.
  - reference: PMID:39406516
    reference_title: "Developmental Syngap1 Haploinsufficiency in Medial Ganglionic Eminence-Derived Interneurons Impairs Auditory Cortex Activity, Social Behavior, and Extinction of Fear Memory."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with prenatal-onset Syngap1 haploinsufficiency restricted to Nkx2.1-expressing neurons show abnormal cortical oscillations and increased entrainment induced by 40 Hz auditory stimulation but lack stimulus-specific adaptation"
    explanation: Mouse study showing Syngap1 haploinsufficiency restricted to MGE-derived (Nkx2.1-expressing) interneurons produces abnormal cortical oscillations, linking interneuron dysfunction to network-level alterations in SRD.
- name: Complement System Activation and Dysregulation
  description: >
    Aberrant activation of the complement cascade (C1q, C3, C5) leads to dysregulated
    complement-mediated signaling, driving both neuroinflammation and synaptic remodeling
    that directly contribute to seizure development and disease progression. Complement
    dysregulation is not merely an epiphenomenon of neuroinflammation but a potential
    driver of epileptogenesis.
  cell_types:
  - preferred_term: Microglia
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  - preferred_term: Regulation of Complement Activation
    term:
      id: GO:0030449
      label: regulation of complement activation
  downstream:
  - target: Neuroinflammation and Gliosis
    description: Complement dysregulation drives microglial C3 deposition and inflammatory mediator release, contributing to the neuroinflammatory cascade.
  - target: Synaptic Reorganization
    description: Complement-mediated C3b deposition and microglial-synaptic pruning alter synaptic structure, connectivity, and plasticity.
  evidence:
  - reference: PMID:42269875
    reference_title: "Complement System-Mediated Immunomodulation in Epilepsy: From Pathogenesis to Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis"
    explanation: Review synthesis establishing complement activation as a key driver of epileptogenesis, with focus on neuroinflammation, synaptic remodeling, and glial proliferation mechanisms.
phenotypes:
- name: Seizures
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
- name: Generalized Tonic-Clonic Seizures
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: Juvenile Absence Epilepsy
  description: >
    Bilateral tonic stiffening followed by rhythmic clonic jerking, with loss
    of consciousness. The most common seizure type across multiple epilepsy syndromes.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: ORPHA:1941
    reference_title: "Juvenile absence epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0002069 | Bilateral tonic-clonic seizure | Very frequent (99-80%)"
    explanation: Orphanet phenotype data for juvenile absence epilepsy shows bilateral tonic-clonic seizures are very frequent.
- name: Absence Seizures
  category: Neurological
  frequency: FREQUENT
  subtype: Juvenile Absence Epilepsy
  description: >
    Brief episodes of impaired awareness with behavioral arrest, typically lasting
    5-30 seconds with abrupt onset and offset. Characteristic 3 Hz spike-and-wave
    discharges on EEG.
  phenotype_term:
    preferred_term: Absence seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: ORPHA:1941
    reference_title: "Juvenile absence epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0002121 | Generalized non-motor (absence) seizure | Frequent (79-30%)"
    explanation: Orphanet data shows absence seizures are frequent in juvenile absence epilepsy.
- name: Myoclonic Seizures
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: Juvenile Myoclonic Epilepsy
  description: >
    Brief, shock-like involuntary jerks of a muscle or group of muscles,
    often occurring in the morning shortly after awakening.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0007000 | Morning myoclonic jerks | Very frequent (99-80%)"
    explanation: Orphanet cites HP:0007000 (Morning myoclonic jerks), a more specific child term of HP:0032794 (Myoclonic seizure). The broader term is used here as it applies across epilepsy subtypes, not just JME.
- name: Focal-Onset Seizures
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: Self-Limited Neonatal Epilepsy
  description: >
    Seizures originating from a specific brain region, with clinical features
    reflecting the function of the cortical area involved. May be with preserved
    or impaired awareness.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: ORPHA:1949
    reference_title: "Self-limited neonatal epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0007359 | Focal-onset seizure | Very frequent (99-80%)"
    explanation: Orphanet data shows focal-onset seizures are very frequent in self-limited neonatal epilepsy.
- name: Myoclonic-Atonic Seizures
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: Epilepsy with Myoclonic-Atonic Seizures
  description: >
    Seizures with a brief myoclonic jerk followed by loss of muscle tone causing
    a fall. The defining seizure type in Doose syndrome.
  phenotype_term:
    preferred_term: Myoclonic-atonic seizure
    term:
      id: HP:0011170
      label: Generalized myoclonic-atonic seizure
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0011170 | Myoclonic atonic seizures | Very frequent (99-80%)"
    explanation: Orphanet data shows myoclonic-atonic seizures are very frequent in Doose syndrome.
