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Atlas / Disease / Generalized epilepsy

Generalized epilepsy

disease
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Summary

Generalized epilepsy (MONDO:0100574) is a disease with 8 cohort genes and 13 clinical trials. Top therapeutic interventions include levetiracetam, cenobamate, and melatonin.

At a glance

  • Cohort genes: 8
  • ClinVar variants: 10
  • Clinical trials: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namegeneralized epilepsy
Mondo IDMONDO:0100574
NCITC3021
UMLSC0014548
MedGen4507
Is cancer (heuristic)no

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record · 186 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › generalized epilepsy

Related subtypes (12): extratemporal epilepsy, focal epilepsy, epilepsy syndrome, monogenic epilepsy, reflex epilepsy, post-traumatic epilepsy, immune epilepsy, metabolic epilepsy, structural epilepsy, infantile-onset epilepsy, epilepsy, unknown whether focal or generalized, developmental and epileptic encephalopathy

Subtypes (2): combined generalized and focal epilepsy, genetic generalized epilepsy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

10 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 not provided, 2 uncertain significance, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVarVariant (HGVS)GeneClassificationReview
39679NM_015214.3(DDHD2):c.1978G>C (p.Asp660His)DDHD2Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
11985NM_000170.3(GLDC):c.1545G>C (p.Arg515Ser)GLDCPathogeniccriteria provided, multiple submitters, no conflicts
206608NM_002693.3(POLG):c.1270_1271del (p.Leu424fs)POLGPathogeniccriteria provided, multiple submitters, no conflicts
68512NM_001165963.4(SCN1A):c.1876A>G (p.Ser626Gly)SCN1APathogeniccriteria provided, single submitter
3384007NM_052874.5(STX1B):c.451C>T (p.Gln151Ter)STX1BPathogeniccriteria provided, single submitter
68510NM_001165963.4(SCN1A):c.1265T>A (p.Val422Glu)SCN1ALikely pathogeniccriteria provided, single submitter
68526NM_001165963.4(SCN1A):c.2917A>G (p.Met973Val)SCN1AUncertain significancecriteria provided, single submitter
397631NM_001365999.1(SZT2):c.9893G>A (p.Arg3298His)SZT2Uncertain significancecriteria provided, multiple submitters, no conflicts
1339851NM_001194.4(HCN2):c.1348G>T (p.Val450Leu)HCN2not providedno classification provided
68507NM_001165963.4(SCN1A):c.1183G>C (p.Ala395Pro)SCN1Anot providedno classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 23 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

GeneClassificationInheritanceDiseaseRecords
SIK1LimitedAutosomal dominantgeneralized epilepsy7

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
SIK1Orphanet:1934Early infantile developmental and epileptic encephalopathy
SIK1Orphanet:697160Infantile epileptic spasms syndrome
SCN1AOrphanet:1942Epilepsy with myoclonic-atonic seizures
SCN1AOrphanet:2382Lennox-Gastaut syndrome
SCN1AOrphanet:293181Epilepsy of infancy with migrating focal seizures
SCN1AOrphanet:33069Dravet syndrome
SCN1AOrphanet:36387Genetic epilepsy with febrile seizure plus
SCN1AOrphanet:442835Non-specific early-onset epileptic encephalopathy
SCN1AOrphanet:569Familial or sporadic hemiplegic migraine
STX1BOrphanet:36387Genetic epilepsy with febrile seizure plus
SZT2Orphanet:442835Non-specific early-onset epileptic encephalopathy
DDHD2Orphanet:320380Autosomal recessive spastic paraplegia type 54
GLDCOrphanet:289857Neonatal glycine encephalopathy
GLDCOrphanet:289860Infantile glycine encephalopathy
GLDCOrphanet:289863Atypical glycine encephalopathy
POLGOrphanet:254881Spinocerebellar ataxia with epilepsy
POLGOrphanet:254886Autosomal recessive progressive external ophthalmoplegia
POLGOrphanet:254892Autosomal dominant progressive external ophthalmoplegia
POLGOrphanet:298Mitochondrial neurogastrointestinal encephalomyopathy
POLGOrphanet:402082Progressive myoclonic epilepsy type 5
POLGOrphanet:70595Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLGOrphanet:726Alpers-Huttenlocher syndrome
POLGOrphanet:94125Recessive mitochondrial ataxia syndrome

