Dravet_syndrome

Genetic MONDO:0100135 Pathograph 44 Show in embeddings browser Epileptic Encephalopathy Neurologic Disorder

Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by treatment-resistant seizures beginning in infancy, developmental regression, and cognitive impairment. It is primarily caused by de novo loss-of-function mutations in SCN1A, encoding the Nav1.1 voltage-gated sodium channel.

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1
Mappings
1
Inheritance
3
Pathophys.
49
Phenotypes
44
Pathograph
11
Genes
9
Medical Actions
4
References
2
Deep Research
🏷

Classifications

Harrison's Chapter
NEUROLOGIC GENETICS_ENVIRONMENT_DISEASE
🔗

Mappings

MONDO
MONDO:0100135 Dravet syndrome
skos:exactMatch Orphanet ORPHA:33069: CONSISTENT
Orphanet ORPHA:33069 lists MONDO:0011794 as an exact cross-reference; MONDO:0100135 is the current preferred MONDO identifier for Dravet syndrome.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Orphanet classifies Dravet syndrome as autosomal dominant, consistent with de novo heterozygous loss-of-function mutations in SCN1A.
Autosomal dominant inheritance
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"Autosomal dominant"
Orphanet directly lists autosomal dominant inheritance for ORPHA:33069.
⚙

Pathophysiology

3
SCN1A Gene Mutation
Heterozygous loss-of-function mutations in SCN1A cause reduced Nav1.1 sodium channel function, primarily affecting GABAergic inhibitory interneurons, particularly parvalbumin-positive fast-spiking interneurons.
inhibitory interneuron CL:0000498
neuronal action potential GO:0019228
voltage-gated sodium channel activity GO:0005248
cerebral cortex UBERON:0000956 Ammon's horn UBERON:0001954
Downstream
Neuronal Hyperexcitability Reduced Nav1.1 sodium current selectively impairs firing of GABAergic inhibitory interneurons, lowering inhibitory tone and tilting cortical and hippocampal networks toward hyperexcitability.
Show evidence (2 references)
PMID:21463282 SUPPORT Model Organism
"Loss-of-function in Na(v) 1.1 channels results in severely impaired sodium current and action potential firing in hippocampal γ-aminobutyric acid (GABA)ergic interneurons without detectable changes in excitatory pyramidal neurons."
ORPHA:33069 SUPPORT Other
"SCN1A | sodium voltage-gated channel alpha subunit 1 | hgnc:10585 | Disease-causing germline mutation(s) in"
Orphanet gene table confirms SCN1A as a disease-causing gene for Dravet syndrome.
Neuronal Hyperexcitability
Reduced inhibitory interneuron function leads to excitatory-inhibitory imbalance and network hyperexcitability across cortico-hippocampal and thalamocortical circuits.
inhibitory interneuron CL:0000498
synaptic transmission, GABAergic GO:0051932
cerebral cortex UBERON:0000956 Ammon's horn UBERON:0001954 dorsal plus ventral thalamus UBERON:0001897
Downstream
Seizures
Complex Febrile Seizure
Febrile Seizures
Atypical Absence Seizure
Focal Aware Seizure
Focal Impaired Awareness Seizure
Focal-onset Seizure
Focal Hemiclonic Seizure
Generalized Clonic Seizure
Generalized Myoclonic Seizure
Generalized Tonic Seizure
Photosensitive Myoclonic Seizures
Photosensitive Tonic-Clonic Seizures
Epilepsia Partialis Continua
Status Epilepticus Without Prominent Motor Symptoms
EEG with Focal Epileptiform Discharges
EEG with Generalized Epileptiform Discharges
Multifocal Epileptiform Discharges
Interictal Epileptiform Activity
Cyanotic Episode
Developmental Regression
Cognitive Impairment
Autistic Behavior
Anxiety
Impulsivity
Short Attention Span
Obsessive-Compulsive Trait
Action Tremor
Myoclonus
Progressive Gait Ataxia
Incoordination
Poor Fine Motor Coordination
Global Brain Atrophy
Show evidence (1 reference)
PMID:21463282 SUPPORT Model Organism
"The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures."
Astrocyte Dysregulation
Aberrant astrocyte calcium signaling and gliotransmission may exacerbate network hyperexcitability and seizure susceptibility.
astrocyte CL:0000127
regulation of cytosolic calcium ion concentration GO:0051480 ↕ DYSREGULATED
cerebral cortex UBERON:0000956 Ammon's horn UBERON:0001954
Downstream
Neuronal Hyperexcitability Facilitated astrocytic Ca2+ signaling and gliotransmission are proposed to further exacerbate network hyperexcitability, although the precise coupling between astrocytic Ca2+ dynamics and neuronal excitability in Dravet syndrome remains to be established.
Show evidence (2 references)
PMID:36610382 SUPPORT Model Organism
"We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a+/- astrocytes."
Scn1a+/- Dravet model astrocytes show facilitated spontaneous and ATP-evoked Ca2+ signaling, supporting astrocyte Ca2+ dysregulation as a contributor to network hyperexcitability.
PMID:36610382 SUPPORT Model Organism
"These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS."
The authors conclude perturbed astrocytic Ca2+ dynamics may participate in Dravet syndrome pathogenesis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dravet_syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