- name: Status Epilepticus
  category: Neurological
  frequency: VERY_RARE
  subtype: Juvenile Myoclonic Epilepsy
  description: >
    Prolonged seizure activity (>5 minutes) or recurrent seizures without recovery
    of consciousness between episodes. A medical emergency with significant mortality risk.
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0002133 | Status epilepticus | Very rare (<4-1%)"
    explanation: Orphanet data shows status epilepticus is very rare in JME.
- name: Febrile Seizures
  category: Neurological
  frequency: OCCASIONAL
  description: >
    Seizures occurring in the setting of fever in children aged 3 months to 6 years.
    A risk factor for later development of epilepsy.
  phenotype_term:
    preferred_term: Febrile seizure
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  evidence:
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0002373 | Febrile seizure (within the age range of 3 months to 6 years) | Occasional (29-5%)"
    explanation: Orphanet data shows febrile seizures occur occasionally in JME patients.
- name: EEG Abnormality
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Abnormal electroencephalographic patterns including interictal epileptiform
    discharges, spike-and-wave complexes, and polyspike-wave complexes. EEG is
    a cornerstone of epilepsy diagnosis and classification.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0002392 | EEG with polyspike wave complexes | Very frequent (99-80%)"
    explanation: Orphanet data shows polyspike-wave complexes on EEG are very frequent in JME.
  - reference: ORPHA:1949
    reference_title: "Self-limited neonatal epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0011188 | Focal EEG discharges with secondary generalization | Very frequent (99-80%)"
    explanation: Orphanet data shows focal EEG discharges with secondary generalization are very frequent in self-limited neonatal epilepsy.
- name: Postictal Confusion
  category: Neurological
  frequency: FREQUENT
  notes: Confusion following generalized or complex partial seizures
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
- name: Aura
  category: Neurological
  frequency: FREQUENT
  subtype: Focal Epilepsy
  notes: Warning symptoms before focal seizures including visual, somatosensory, olfactory, or psychic phenomena
  phenotype_term:
    preferred_term: Sensory Disturbance
    term:
      id: HP:0003474
      label: Somatic sensory dysfunction
- name: Automatisms
  category: Neurological
  frequency: FREQUENT
  subtype: Temporal Lobe Epilepsy
  description: >
    Repetitive, semi-purposeful motor activities occurring during focal seizures
    with impaired awareness. Common in temporal lobe epilepsy, including orofacial
    and manual automatisms.
  phenotype_term:
    preferred_term: Focal automatism seizure
    term:
      id: HP:0032898
      label: Focal automatism seizure
- name: Memory Impairment
  category: Cognitive
  description: >
    Cognitive dysfunction affecting memory is common, particularly in temporal
    lobe epilepsy. Both seizures and some antiseizure medications contribute.
  notes: Frequently reported in temporal lobe epilepsy; quantitative frequency data across all epilepsy subtypes is limited.
  phenotype_term:
    preferred_term: Memory Impairment
    term:
      id: HP:0002354
      label: Memory impairment
- name: Intellectual Disability
  category: Cognitive
  frequency: FREQUENT
  subtype: Epilepsy with Myoclonic-Atonic Seizures
  description: >
    Intellectual disability is associated with several epilepsy syndromes,
    particularly the epileptic encephalopathies and myoclonic-atonic epilepsy.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
    explanation: Orphanet data shows intellectual disability is frequent in epilepsy with myoclonic-atonic seizures.
- name: Attention Deficit Hyperactivity Disorder
  category: Psychiatric
  frequency: FREQUENT
  subtype: Epilepsy with Myoclonic-Atonic Seizures
  description: >
    ADHD is a common comorbidity across epilepsy syndromes, particularly
    in childhood-onset forms.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0007018 | Attention deficit hyperactivity disorder | Frequent (79-30%)"
    explanation: Orphanet data shows ADHD is frequent in epilepsy with myoclonic-atonic seizures.
- name: Depression
  category: Psychiatric
  frequency: OCCASIONAL
  description: >
    Depression is highly prevalent in people with epilepsy, with a bidirectional
    relationship. Both shared neurobiological mechanisms and psychosocial factors
    contribute.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:23175727
    reference_title: "Depression in epilepsy: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overall prevalence of active (current or past-year) depression of 23.1%"
    explanation: Systematic review and meta-analysis of 14 studies showing 23.1% prevalence of active depression in people with epilepsy.
  - reference: PMID:23175727
    reference_title: "Depression in epilepsy: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overall OR of active depression of 2.77 (95% CI 2.09-3.67) in PWE"
    explanation: People with epilepsy have 2.77 times higher odds of active depression compared to the general population.
  - reference: PMID:26549780
    reference_title: "Comorbidities of epilepsy: current concepts and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several mechanisms explain how epilepsy and comorbidities are associated, including shared risk factors and bidirectional relations."
    explanation: Keezer et al. reviews the bidirectional relationship between epilepsy and depression, with shared pathophysiological mechanisms.