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence8

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SIK1HGNC:11142ENSG00000142178P57059Serine/threonine-protein kinase SIK1gencc
SCN1AHGNC:10585ENSG00000144285P35498Sodium channel protein type 1 subunit alphaclinvar
STX1BHGNC:18539ENSG00000099365P61266Syntaxin-1Bclinvar
SZT2HGNC:29040ENSG00000198198Q5T011KICSTOR complex protein SZT2clinvar
DDHD2HGNC:29106ENSG00000085788O94830Triacylglycerol hydrolase DDHD2clinvar
GLDCHGNC:4313ENSG00000178445P23378Glycine dehydrogenase (decarboxylating), mitochondrialclinvar
HCN2HGNC:4846ENSG00000099822Q9UL51Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2clinvar
POLGHGNC:9179ENSG00000140521P54098DNA polymerase subunit gamma-1clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SIK1Serine/threonine-protein kinase SIK1Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression.
SCN1ASodium channel protein type 1 subunit alphaPore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
STX1BSyntaxin-1BPotentially involved in docking of synaptic vesicles at presynaptic active zones.
SZT2KICSTOR complex protein SZT2As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway.
DDHD2Triacylglycerol hydrolase DDHD2Diacylglycerol (DAG) and triacylglycerol (TAG) lipase required for proper lipid homeostasis in the central nervous system.
GLDCGlycine dehydrogenase (decarboxylating), mitochondrialThe glycine cleavage system catalyzes the degradation of glycine.
HCN2Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2Hyperpolarization-activated ion channel that is permeable to sodium and potassium ions.
POLGDNA polymerase subunit gamma-1Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Ion channel227.9×0.009
Kinase13.5×0.509
Enzyme (other)11.5×0.669
Other/Unknown40.9×0.755

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SIK1KinaseyesProt_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SCN1AIon channelyesNa_channel_asu, Ion_trans_dom, Na_channel_a1su
STX1BOther/UnknownnoT_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
SZT2Other/UnknownnoSZT2
DDHD2Other/UnknownnoSAM, WWE_dom, DDHD_dom
GLDCEnzyme (other)yes1.4.1.27ArAA_b-elim_lyase/Thr_aldolase, GcvP, PyrdxlP-dep_Trfase_major
HCN2Ion channelyescNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
POLGOther/UnknownnoDNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)8
unknown0

Top tissues across cohort

TissueCohort genes
Brodmann (1909) area 232
granulocyte2
mucosa of stomach1
skin of abdomen1
zone of skin1
lateral nuclear group of thalamus1
primary visual cortex1
cerebellar cortex1
cerebellar hemisphere1
right hemisphere of cerebellum1
colonic epithelium1
sural nerve1
endothelial cell1
middle temporal gyrus1
liver1
nephron tubule1
right lobe of liver1
C1 segment of cervical spinal cord1
putamen1
right frontal lobe1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SIK1138not_expressedmarkermucosa of stomach, skin of abdomen, zone of skin
SCN1A154tissue_specificmarkerBrodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
STX1B176ubiquitousmarkerright hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SZT2238ubiquitousmarkercolonic epithelium, sural nerve, granulocyte
DDHD2294ubiquitousmarkerendothelial cell, Brodmann (1909) area 23, middle temporal gyrus
GLDC216broadmarkerright lobe of liver, liver, nephron tubule
HCN2177broadyesC1 segment of cervical spinal cord, right frontal lobe, putamen
POLG295ubiquitousmarkergranulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
POLG3,400
GLDC2,559
SCN1A2,287
STX1B2,130
SIK11,840
DDHD21,153
HCN21,103
SZT2648

Structural data

PDB: 5 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
POLGP5409836
SZT2Q5T0119
GLDCP233783
HCN2Q9UL513
SCN1AP354981