49
Head and Neck 1
Drooling OCCASIONAL Drooling HP:0002307
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002307 | Drooling | Occasional (29-5%)"
Orphanet's curated HPO table classifies drooling as occasional in Dravet syndrome.
Integument 1
Pallor OCCASIONAL Pallor HP:0000980
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0000980 | Pallor | Occasional (29-5%)"
Orphanet's curated HPO table classifies pallor as occasional in Dravet syndrome.
Limbs 1
Pes Planus OCCASIONAL Pes planus HP:0001763
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0001763 | Pes planus | Occasional (29-5%)"
Orphanet's curated HPO table classifies pes planus as occasional in Dravet syndrome.
Musculoskeletal 2
Rigidity FREQUENT Rigidity HP:0002063
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002063 | Rigidity | Frequent (79-30%)"
Orphanet's curated HPO table classifies rigidity as frequent in Dravet syndrome.
Floppy Infant OCCASIONAL Floppy infant HP:0008947
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0008947 | Floppy infant | Occasional (29-5%)"
Orphanet's curated HPO table classifies infantile hypotonia as occasional in Dravet syndrome.
Nervous System 12
Seizures VERY_FREQUENT Seizure HP:0001250
Include prolonged febrile seizures and various types of epilepsy as the condition progresses.
Show evidence (2 references)
PMID:21463282 SUPPORT Model Organism
"a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications."
ORPHA:33069 SUPPORT Other
"HP:0007359 | Focal-onset seizure | Very frequent (99-80%)"
Orphanet's curated HPO table classifies focal-onset seizures as very frequent in Dravet syndrome, corroborating the high seizure burden.
Focal-onset Seizure VERY_FREQUENT Focal-onset seizure HP:0007359
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0007359 | Focal-onset seizure | Very frequent (99-80%)"
Orphanet's curated HPO table classifies focal-onset seizures as very frequent in Dravet syndrome.
Febrile Seizures FREQUENT Febrile seizure (within the age range of 3 months to 6 years) HP:0002373
Characteristic presenting feature in early infancy, often prompts genetic evaluation for Dravet syndrome.
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002373 | Febrile seizure (within the age range of 3 months to 6 years) | Frequent (79-30%)"
Orphanet's curated HPO table classifies febrile seizures as frequent in Dravet syndrome.
Generalized Myoclonic Seizure FREQUENT Generalized myoclonic seizure HP:0002123
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002123 | Generalized myoclonic seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies generalized myoclonic seizures as frequent in Dravet syndrome.
Atypical Absence Seizure FREQUENT Atypical absence seizure HP:0007270
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0007270 | Atypical absence seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies atypical absence seizures as frequent in Dravet syndrome.
Developmental Regression VERY_FREQUENT Developmental regression HP:0002376
Show evidence (2 references)
PMID:21463282 SUPPORT Model Organism
"a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications."
ORPHA:33069 SUPPORT Other
"HP:0002376 | Developmental regression | Very frequent (99-80%)"
Orphanet's curated HPO table classifies developmental regression as very frequent in Dravet syndrome.
Cognitive Impairment FREQUENT Cognitive impairment HP:0100543
Ranges from mild to severe.
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0100543 | Cognitive impairment | Frequent (79-30%)"
Orphanet's curated HPO table classifies cognitive impairment as frequent in Dravet syndrome.
PMID:25772213 SUPPORT Human Clinical
"Intellectual disability was diagnosed in 28 (67%) children"
Swedish population-based study found intellectual disability in 67% of children with Dravet syndrome.
Autistic Behavior FREQUENT Autistic behavior HP:0000729
Behavioral and autism-like traits frequently observed and may relate to disrupted circuit development.
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0000729 | Autistic behavior | Frequent (79-30%)"
Orphanet's curated HPO table classifies autistic behavior as frequent in Dravet syndrome.
PMID:25772213 SUPPORT Human Clinical
"18 out of 30 patients investigated had autism spectrum disorder"
Swedish population-based study found autism spectrum disorder in 60% of investigated Dravet patients.
Anxiety FREQUENT Anxiety HP:0000739
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0000739 | Anxiety | Frequent (79-30%)"
Orphanet's curated HPO table classifies anxiety as frequent in Dravet syndrome.
Myoclonus FREQUENT Myoclonus HP:0001336
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0001336 | Myoclonus | Frequent (79-30%)"
Orphanet's curated HPO table classifies myoclonus as frequent in Dravet syndrome.
Parkinsonism FREQUENT Parkinsonism HP:0001300
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0001300 | Parkinsonism | Frequent (79-30%)"
Orphanet's curated HPO table classifies parkinsonism as frequent in Dravet syndrome.