- name: Anxiety
  category: Psychiatric
  frequency: OCCASIONAL
  subtype: Juvenile Absence Epilepsy
  description: >
    Anxiety disorders are common in epilepsy, with both interictal and
    peri-ictal anxiety. Prevalence is significantly elevated compared to
    the general population.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: ORPHA:1941
    reference_title: "Juvenile absence epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "HP:0000739 | Anxiety | Occasional (29-5%)"
    explanation: Orphanet data shows anxiety is an occasional phenotype in juvenile absence epilepsy.
  - reference: PMID:26549780
    reference_title: "Comorbidities of epilepsy: current concepts and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight times more common in people with epilepsy"
    explanation: Keezer et al. Lancet Neurol review documents anxiety among the major comorbidities of epilepsy.
- name: Headache
  category: Neurological
  description: >
    Migraine and other headache disorders are common comorbidities of epilepsy,
    with a bidirectional relationship. Both peri-ictal headaches and interictal
    migraine occur.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:26549780
    reference_title: "Comorbidities of epilepsy: current concepts and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight times more common in people with epilepsy"
    explanation: Keezer et al. Lancet Neurol review documents migraine as a major comorbidity of epilepsy.
- name: Moderate-to-Severe Intellectual Disability
  category: Cognitive
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Developmental delay or intellectual disability is the defining, near-universal
    feature of SYNGAP1-related disorder, affecting essentially all individuals. In
    most it is moderate to severe, with a disproportionately severe expressive
    language impairment relative to the overall cognitive level (captured separately).
    This is the phenotype for which the disorder was historically named
    ("SYNGAP1-related intellectual disability").
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30789692
    reference_title: "SYNGAP1-Related Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay (DD) or intellectual disability (ID) (100% of affected individuals)"
    explanation: GeneReviews reports developmental delay or intellectual disability in 100% of individuals with SYNGAP1-related intellectual disability, establishing it as the defining near-universal feature and supporting the VERY_FREQUENT classification.
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all individuals with SRD have moderate-to-severe intellectual disability"
    explanation: Samanta 2026 review confirms that nearly all individuals with SRD have moderate-to-severe intellectual disability.
- name: Autism Spectrum Features
  category: Psychiatric
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Autism spectrum behavioral features are a near-universal comorbidity of SRD,
    co-occurring with intellectual disability and generalized epilepsy. ASD and
    other behavioral abnormalities affect up to half of individuals with SYNGAP1-
    related intellectual disability per GeneReviews, and Samanta 2026 positions
    autism spectrum features among the comorbidities present in almost all SRD
    individuals.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: Samanta 2026 review identifies autism spectrum features as part of the cluster of almost-universal SRD comorbidities, substantiating the VERY_FREQUENT classification.
  - reference: PMID:30789692
    reference_title: "SYNGAP1-Related Intellectual Disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "autism spectrum disorder (ASD) and other behavioral abnormalities (≤50%)"
    explanation: GeneReviews quantifies formal ASD diagnosis at ≤50% prevalence, which on its own supports FREQUENT rather than VERY_FREQUENT. Marked PARTIAL because Samanta 2026 uses the broader "autism spectrum features" construct (almost universal); the GeneReviews figure refers to the narrower formal ASD diagnosis.
- name: Profound Expressive Language Impairment
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Disproportionately severe expressive language impairment is a clinically
    distinctive SRD feature — expressive deficits exceed what would be expected
    from the level of intellectual disability alone, and exceed receptive
    language ability.
  phenotype_term:
    preferred_term: Profound expressive language impairment
    term:
      id: HP:0002474
      label: Expressive language delay
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all individuals with SRD have moderate-to-severe intellectual disability, characterized by disproportionately severe expressive language impairment."
    explanation: Samanta 2026 review identifies disproportionately severe expressive language impairment as a near-universal, clinically distinctive SRD feature.
- name: Reflex Seizures
  category: Neurological
  frequency: FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Seizures precipitated by specific external triggers including eye-closure,
    fixation-off, and eating. The constellation of reflex seizure triggers is
    a distinctive SRD signature that, when present, supports clinical recognition
    of the syndrome.
  phenotype_term:
    preferred_term: Reflex seizure
    term:
      id: HP:0020207
      label: Reflex seizure
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eye-closure, fixation-off, or eating-induced reflex triggers"
    explanation: Samanta 2026 review documents the characteristic eye-closure, fixation-off, and eating-induced reflex seizure triggers in SRD.