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
STX1BP6126684.17
DDHD2O9483074.70
SIK1P5705961.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 8 evidence-associated genes (8 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Toxicity of botulinum toxin type C (botC)1475.8×0.035STX1B
HCN channels1356.9×0.035HCN2
Glycine degradation1203.9×0.035GLDC
Neurotoxicity of clostridium toxins1178.4×0.035STX1B
Strand-asynchronous mitochondrial DNA replication1142.8×0.035POLG
Uptake and actions of bacterial toxins1102.0×0.035STX1B
LGI-ADAM interactions1102.0×0.035STX1B
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes159.5×0.049SIK1
Interaction between L1 and Ankyrins146.0×0.049SCN1A
R-HSA-400253143.3×0.049SIK1
Phase 0 - rapid depolarisation143.3×0.049SCN1A
Bacterial Infection Pathways142.0×0.049STX1B
Synthesis of PA136.6×0.052DDHD2
Amino acids regulate mTORC1125.0×0.070SZT2
Cellular response to starvation120.7×0.079SZT2
L1CAM interactions115.0×0.101SCN1A
Cardiac conduction113.6×0.105SCN1A
Muscle contraction19.7×0.133SCN1A
Developmental Biology23.6×0.133SCN1A, STX1B
Axon guidance15.6×0.205SCN1A
Nervous system development15.4×0.205SCN1A
Cellular responses to stress14.6×0.225SZT2
Cellular responses to stimuli13.9×0.248SZT2
Infectious disease13.1×0.292STX1B
Disease11.6×0.471STX1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
response to methylamine12106.5×0.008GLDC
regulation of superoxide dismutase activity12106.5×0.008SZT2
negative regulation of synaptic vesicle recycling12106.5×0.008STX1B
positive regulation of spontaneous neurotransmitter secretion12106.5×0.008STX1B
negative regulation of macropinocytosis12106.5×0.008STX1B
sodium ion transmembrane transport250.8×0.009SCN1A, HCN2
glycine catabolic process11053.2×0.010GLDC
response to lipoic acid11053.2×0.010GLDC
glycine decarboxylation via glycine cleavage system1702.2×0.011GLDC
DNA replication proofreading1702.2×0.011POLG
negative regulation of triglyceride biosynthetic process1526.6×0.011SIK1
obsolete negative regulation of CREB transcription factor activity1526.6×0.011SIK1
calcium ion-regulated exocytosis of neurotransmitter1526.6×0.011STX1B
regulation of synaptic activity1526.6×0.011STX1B
regulation of myotube differentiation1421.3×0.013SIK1
spontaneous neurotransmitter secretion1351.1×0.015STX1B
corpus callosum morphogenesis1300.9×0.015SZT2
cellular response to aldosterone1300.9×0.015HCN2
cellular response to cGMP1263.3×0.015HCN2
positive regulation of neurotransmitter secretion1234.1×0.015STX1B
regulation of membrane depolarization1234.1×0.015HCN2
ammonium transmembrane transport1234.1×0.015HCN2
positive regulation of anoikis1234.1×0.015SIK1
regulation of synaptic vesicle priming1210.7×0.015STX1B
synaptic vesicle fusion to presynaptic active zone membrane1210.7×0.015STX1B
membrane depolarization during action potential1210.7×0.015SCN1A
mitochondrial DNA replication1191.5×0.016POLG
neuronal action potential propagation1175.5×0.016SCN1A
membrane depolarization during cardiac muscle cell action potential1175.5×0.016HCN2
obsolete synaptic vesicle docking1162.0×0.016STX1B

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 5 of 8 evidence-associated genes (62%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
SIK1FEDRATINIB
SCN1AMEXILETINE HYDROCHLORIDE
POLGADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

SymbolMoleculesMax phase
SCN1A944
SIK1194
POLG14
STX1B00
SZT200
DDHD200
GLDC00
HCN200

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
FEDRATINIB4SIK1
AXITINIB4SIK1
NERATINIB4SIK1
VANDETANIB4SIK1
BOSUTINIB4SIK1
PAZOPANIB4SIK1
NINTEDANIB4SIK1
SUNITINIB4SIK1
DASATINIB4SIK1
MIDOSTAURIN4SIK1
MEXILETINE HYDROCHLORIDE4SCN1A
BEPRIDIL4SCN1A
DIBUCAINE4SCN1A
ARTICAINE4SCN1A
BUPIVACAINE4SCN1A
IMIPRAMINE4SCN1A
DROPERIDOL4SCN1A
DICYCLOMINE4SCN1A
TETRABENAZINE4SCN1A
PHENIRAMINE4SCN1A
PRILOCAINE4SCN1A
PROPOXYCAINE4SCN1A
PROPARACAINE4SCN1A
HEXYLCAINE4SCN1A
PRAMOXINE4SCN1A
BENOXINATE4SCN1A
QUINIDINE4SCN1A
FELODIPINE4SCN1A
PHENYTOIN4SCN1A
QUININE4SCN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
SIK1210Binding:205, Toxicity:4, ADMET:1
SCN1A149Binding:115, Functional:18, ADMET:14, Toxicity:2
POLG33Binding:30, ADMET:2, Functional:1
HCN212Binding:6, Functional:4, ADMET:2
DDHD22Functional:2