Bradykinesia FREQUENT Bradykinesia HP:0002067
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002067 | Bradykinesia | Frequent (79-30%)"
Orphanet's curated HPO table classifies bradykinesia as frequent in Dravet syndrome.
Respiratory 1
Respiratory Failure OCCASIONAL Respiratory failure HP:0002878
Postictal ventilatory dysfunction can occur, particularly during sleep.
Constitutional 1
Sudden Unexpected Death in Epilepsy OCCASIONAL Sudden unexpected death in epilepsy HP:0033258
High premature mortality with SUDEP as leading cause. Risk peaks at ages 1-3 years and around 18 years.
Other 30
Complex Febrile Seizure FREQUENT Complex febrile seizure HP:0011172
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0011172 | Complex febrile seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies complex febrile seizures as frequent in Dravet syndrome.
Focal Hemiclonic Seizure FREQUENT Focal hemiclonic seizure HP:0006813
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0006813 | Focal hemiclonic seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies focal hemiclonic seizures as frequent in Dravet syndrome.
Photosensitive Myoclonic Seizures FREQUENT Photosensitive myoclonic seizure HP:0001327
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0001327 | Photomyoclonic seizures | Frequent (79-30%)"
Orphanet's curated HPO table classifies photomyoclonic seizures as frequent in Dravet syndrome.
Photosensitive Tonic-Clonic Seizures FREQUENT Photosensitive tonic-clonic seizure HP:0007207
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0007207 | Photosensitive tonic-clonic seizures | Frequent (79-30%)"
Orphanet's curated HPO table classifies photosensitive tonic-clonic seizures as frequent in Dravet syndrome.
Focal Aware Seizure FREQUENT Focal aware seizure HP:0002349
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002349 | Focal aware seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies focal aware seizures as frequent in Dravet syndrome.
Focal Impaired Awareness Seizure FREQUENT Focal impaired awareness seizure HP:0002384
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002384 | Focal impaired awareness seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies focal impaired awareness seizures as frequent in Dravet syndrome.
Generalized Clonic Seizure FREQUENT Generalized clonic seizure HP:0011169
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0011169 | Generalized clonic seizure | Frequent (79-30%)"
Orphanet's curated HPO table classifies generalized clonic seizures as frequent in Dravet syndrome.
Epilepsia Partialis Continua FREQUENT Epilepsia partialis continua HP:0012847
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0012847 | Epilepsia partialis continua | Frequent (79-30%)"
Orphanet's curated HPO table classifies epilepsia partialis continua as frequent in Dravet syndrome.
Status Epilepticus Without Prominent Motor Symptoms OCCASIONAL Status epilepticus without prominent motor symptoms HP:0031475
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0031475 | Status epilepticus without prominent motor symptoms | Occasional (29-5%)"
Orphanet's curated HPO table classifies non-convulsive status epilepticus as occasional in Dravet syndrome.
PMID:22719002 SUPPORT Human Clinical
"status epilepticus (odds ratio = 3.1; confidence interval = 1.5-6.3; P = 0.003)"
Brunklaus et al. identify status epilepticus as a significant prognostic predictor of worse developmental outcome.
Generalized Tonic Seizure VERY_RARE Generalized tonic seizure HP:0010818
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0010818 | Generalized tonic seizure | Very rare (<4-1%)"
Orphanet's curated HPO table classifies generalized tonic seizures as very rare in Dravet syndrome.
Multifocal Epileptiform Discharges FREQUENT Multifocal epileptiform discharges HP:0010841
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0010841 | Multifocal epileptiform discharges | Frequent (79-30%)"
Orphanet's curated HPO table classifies multifocal epileptiform discharges as frequent in Dravet syndrome.
Interictal Epileptiform Activity FREQUENT Interictal epileptiform activity HP:0011182
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0011182 | Interictal epileptiform activity | Frequent (79-30%)"
Orphanet's curated HPO table classifies interictal epileptiform activity as frequent in Dravet syndrome.
PMID:22719002 SUPPORT Human Clinical
"interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = 1.9-16.8; P = 0.002)"
UK cohort identifies interictal EEG abnormalities in the first year as a strong predictor of worse developmental outcome.
EEG with Focal Epileptiform Discharges OCCASIONAL EEG with focal epileptiform discharges HP:0011185
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0011185 | EEG with focal epileptiform discharges | Occasional (29-5%)"
Orphanet's curated HPO table classifies focal EEG epileptiform discharges as occasional in Dravet syndrome.
EEG with Generalized Epileptiform Discharges OCCASIONAL EEG with generalized epileptiform discharges HP:0011198