- name: SRD-Associated Insomnia
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Sleep-onset and sleep-maintenance insomnia are near-universal in SRD and
    are major drivers of caregiver burden, distinct from the more general
    sleep disturbances seen across many epilepsy syndromes.
  phenotype_term:
    preferred_term: Insomnia
    term:
      id: HP:0100785
      label: Insomnia
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"
    explanation: Samanta 2026 review identifies sleep-onset and maintenance insomnia among the cluster of almost-universal SRD comorbidities, substantiating the VERY_FREQUENT classification.
- name: Sensory Behavioral Abnormality
  category: Neurological
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Marked sensory processing abnormalities — including atypical reactivity to
    sensory stimuli and sensory-seeking or -avoiding behaviors — are near-universal
    comorbidities of SRD that contribute substantially to caregiver burden.
  phenotype_term:
    preferred_term: Sensory behavioral abnormality
    term:
      id: HP:5200046
      label: Sensory behavioral abnormality
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "marked sensory abnormalities are almost universal comorbidities"
    explanation: Samanta 2026 review identifies marked sensory abnormalities as a near-universal SRD comorbidity.
- name: ADHD-like Features
  category: Psychiatric
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Attention-deficit/hyperactivity-like symptoms are among the cluster of
    almost-universal SRD behavioral comorbidities, co-occurring with autism
    spectrum features and intellectual disability and contributing substantially
    to caregiver burden.
  phenotype_term:
    preferred_term: ADHD-like features
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADHD-like symptoms, severe irritability, self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"
    explanation: Samanta 2026 review lists ADHD-like symptoms among the almost-universal SRD behavioral comorbidities, supporting the VERY_FREQUENT classification.
- name: Severe Irritability
  category: Psychiatric
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Severe irritability is a near-universal SRD behavioral comorbidity that,
    together with self-injurious behavior and sensory abnormalities, is a major
    driver of caregiver burden.
  phenotype_term:
    preferred_term: Severe irritability
    term:
      id: HP:0000737
      label: Irritability
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe irritability, self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"
    explanation: Samanta 2026 review lists severe irritability among the almost-universal SRD behavioral comorbidities, supporting the VERY_FREQUENT classification.
- name: Self-Injurious Behavior
  category: Psychiatric
  frequency: VERY_FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Self-injurious behavior is a near-universal SRD behavioral comorbidity and a
    major driver of caregiver burden, co-occurring with severe irritability and
    sensory processing abnormalities.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "self-injury, sleep-onset and maintenance insomnia, and marked sensory abnormalities are almost universal comorbidities"
    explanation: Samanta 2026 review lists self-injury among the almost-universal SRD behavioral comorbidities, supporting the VERY_FREQUENT classification.
- name: Infantile Hypotonia
  category: Neurological
  frequency: FREQUENT
  subtype: SYNGAP1-related Disorder
  description: >
    Generalized hypotonia presenting in infancy is part of the early-onset SRD
    phenotype, typically co-occurring with global developmental delay and
    preceding the later-onset generalized epilepsy.
  phenotype_term:
    preferred_term: Infantile hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most individuals present in infancy with global developmental delay, hypotonia"
    explanation: Samanta 2026 review reports that most individuals with SRD present in infancy with global developmental delay and hypotonia, supporting hypotonia as a frequent early feature.
- name: Feeding Difficulties
  category: Gastrointestinal
  subtype: SYNGAP1-related Disorder
  description: >
    Feeding difficulties can be clinically significant in a subset of individuals
    with SRD, sometimes requiring nasogastric or gastrostomy feeding support per
    GeneReviews management guidance.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:30789692
    reference_title: "SYNGAP1-Related Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding difficulties can be significant in some"
    explanation: GeneReviews SYNGAP1-related intellectual disability chapter documents clinically significant feeding difficulties in a subset of affected individuals.
progression:
- phase: SUDEP Risk
  notes: >
    Sudden unexpected death in epilepsy (SUDEP) can affect individuals of any age
    but is most common in younger adults (aged 20-45 years). Generalized tonic-clonic
    seizures are the greatest risk factor. Postictal apnea and bradycardia progress
    to asystole.
  evidence:
  - reference: PMID:27571159
    reference_title: "Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sudden unexpected death in epilepsy (SUDEP) can affect individuals of any age, but is most common in younger adults (aged 20-45 years)."
    explanation: Devinsky et al. Lancet Neurol review establishes SUDEP epidemiology and age distribution.
  - reference: PMID:27571159
    reference_title: "Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalised tonic-clonic seizures are the greatest risk factor for SUDEP"
    explanation: Identifies the primary risk factor for SUDEP.
  - reference: PMID:27571159
    reference_title: "Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, postictal apnoea and bradycardia progress to asystole and death."
    explanation: Describes the pathophysiological mechanism of SUDEP.
genetic:
- name: SCN1A
  association: Causative
  notes: Dravet syndrome, GEFS+; also disease-causing in epilepsy with myoclonic-atonic seizures
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "SCN1A | sodium voltage-gated channel alpha subunit 1 | hgnc:10585 | Disease-causing germline mutation(s) in"
    explanation: Orphanet confirms SCN1A as disease-causing in epilepsy with myoclonic-atonic seizures.