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
GLDC1.4.1.27, 1.4.4.2glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
SIK1210
SCN1A149

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

CompoundMax phaseCohort target (bioactivity)
FEDRATINIB4SIK1
AXITINIB4SIK1
NERATINIB4SIK1
VANDETANIB4SIK1
BOSUTINIB4SIK1
PAZOPANIB4SIK1
NINTEDANIB4SIK1
SUNITINIB4SIK1
DASATINIB4SIK1
MIDOSTAURIN4SIK1
MEXILETINE HYDROCHLORIDE4SCN1A
BEPRIDIL4SCN1A
DIBUCAINE4SCN1A
ARTICAINE4SCN1A
BUPIVACAINE4SCN1A
IMIPRAMINE4SCN1A
DROPERIDOL4SCN1A
DICYCLOMINE4SCN1A
TETRABENAZINE4SCN1A
PHENIRAMINE4SCN1A
PRILOCAINE4SCN1A
PROPOXYCAINE4SCN1A
PROPARACAINE4SCN1A
HEXYLCAINE4SCN1A
PRAMOXINE4SCN1A
BENOXINATE4SCN1A
QUINIDINE4SCN1A
FELODIPINE4SCN1A
PHENYTOIN4SCN1A
QUININE4SCN1A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)3SIK1, SCN1A, POLG
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug2GLDC, HCN2
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug3STX1B, SZT2, DDHD2

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
STX1B0—
SZT20—
DDHD22—
GLDC0—
HCN212—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified7
PHASE33
PHASE41
PHASE2/PHASE31
PHASE21

Top trials by phase / activity

NCTPhaseStatusTitle
NCT03590197PHASE4COMPLETEDEffect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT00150735PHASE3COMPLETEDMonotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
NCT00150748PHASE3COMPLETEDLong Term Follow up Treatment With Levetiracetam in Subjects of 4 Years and Older With Generalized Epilepsy
NCT03678753PHASE3COMPLETEDRandomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
NCT06425159PHASE2/PHASE3TERMINATEDA Study to Determine if BHV-7000 is Effective and Safe in Adults With Idiopathic Generalized Epilepsy With Generalized Tonic-clonic Seizures
NCT06908356PHASE2RECRUITINGAn Open Label Trial to Evaluate the Efficacy and Safety of PRAX-628 in Adults With Focal Onset or Tonic-Clonic Seizures
NCT00001325Not specifiedCOMPLETEDMetabolic Abnormalities in Children With Epilepsy
NCT01311440Not specifiedCOMPLETEDModified Atkins Diet Treatment for Adults With Drug-resistant Epilepsy
NCT03368469Not specifiedWITHDRAWNTranscranial Direct Current Stimulation (tDCS) in Children and Adolescents With Epilepsy and Depression
NCT03457961Not specifiedUNKNOWNPost-market Study of AMPA Receptor Antagonists for Epilepsy Patients in Hong Kong
NCT03955432Not specifiedTERMINATEDLong-term Cardiac Monitoring in Epilepsy
NCT04965571Not specifiedCOMPLETEDClinical Features and Outcome of Wilson’s Disease With Generalized Epilepsy in Chinese Patients
NCT06797791Not specifiedCOMPLETEDAssessment of Multifocal Continuous Theta Burst Transcranial Magnetic Stimulation (cTBS) Effects in Generalized Epilepsy Patients.

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
LEVETIRACETAM42
CENOBAMATE41
MELATONIN41
PERAMPANEL41
ETIRACETAM22
LEVITIRACETAM02

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
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Sources 68

This page pulls from 68 datasets indexed by BioBTree:

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