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0011198 | EEG with generalized epileptiform discharges | Occasional (29-5%)"
Orphanet's curated HPO table classifies generalized EEG epileptiform discharges as occasional in Dravet syndrome.
Progressive Gait Ataxia VERY_FREQUENT Progressive gait ataxia HP:0007240
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0007240 | Progressive gait ataxia | Very frequent (99-80%)"
Orphanet's curated HPO table classifies progressive gait ataxia as very frequent in Dravet syndrome.
PMID:22719002 SUPPORT Human Clinical
"motor disorder (odds ratio = 3.3; confidence interval = 1.7-6.4; P < 0.001)"
UK cohort identifies motor disorder as a strong predictor of worse developmental outcome, consistent with prominent gait ataxia.
Obsessive-Compulsive Trait FREQUENT Obsessive-compulsive trait HP:0008770
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0008770 | Obsessive-compulsive trait | Frequent (79-30%)"
Orphanet's curated HPO table classifies obsessive-compulsive traits as frequent in Dravet syndrome.
Short Attention Span OCCASIONAL Short attention span HP:0000736
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0000736 | Short attention span | Occasional (29-5%)"
Orphanet's curated HPO table classifies short attention span as occasional in Dravet syndrome.
Impulsivity OCCASIONAL Impulsivity HP:0100710
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0100710 | Impulsivity | Occasional (29-5%)"
Orphanet's curated HPO table classifies impulsivity as occasional in Dravet syndrome.
Cogwheel Rigidity FREQUENT Cogwheel rigidity HP:0002396
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002396 | Cogwheel rigidity | Frequent (79-30%)"
Orphanet's curated HPO table classifies cogwheel rigidity as frequent in Dravet syndrome.
Action Tremor OCCASIONAL Action tremor HP:0002345
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002345 | Action tremor | Occasional (29-5%)"
Orphanet's curated HPO table classifies action tremor as occasional in Dravet syndrome.
Facial Tics FREQUENT Facial tics HP:0011468
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0011468 | Facial tics | Frequent (79-30%)"
Orphanet's curated HPO table classifies facial tics as frequent in Dravet syndrome.
Incoordination OCCASIONAL Incoordination HP:0002311
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0002311 | Incoordination | Occasional (29-5%)"
Orphanet's curated HPO table classifies incoordination as occasional in Dravet syndrome.
Poor Fine Motor Coordination OCCASIONAL Poor fine motor coordination HP:0007010
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0007010 | Poor fine motor coordination | Occasional (29-5%)"
Orphanet's curated HPO table classifies poor fine motor coordination as occasional in Dravet syndrome.
Global Brain Atrophy OCCASIONAL Global brain atrophy HP:0002283
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0002283 | Global brain atrophy | Occasional (29-5%)"
Orphanet's curated HPO table classifies global brain atrophy as occasional in Dravet syndrome.
PMID:22719002 SUPPORT Human Clinical
"Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes."
UK cohort found brain atrophy or hippocampal changes in 11% of Dravet cases.
Dysgenesis of the Hippocampus OCCASIONAL Dysgenesis of the hippocampus HP:0025101
Show evidence (2 references)
ORPHA:33069 SUPPORT Other
"HP:0025101 | Dysgenesis of the hippocampus | Occasional (29-5%)"
Orphanet's curated HPO table classifies hippocampal dysgenesis as occasional in Dravet syndrome.
PMID:22719002 SUPPORT Human Clinical
"principally with findings of non-specific brain atrophy or hippocampal changes"
UK cohort found hippocampal changes among the neuroimaging abnormalities in Dravet syndrome.
Limited Neck Range of Motion FREQUENT Limited neck range of motion HP:0000466
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0000466 | Limited neck range of motion | Frequent (79-30%)"
Orphanet's curated HPO table classifies limited neck range of motion as frequent in Dravet syndrome.
Pes Valgus OCCASIONAL Pes valgus HP:0008081
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0008081 | Pes valgus | Occasional (29-5%)"
Orphanet's curated HPO table classifies pes valgus as occasional in Dravet syndrome.
Limited Knee Extension OCCASIONAL Limited knee extension HP:0003066
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0003066 | Limited knee extension | Occasional (29-5%)"
Orphanet's curated HPO table classifies limited knee extension as occasional in Dravet syndrome.
Tibial Torsion OCCASIONAL Tibial torsion HP:0100694
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0100694 | Tibial torsion | Occasional (29-5%)"
Orphanet's curated HPO table classifies tibial torsion as occasional in Dravet syndrome.
Cyanotic Episode OCCASIONAL Cyanotic episode HP:0200048
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"HP:0200048 | Cyanotic episode | Occasional (29-5%)"
Orphanet's curated HPO table classifies cyanotic episodes as occasional in Dravet syndrome.
🧬