  - reference: PMID:37812819
    reference_title: "Temporal manipulation of the Scn1a gene reveals its essential role in adult brain function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by haploinsufficiency of SCN1A gene encoding for the α-subunit of the voltage-gated sodium channel Nav1.1."
    explanation: Establishes SCN1A haploinsufficiency as the genetic cause of Dravet syndrome epileptic encephalopathy.
  - reference: PMID:37812819
    reference_title: "Temporal manipulation of the Scn1a gene reveals its essential role in adult brain function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Induction of heterozygous Nav1.1 mutation at P30 and P60 elicited susceptibility to the development of both spontaneous and hyperthermia-induced seizures and SUDEP rates comparable to P2-induced mice, with symptom onset accompanied by the characteristic GABAergic interneuron dysfunction."
    explanation: Demonstrates that SCN1A haploinsufficiency causes seizures through GABAergic interneuron dysfunction, and this mechanism is active throughout life, not just during development.
- name: SCN2A
  association: Causative
  notes: Phenotypic spectrum from benign familial infantile seizures (BFIS) to severe early infantile epileptic encephalopathy (EIEE)
  evidence:
  - reference: PMID:31205438
    reference_title: "Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review."
    supports: SUPPORT
    snippet: "The voltage-gated sodium channel neuronal type 2 alpha subunit (Navα1.2) encoded by the SCN2A gene causes early infantile epileptic encephalopathy (EIEE) inherited in an autosomal dominant manner."
    explanation: Establishes SCN2A mutations as a cause of early infantile epileptic encephalopathy.
  - reference: PMID:31205438
    reference_title: "Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, it has variable presentations, ranging from benign familial infantile seizures (BFIS) to severe EIEE"
    explanation: Documents the broad SCN2A phenotypic spectrum, from self-limiting benign familial infantile seizures at the mild end to severe early infantile epileptic encephalopathy, reflecting the allelic gain- versus loss-of-function heterogeneity of SCN2A-related epilepsy.
- name: KCNQ2
  association: Causative
  notes: Benign familial neonatal seizures (self-limited neonatal epilepsy)
  evidence:
  - reference: PMID:17675531
    reference_title: "Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures."
    supports: SUPPORT
    snippet: "Benign familial neonatal seizures are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half of which lead to protein truncation."
    explanation: Establishes KCNQ2 as the most common genetic cause of benign familial neonatal seizures.
  - reference: ORPHA:1949
    reference_title: "Self-limited neonatal epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "KCNQ2 | potassium voltage-gated channel subfamily Q member 2 | hgnc:6296 | Disease-causing germline mutation(s) in"
    explanation: Orphanet confirms KCNQ2 as disease-causing in self-limited neonatal epilepsy.
- name: KCNQ3
  association: Causative
  notes: Self-limited neonatal epilepsy; major susceptibility factor in JME
  evidence:
  - reference: ORPHA:1949
    reference_title: "Self-limited neonatal epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "KCNQ3 | potassium voltage-gated channel subfamily Q member 3 | hgnc:6297 | Disease-causing germline mutation(s) in"
    explanation: Orphanet data shows KCNQ3 as disease-causing in self-limited neonatal epilepsy.
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "KCNQ3 | potassium voltage-gated channel subfamily Q member 3 | hgnc:6297 | Major susceptibility factor in"
    explanation: Orphanet data shows KCNQ3 as a major susceptibility factor in juvenile myoclonic epilepsy.
- name: EFHC1
  association: Susceptibility
  notes: Major susceptibility factor in JME and juvenile absence epilepsy
  evidence:
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "EFHC1 | EF-hand domain containing 1 | hgnc:16406 | Major susceptibility factor in"
    explanation: Orphanet data identifies EFHC1 as a major susceptibility factor in JME.
  - reference: ORPHA:1941
    reference_title: "Juvenile absence epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "EFHC1 | EF-hand domain containing 1 | hgnc:16406 | Major susceptibility factor in"
    explanation: Orphanet data identifies EFHC1 as a major susceptibility factor in juvenile absence epilepsy.
- name: SLC6A1
  association: Causative
  notes: Epilepsy with myoclonic-atonic seizures (loss of function mutations)
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "SLC6A1 | solute carrier family 6 member 1 | hgnc:11042 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet data shows SLC6A1 loss-of-function mutations as disease-causing in epilepsy with myoclonic-atonic seizures.
- name: SYNGAP1
  gene_term:
    preferred_term: SYNGAP1
    term:
      id: hgnc:11497
      label: SYNGAP1
  association: Causative
  notes: >
    Haploinsufficiency causes SYNGAP1-related disorder (SRD), a monogenic developmental
    and epileptic encephalopathy presenting with generalized epilepsy (eyelid myoclonia,
    atypical absences, myoclonic-atonic seizures), intellectual disability, and autism
    spectrum features. Also implicated in epilepsy with myoclonic-atonic seizures.
  evidence:
  - reference: ORPHA:1942
    reference_title: "Epilepsy with myoclonic-atonic seizures (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "SYNGAP1 | synaptic Ras GTPase activating protein 1 | hgnc:11497 | Disease-causing germline mutation(s) in"
    explanation: Orphanet data shows SYNGAP1 mutations as disease-causing in epilepsy with myoclonic-atonic seizures.
  - reference: PMID:42161154
    reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused"
    explanation: Comprehensive review establishing SYNGAP1 haploinsufficiency as the molecular cause of SRD.
- name: GABRA1
  association: Susceptibility
  notes: Major susceptibility factor in juvenile myoclonic epilepsy
  evidence:
  - reference: PMID:11992121
    reference_title: "Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy."
    supports: SUPPORT
    snippet: "We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy."
    explanation: Establishes GABRA1 mutations as a cause of juvenile myoclonic epilepsy through GABA receptor dysfunction.
  - reference: ORPHA:307
    reference_title: "Juvenile myoclonic epilepsy (Orphanet structured-database record)"
    supports: SUPPORT
    snippet: "GABRA1 | gamma-aminobutyric acid type A receptor subunit alpha1 | hgnc:4075 | Major susceptibility factor in"
    explanation: Orphanet confirms GABRA1 as a major susceptibility factor in JME.
  - reference: CGGV:assertion_60478d36-384e-4246-ba8a-730755d6f216-2024-09-03T170000.000Z
    reference_title: "GABRA1 / epilepsy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GABRA1 | HGNC:4075 | epilepsy | MONDO:0005027 | AD | Definitive"
    explanation: ClinGen classifies the GABRA1-epilepsy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: CDKL5
  association: Causative
  notes: Early-onset epileptic encephalopathy
  evidence:
  - reference: PMID:20493745
    reference_title: "Epilepsy caused by CDKL5 mutations."
    supports: SUPPORT
    snippet: "Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype."
    explanation: Establishes CDKL5 mutations as a cause of early-onset epileptic encephalopathy.
- name: DEPDC5
  association: Causative
  notes: Familial focal epilepsy, focal cortical dysplasia; mTOR pathway (GATOR1 complex)
  evidence:
  - reference: PMID:31174205
    reference_title: "Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DEPDC5 is now recognized as one of the genes most often implicated in familial/inherited focal epilepsy and brain malformations."
    explanation: Background statement in a mouse model study establishing DEPDC5 as a major gene in familial focal epilepsy.
  - reference: PMID:31174205
    reference_title: "Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Individuals with pathogenic variants in DEPDC5 are at risk for epilepsy, associated neuropsychiatric comorbidities and sudden unexplained death in epilepsy."
    explanation: Background statement documenting the clinical spectrum of DEPDC5-related epilepsy including SUDEP risk.
- name: GABRD
  gene_term:
    preferred_term: GABRD
    term:
      id: hgnc:4084
      label: GABRD
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_64f743b4-408d-40d6-855b-ef9d67fc172e-2023-07-18T190000.000Z
    reference_title: "GABRD / epilepsy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GABRD | HGNC:4084 | epilepsy | MONDO:0005027 | AD | Limited"
    explanation: ClinGen classifies the GABRD-epilepsy gene-disease relationship as limited with autosomal dominant inheritance.
- name: GABRG2
  gene_term:
    preferred_term: GABRG2
    term:
      id: hgnc:4087
      label: GABRG2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_3a3176e9-ac0c-41fe-ae40-0750726c33d8-2020-01-21T170000.000Z
    reference_title: "GABRG2 / epilepsy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GABRG2 | HGNC:4087 | epilepsy | MONDO:0005027 | AD | Definitive"
    explanation: ClinGen classifies the GABRG2-epilepsy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: KPNA7
  gene_term:
    preferred_term: KPNA7
    term:
      id: hgnc:21839
      label: KPNA7
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_9aa05adf-d315-4a06-b4f2-c5a5f6a23700-2025-10-07T160000.000Z
    reference_title: "KPNA7 / epilepsy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KPNA7 | HGNC:21839 | epilepsy | MONDO:0005027 | AR | Limited"
    explanation: ClinGen classifies the KPNA7-epilepsy gene-disease relationship as limited with autosomal recessive inheritance.