Genetic Associations

11
SCN1A (Pathogenic Mutations)
Show evidence (4 references)
PMID:21463282 SUPPORT Model Organism
"Complete loss of function in the Na(v) 1.1 channel encoded by the SCN1A gene is associated with severe myoclonic epilepsy in infancy (SMEI)"
ORPHA:33069 SUPPORT Other
"SCN1A | sodium voltage-gated channel alpha subunit 1 | hgnc:10585 | Disease-causing germline mutation(s) in"
Orphanet gene table confirms SCN1A as a disease-causing gene for Dravet syndrome.
PMID:25772213 SUPPORT Human Clinical
"A mutation in the SCN1A gene was found in 37 patients (88%)"
Swedish population-based study found SCN1A mutations in 88% of Dravet patients.
+ 1 more reference
SCN1B (Rare Pathogenic Mutations)
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"SCN1B | sodium voltage-gated channel beta subunit 1 | hgnc:10586 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet gene table confirms SCN1B loss-of-function mutations as disease-causing in Dravet syndrome.
SCN2A (Rare Pathogenic Mutations)
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"SCN2A | sodium voltage-gated channel alpha subunit 2 | hgnc:10588 | Disease-causing germline mutation(s) in"
Orphanet gene table lists SCN2A as a disease-causing gene for Dravet syndrome.
SCN9A (Candidate Gene)
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"SCN9A | sodium voltage-gated channel alpha subunit 9 | hgnc:10597 | Candidate gene tested in"
Orphanet gene table lists SCN9A as a candidate gene tested in Dravet syndrome.
GABRA1 (Rare Pathogenic Mutations)
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"GABRA1 | gamma-aminobutyric acid type A receptor subunit alpha1 | hgnc:4075 | Disease-causing germline mutation(s) in"
Orphanet gene table confirms GABRA1 as a disease-causing gene for Dravet syndrome.
GABRG2 (Rare Pathogenic Mutations)
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"GABRG2 | gamma-aminobutyric acid type A receptor subunit gamma2 | hgnc:4087 | Disease-causing germline mutation(s) in"
Orphanet gene table confirms GABRG2 as a disease-causing gene for Dravet syndrome.
PCDH19 (Rare Pathogenic Mutations)
Show evidence (1 reference)
ORPHA:33069 SUPPORT Other
"PCDH19 | protocadherin 19 | hgnc:14270 | Disease-causing germline mutation(s) in"
Orphanet gene table lists PCDH19 as a disease-causing gene for Dravet syndrome.
STXBP1 (Rare Pathogenic Mutations)
HCN1 (Rare Associated Variants)
CHD2 (Modifier Gene)
DEPDC5 (Modifier Gene)
💊

Medical Actions

9
Antiepileptic Medications
Action: antiepileptic drug therapy Ontology label: anticonvulsant agent therapy MAXO:0000167
Includes clobazam, stiripentol, and valproate as first-line agents. Sodium channel blockers should be avoided as they may worsen seizures.
Mechanism Target:
INHIBITS Neuronal Hyperexcitability — GABAergic agents (clobazam, stiripentol) and valproate suppress pathological neuronal firing driven by Nav1.1 haploinsufficiency, reducing seizure frequency. Sodium channel blockers are contraindicated as they worsen inhibitory interneuron dysfunction.
Show evidence (1 reference)
PMID:22719002 SUPPORT Human Clinical
"Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine."
UK cohort confirms first-line medications and identifies sodium channel blockers that worsen seizures.
Ketogenic Diet
Action: dietary intervention MAXO:0000088
High-fat, low-carbohydrate diet that can provide significant seizure reduction in some patients.
Mechanism Target:
MODULATES Neuronal Hyperexcitability — Metabolic shift to ketone body utilization reduces neuronal excitability and seizure frequency in SCN1A-deficient networks, independent of sodium channel modulation.
Supportive Therapies
Action: supportive care MAXO:0000950
Therapies such as physical, occupational, and speech therapy to address developmental delays and cognitive impairment.
Vagus Nerve Stimulation (VNS)
Action: surgical procedure MAXO:0000004
Implanted device that may help reduce seizure frequency in drug-resistant cases.
Mechanism Target:
MODULATES Neuronal Hyperexcitability — Vagal afferent stimulation modulates cortical and subcortical excitability through ascending noradrenergic and serotonergic pathways, reducing seizure propagation in drug-resistant Dravet syndrome.