- name: PRIMA1
  gene_term:
    preferred_term: PRIMA1
    term:
      id: hgnc:18319
      label: PRIMA1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_2247fe32-492c-4a1b-8e1c-5ee13bae944a-2025-01-07T180000.000Z
    reference_title: "PRIMA1 / epilepsy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRIMA1 | HGNC:18319 | epilepsy | MONDO:0005027 | AR | Limited"
    explanation: ClinGen classifies the PRIMA1-epilepsy gene-disease relationship as limited with autosomal recessive inheritance.
environmental:
- name: Traumatic Brain Injury
  notes: Major cause of acquired epilepsy
- name: CNS Infections
  notes: Meningitis, encephalitis
- name: Stroke
  notes: Leading cause in older adults
- name: Brain Tumors
  notes: Can cause focal epilepsy
- name: Perinatal Injury
  notes: Hypoxic-ischemic encephalopathy
treatments:
- name: Antiseizure Medications
  description: First-line treatment - levetiracetam, lamotrigine, valproate, carbamazepine.
  evidence:
  - reference: PMID:30587993
    reference_title: "Levetiracetam for epilepsy: an evidence map of efficacy, safety and economic profiles."
    supports: SUPPORT
    snippet: "Meta-analysis of the included RCTs indicated that LEV was as effective as carbamazepine (CBZ; treatment for 6 months: 58.9% vs 64.8%, OR=0.76, 95% CI: 0.50-1.16; 12 months: 54.9% vs 55.5%, OR=1.24, 95% CI: 0.79-1.93), oxcarbazepine (57.7% vs 59.8%, OR=1.34, 95% CI: 0.34-5.23), phenobarbital (50.0% vs 50.9%, OR=1.20, 95% CI: 0.51-2.82) and lamotrigine (LTG; 61.5% vs 57.7%, OR=1.22, 95% CI: 0.90-1.66)."
    explanation: Meta-analysis demonstrates comparable efficacy of levetiracetam with other first-line antiseizure medications.
- name: Ketogenic Diet
  description: High-fat, low-carbohydrate diet effective for drug-resistant epilepsy.
  evidence:
  - reference: PMID:18456557
    reference_title: "The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial."
    supports: SUPPORT
    snippet: "28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls"
    explanation: Landmark RCT demonstrating significant seizure reduction with ketogenic diet in drug-resistant childhood epilepsy.
- name: Vagus Nerve Stimulation
  description: Implanted device for drug-resistant epilepsy.
  evidence:
  - reference: PMID:21838505
    reference_title: "Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response."
    supports: SUPPORT
    snippet: "After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy."
    explanation: Meta-analysis of 74 studies with 3321 patients demonstrates VNS efficacy in medically refractory epilepsy.
- name: Epilepsy Surgery
  description: Resection of seizure focus for drug-resistant focal epilepsy.
  evidence:
  - reference: PMID:11484687
    reference_title: "A randomized, controlled trial of surgery for temporal-lobe epilepsy."
    supports: SUPPORT
    snippet: "At one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58 percent in the surgical group and 8 percent in the medical group (P<0.001)."
    explanation: Landmark RCT in NEJM demonstrating surgery is superior to prolonged medical therapy for temporal-lobe epilepsy.
- name: Responsive Neurostimulation
  description: Closed-loop brain stimulation for focal epilepsy.
  evidence:
  - reference: PMID:32690786
    reference_title: "Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy."
    supports: SUPPORT
    snippet: "At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency."
    explanation: Nine-year prospective study demonstrates sustained efficacy and safety of brain-responsive neurostimulation.
- name: Deep Brain Stimulation
  description: Anterior thalamic stimulation for drug-resistant epilepsy.
  evidence:
  - reference: PMID:25663221
    reference_title: "Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy."
    supports: SUPPORT
    snippet: "The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years."
    explanation: SANTE trial 5-year follow-up demonstrates sustained efficacy of anterior thalamic deep brain stimulation.
- name: SYNGAP1 Allele-Upregulating Antisense Oligonucleotide
  description: >
    Allele-upregulating antisense oligonucleotides aim to compensate for SYNGAP1
    haploinsufficiency by increasing translation from the intact wild-type allele,
    rather than replacing or correcting the mutant transcript. ASO programs
    targeting SRD are in preclinical and early translational development as part
    of the SRD precision-therapy pipeline.
  treatment_term:
    preferred_term: antisense oligonucleotide therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antisense oligonucleotide
      term:
        id: NCIT:C1291
        label: Antisense Oligonucleotides
  target_mechanisms:
  - target: SYNGAP1 Haploinsufficiency
    treatment_effect: RESTORES
    description: >
      Allele-upregulating ASOs increase translation from the intact SYNGAP1 allele,
      partially compensating for the haploinsufficient lesion that drives downstream
      SynGAP loss.
    evidence:
    - reference: PMID:42161154
      reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "antisense oligonucleotides to upregulate the intact allele"
      explanation: Samanta 2026 review identifies allele-upregulating ASOs as a precision-therapy approach in development for SRD.