Antisense Oligonucleotide Therapy (Zorevunersen/STK-001)
Action: Pharmacotherapy NCIT:C15986
Agent: zorevunersen NCIT:C184885
Zorevunersen (STK-001) is an investigational splice-modulating antisense oligonucleotide that uses Targeted Augmentation of Nuclear Gene Output (TANGO) technology to prevent inclusion of the non-productive, nonsense-mediated-decay "poison" exon 20N in SCN1A pre-mRNA. Skipping the poison exon increases productive SCN1A transcript and Nav1.1 protein from the non-mutant allele, restoring inhibitory interneuron excitability rather than acting on seizure symptoms. Administered intrathecally. Preclinical models show increased productive Scn1a transcript with reduced seizures and SUDEP, and early clinical data report reduced seizure frequency.
Mechanism Target:
MODULATES SCN1A Gene Mutation — STK-001 is a splice-switching ASO that blocks inclusion of the non-productive poison exon 20N, raising productive SCN1A transcript and functional Nav1.1 protein in inhibitory interneurons to compensate for haploinsufficiency.
MODULATES Neuronal Hyperexcitability — Restoration of Nav1.1 in GABAergic interneurons rescues inhibitory tone, reducing pathological hyperexcitability downstream of SCN1A haploinsufficiency.
Show evidence (2 references)
PMID:32848094 SUPPORT Model Organism
"we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model."
Foundational TANGO study showing the ASO upregulates productive Scn1a transcript and reduces electrographic seizures and SUDEP in a Dravet mouse model.
PMID:37812817 SUPPORT Model Organism
"STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression"
Confirms the STK-001 mechanism targets poison exon 20N to raise productive SCN1A and Nav1.1, restoring interneuron sodium current and GABAergic signalling.
AAV Gene Therapy (ETX101)
Action: gene therapy MAXO:0001001
Investigational AAV9-based viral vector gene therapy designed to increase SCN1A expression through transcriptional activation in inhibitory neurons. Preclinical models demonstrate seizure reduction and improved survival.
Mechanism Target:
ACTIVATES SCN1A Gene Mutation — ETX101 delivers an AAV9-encoded transcriptional activator to inhibitory interneurons, directly increasing SCN1A expression and restoring Nav1.1-dependent inhibitory current.
MODULATES Neuronal Hyperexcitability — Interneuron-specific Nav1.1 restoration rescues inhibitory interneuron firing capacity, correcting the excitation-inhibition imbalance that drives Dravet syndrome seizures.
Cannabidiol
Action: Pharmacotherapy NCIT:C15986
Agent: cannabidiol CHEBI:69478
Pharmaceutical-grade cannabidiol approved as add-on therapy for reducing convulsive seizure frequency in Dravet syndrome.
Mechanism Target:
INHIBITS Neuronal Hyperexcitability — Cannabidiol reduces seizure frequency through multiple mechanisms including modulation of sodium currents, TRP channels, and adenosine signaling, suppressing pathological neuronal firing in SCN1A-deficient networks.
Fenfluramine
Action: Pharmacotherapy NCIT:C15986
Agent: fenfluramine CHEBI:5000
Approved add-on therapy for convulsive seizures in Dravet syndrome, with serotonergic mechanism of action.
Mechanism Target:
INHIBITS Neuronal Hyperexcitability — Fenfluramine releases serotonin and activates sigma-1 receptors, modulating serotonergic neurotransmission to suppress seizure activity in Nav1.1-deficient inhibitory networks.
Stiripentol
Action: Pharmacotherapy NCIT:C15986
Agent: stiripentol NCIT:C152433
Approved antiepileptic drug used in combination with clobazam and valproate for convulsive seizures in Dravet syndrome.
Mechanism Target:
INHIBITS Neuronal Hyperexcitability — Stiripentol potentiates GABA-A receptor activity and inhibits cytochrome P450 enzymes to increase clobazam levels, augmenting inhibitory tone in SCN1A-haploinsufficient networks.
Show evidence (1 reference)
PMID:25772213 SUPPORT Human Clinical
"Stiripentol, as an add-on medication, was used in 18 patients. Among these patients, seven were seizure free, six had >50% seizure reduction, and five <50% seizure reduction."
Swedish cohort provides real-world efficacy data for stiripentol add-on therapy.
🌍

Environmental Factors

2
Fever
Management of fever is crucial to minimize seizure risk.
Excessive Heat and Overexertion
Can trigger or worsen seizures.
{ }

Source YAML

click to show 
name: Dravet_syndrome
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-28T18:00:00Z'
description: Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by treatment-resistant seizures beginning in infancy, developmental regression, and cognitive impairment. It is primarily caused by de novo loss-of-function mutations in SCN1A, encoding the Nav1.1 voltage-gated sodium channel.
category: Genetic
disease_term:
  preferred_term: Dravet syndrome
  term:
    id: MONDO:0100135
    label: Dravet syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100135
      label: Dravet syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet
    mapping_justification: Orphanet ORPHA:33069 lists MONDO:0011794 as an exact cross-reference; MONDO:0100135 is the current preferred MONDO identifier for Dravet syndrome.
    consistency:
    - reference: ORPHA:33069
      consistent: CONSISTENT
      notes: "ORPHA cross-reference row: MONDO:0011794 | Exact"
external_assertions:
- name: Orphanet Dravet syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:33069
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=33069
  description: >
    Orphanet identifies Dravet syndrome as ORPHA:33069 and provides
    exact cross-references including MONDO:0011794 and OMIM:607208.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0011794 | Exact"
    explanation: Orphanet's cross-reference table maps ORPHA:33069 exactly to the MONDO term for Dravet syndrome.
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:607208 | Exact"
    explanation: Orphanet also provides an exact OMIM cross-reference for Dravet syndrome.
parents:
- Epileptic Encephalopathy
- Neurologic Disorder
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Orphanet classifies Dravet syndrome as autosomal dominant,
    consistent with de novo heterozygous loss-of-function mutations in SCN1A.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet directly lists autosomal dominant inheritance for ORPHA:33069.
prevalence:
- population: Europe
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 9.0
  percentage: "1-9 / 100 000"
  notes: >
    Orphanet prevalence at birth class for Dravet syndrome. Population-based
    studies estimate incidence of 1:40,900 UK births (PMID:22719002),
    1:33,000 Swedish births (PMID:25772213), and SCN1A-specific incidence of
    1:12,200 Scottish births (PMID:31302675).
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Europe | Prevalence at birth | PMID:22719002,PMID:25772213,PMID:31302675"
    explanation: Orphanet reports the European prevalence-at-birth class for Dravet syndrome based on three population-based studies.
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of mutation-positive Dravet syndrome is at least 1:40 900 UK births."
    explanation: UK population-based cohort establishing incidence of SCN1A mutation-positive Dravet syndrome.
  - reference: PMID:25772213
    reference_title: "Dravet syndrome in Sweden: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The estimated incidence was one in 33 000 live births (95% CI 1:20 400-1:56 200)"
    explanation: Swedish population-based study confirming Dravet syndrome incidence.
  - reference: PMID:31302675
    reference_title: "Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6)"
    explanation: Scottish prospective cohort providing SCN1A-specific epilepsy incidence.
progression:
- phase: Onset
  age_range: Infancy to Neonatal
  notes: >
    Orphanet lists onset as Infancy and Neonatal. Seizures typically begin
    between 3 and 12 months of age, often triggered by fever.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet's natural-history section classifies Dravet syndrome onset as infantile.
  - reference: PMID:25772213
    reference_title: "Dravet syndrome in Sweden: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median age at seizure onset was 6 months (range 0-12mo)"
    explanation: Swedish cohort confirms median seizure onset at 6 months.
pathophysiology:
- name: SCN1A Gene Mutation
  description: Heterozygous loss-of-function mutations in SCN1A cause reduced Nav1.1 sodium channel function, primarily affecting GABAergic inhibitory interneurons, particularly parvalbumin-positive fast-spiking interneurons.
  cell_types:
  - preferred_term: inhibitory interneuron
    term:
      id: CL:0000498
      label: inhibitory interneuron
  biological_processes:
  - preferred_term: neuronal action potential
    term:
      id: GO:0019228
      label: neuronal action potential
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  evidence:
  - reference: PMID:21463282
    reference_title: "Insights into pathophysiology and therapy from a mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Loss-of-function in Na(v) 1.1 channels results in severely impaired sodium current and action potential firing in hippocampal γ-aminobutyric acid (GABA)ergic interneurons without detectable changes in excitatory pyramidal neurons.
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN1A | sodium voltage-gated channel alpha subunit 1 | hgnc:10585 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene table confirms SCN1A as a disease-causing gene for Dravet syndrome.
  downstream:
  - target: Neuronal Hyperexcitability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced Nav1.1 sodium current selectively impairs firing of GABAergic
      inhibitory interneurons, lowering inhibitory tone and tilting cortical
      and hippocampal networks toward hyperexcitability.
    intermediate_mechanisms:
    - Loss of Nav1.1 current reduces action-potential firing in fast-spiking GABAergic interneurons, decreasing GABA release and inhibitory drive onto excitatory neurons.
    evidence:
    - reference: PMID:21463282
      reference_title: "Insights into pathophysiology and therapy from a mouse model of Dravet syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures.
      explanation: Links impaired interneuron sodium current to the excitation-inhibition imbalance that drives network hyperexcitability.
- name: Neuronal Hyperexcitability
  description: Reduced inhibitory interneuron function leads to excitatory-inhibitory imbalance and network hyperexcitability across cortico-hippocampal and thalamocortical circuits.
  cell_types:
  - preferred_term: inhibitory interneuron
    term:
      id: CL:0000498
      label: inhibitory interneuron
  biological_processes:
  - preferred_term: synaptic transmission, GABAergic
    term:
      id: GO:0051932
      label: synaptic transmission, GABAergic
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  - preferred_term: dorsal plus ventral thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  evidence:
  - reference: PMID:21463282
    reference_title: "Insights into pathophysiology and therapy from a mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures.
  downstream:
  - target: Seizures
    causal_link_type: DIRECT
  - target: Complex Febrile Seizure
    causal_link_type: DIRECT
  - target: Febrile Seizures
    causal_link_type: DIRECT
  - target: Atypical Absence Seizure
    causal_link_type: DIRECT
  - target: Focal Aware Seizure
    causal_link_type: DIRECT
  - target: Focal Impaired Awareness Seizure
    causal_link_type: DIRECT
  - target: Focal-onset Seizure
    causal_link_type: DIRECT
  - target: Focal Hemiclonic Seizure
    causal_link_type: DIRECT
  - target: Generalized Clonic Seizure
    causal_link_type: DIRECT
  - target: Generalized Myoclonic Seizure
    causal_link_type: DIRECT
  - target: Generalized Tonic Seizure
    causal_link_type: DIRECT
  - target: Photosensitive Myoclonic Seizures
    causal_link_type: DIRECT
  - target: Photosensitive Tonic-Clonic Seizures
    causal_link_type: DIRECT
  - target: Epilepsia Partialis Continua