- name: AAV-Based SYNGAP1 Gene Replacement
  description: >
    Adeno-associated virus (AAV)-mediated delivery of a functional SYNGAP1
    transgene aims to restore SynGAP protein expression in target neurons.
    AAV gene replacement is a precision-therapy strategy in preclinical
    development for SRD.
  treatment_term:
    preferred_term: AAV gene replacement therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: SYNGAP1 Haploinsufficiency
    treatment_effect: RESTORES
    description: >
      AAV-delivered SYNGAP1 transgene restores SynGAP protein levels in target
      neurons, directly addressing the haploinsufficient molecular lesion.
    evidence:
    - reference: PMID:42161154
      reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "AAV-based gene replacement"
      explanation: Samanta 2026 review identifies AAV-based gene replacement among precision-therapy strategies in development for SRD.
- name: CRISPR-Mediated SYNGAP1 Transcriptional Activation
  description: >
    CRISPR activation (CRISPRa) using a catalytically inactive Cas9 fused to
    transcriptional activators is being developed to upregulate the intact
    SYNGAP1 allele in neurons. This complements ASO-based allele upregulation
    by acting at the transcriptional rather than translational level.
  treatment_term:
    preferred_term: CRISPR transcriptional activation therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: SYNGAP1 Haploinsufficiency
    treatment_effect: RESTORES
    description: >
      CRISPRa machinery recruits transcriptional activators to the wild-type
      SYNGAP1 locus, boosting transcription of the intact allele to compensate
      for haploinsufficiency.
    evidence:
    - reference: PMID:42161154
      reference_title: "SYNGAP1-related disorder: pathophysiology, epilepsy, cognitive and behavioral phenotypes, and precision therapeutic approaches."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CRISPR-mediated transcriptional activation"
      explanation: Samanta 2026 review identifies CRISPR-mediated transcriptional activation as a precision-therapy strategy under development for SRD.
clinical_trials:
- name: NCT06555965
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Prospective natural history study of STXBP1- and SYNGAP1-related disorders
    enrolling participants for detailed developmental, seizure, and
    quality-of-life assessments. Establishes baseline clinical-spectrum data
    intended to support upcoming SYNGAP1-targeted treatment trials referenced
    in the SRD precision-therapy block of this entry.
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  - preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: clinicaltrials:NCT06555965
    reference_title: STXBP1 and SYNGAP1 Related Disorders (RD) Natural History Study
    supports: SUPPORT
    snippet: "The primary objective of the study is to better define and outline the clinical spectrum of STXBP1 and SYNGAP1 through detailed developmental, seizure, and quality of life assessments"
    explanation: SRD-specific natural history study capturing developmental,
      seizure, and quality-of-life trajectory needed to support the upcoming
      SYNGAP1 treatment trials referenced in this entry's SRD precision-therapy
      block.
  notes: >-
    Observational study (Natural History Study); phase is NOT_APPLICABLE per
    schema. Co-enrolls SYNGAP1-related Disorder and STXBP1 encephalopathy.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
datasets:
references:
- reference: PMID:30789692
  title: "SYNGAP1-Related Intellectual Disability."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1002/ctm2.70072
  title: Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type IIIa as suggested by single‐nucleus multiomics
  findings: []
- reference: DOI:10.1002/hsr2.1896
  title: 'Advances in understanding the pathogenesis of epilepsy: Unraveling the molecular mechanisms'
  findings: []
- reference: DOI:10.1038/s41467-022-29657-y
  title: Microvascular stabilization via blood-brain barrier regulation prevents seizure activity
  findings: []
- reference: DOI:10.1038/s41593-024-01634-2
  title: Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy
  findings: []
- reference: DOI:10.1093/brain/awad349
  title: Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model
  findings: []
- reference: DOI:10.1093/hmg/ddz123
  title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice
  findings: []
- reference: DOI:10.3389/fneur.2024.1413023
  title: 'Unveiling the hidden connection: the blood-brain barrier’s role in epilepsy'
  findings: []
- reference: DOI:10.3389/fneur.2024.1466075
  title: Voltage-gated potassium channels and genetic epilepsy
  findings: []
- reference: DOI:10.3389/fneur.2025.1642299
  title: Progress in genetic mechanisms and precise treatment of neurocutaneous syndrome-related epilepsy
  findings: []
- reference: DOI:10.3389/fnins.2025.1634718
  title: 'Dravet syndrome: novel insights into SCN1A-mediated epileptic neurodevelopmental disorders within the molecular diagnostic-therapeutic framework'
  findings: []
- reference: DOI:10.3390/ijms25084161
  title: 'Neuroinflammation and Epilepsy: From Pathophysiology to Therapies Based on Repurposing Drugs'
  findings: []
- reference: DOI:10.7554/elife.91010.3
  title: The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function
  findings: []

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