    causal_link_type: DIRECT
  - target: Status Epilepticus Without Prominent Motor Symptoms
    causal_link_type: DIRECT
  - target: EEG with Focal Epileptiform Discharges
    causal_link_type: DIRECT
  - target: EEG with Generalized Epileptiform Discharges
    causal_link_type: DIRECT
  - target: Multifocal Epileptiform Discharges
    causal_link_type: DIRECT
  - target: Interictal Epileptiform Activity
    causal_link_type: DIRECT
  - target: Cyanotic Episode
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Developmental Regression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cognitive Impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Autistic Behavior
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Anxiety
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Impulsivity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Short Attention Span
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Obsessive-Compulsive Trait
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Action Tremor
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Myoclonus
    causal_link_type: DIRECT
  - target: Progressive Gait Ataxia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Incoordination
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Poor Fine Motor Coordination
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Global Brain Atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Astrocyte Dysregulation
  description: Aberrant astrocyte calcium signaling and gliotransmission may exacerbate network hyperexcitability and seizure susceptibility.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: regulation of cytosolic calcium ion concentration
    term:
      id: GO:0051480
      label: regulation of cytosolic calcium ion concentration
    modifier: DYSREGULATED
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  evidence:
  - reference: PMID:36610382
    reference_title: "Astrocyte Ca2+ signaling is facilitated in Scn1a(+/-) mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a+/- astrocytes."
    explanation: Scn1a+/- Dravet model astrocytes show facilitated spontaneous and ATP-evoked Ca2+ signaling, supporting astrocyte Ca2+ dysregulation as a contributor to network hyperexcitability.
  - reference: PMID:36610382
    reference_title: "Astrocyte Ca2+ signaling is facilitated in Scn1a(+/-) mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS."
    explanation: The authors conclude perturbed astrocytic Ca2+ dynamics may participate in Dravet syndrome pathogenesis.
  downstream:
  - target: Neuronal Hyperexcitability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Facilitated astrocytic Ca2+ signaling and gliotransmission are proposed
      to further exacerbate network hyperexcitability, although the precise
      coupling between astrocytic Ca2+ dynamics and neuronal excitability in
      Dravet syndrome remains to be established.
    evidence:
    - reference: PMID:36610382
      reference_title: "Astrocyte Ca2+ signaling is facilitated in Scn1a(+/-) mouse model of Dravet syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS."
      explanation: Supports astrocyte Ca2+ dysregulation as a contributing, mechanistically incompletely defined modifier of network hyperexcitability.
phenotypes:
- category: Neurologic
  name: Seizures
  description: Treatment-resistant seizures beginning in the first year of life, often triggered by fever, with progression to multiple seizure types.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Include prolonged febrile seizures and various types of epilepsy as the condition progresses.
  evidence:
  - reference: PMID:21463282
    reference_title: "Insights into pathophysiology and therapy from a mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications.
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007359 | Focal-onset seizure | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table classifies focal-onset seizures as very frequent in Dravet syndrome, corroborating the high seizure burden.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- category: Neurologic
  name: Focal-onset Seizure
  description: >
    Focal-onset seizures are a very frequent seizure type in Dravet syndrome,
    classified by Orphanet among the most common manifestations.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007359 | Focal-onset seizure | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table classifies focal-onset seizures as very frequent in Dravet syndrome.
- category: Neurologic
  name: Febrile Seizures
  description: Seizures triggered by fever, typically the presenting feature in infancy between 3 months and 6 years. Often prolonged hemiclonic seizures or status epilepticus.
  frequency: FREQUENT
  diagnostic: true
  notes: Characteristic presenting feature in early infancy, often prompts genetic evaluation for Dravet syndrome.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002373 | Febrile seizure (within the age range of 3 months to 6 years) | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies febrile seizures as frequent in Dravet syndrome.
  phenotype_term:
    preferred_term: Febrile seizure (within the age range of 3 months to 6 years)
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
- category: Neurologic
  name: Complex Febrile Seizure
  description: >
    Prolonged or focal febrile seizures, frequently the presenting seizure
    type in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Complex febrile seizure
    term:
      id: HP:0011172
      label: Complex febrile seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011172 | Complex febrile seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies complex febrile seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Focal Hemiclonic Seizure
  description: >
    Hemiclonic seizures are a frequent and characteristic seizure type in
    Dravet syndrome, often occurring during the initial febrile presentation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Focal hemiclonic seizure
    term:
      id: HP:0006813
      label: Focal hemiclonic seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006813 | Focal hemiclonic seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies focal hemiclonic seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Generalized Myoclonic Seizure
  description: >
    Myoclonic seizures are a frequent seizure type in Dravet syndrome,
    consistent with its historical designation as severe myoclonic epilepsy
    of infancy (SMEI).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized myoclonic seizure
    term:
      id: HP:0002123
      label: Generalized myoclonic seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002123 | Generalized myoclonic seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies generalized myoclonic seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Photosensitive Myoclonic Seizures
  description: >
    Seizures triggered by photic stimulation, a frequent feature in
    Dravet syndrome reflecting photosensitivity.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Photosensitive myoclonic seizures
    term:
      id: HP:0001327
      label: Photosensitive myoclonic seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001327 | Photomyoclonic seizures | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies photomyoclonic seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Photosensitive Tonic-Clonic Seizures
  description: >
    Tonic-clonic seizures triggered by photosensitivity, a frequent
    manifestation in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Photosensitive tonic-clonic seizures
    term:
      id: HP:0007207
      label: Photosensitive tonic-clonic seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007207 | Photosensitive tonic-clonic seizures | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies photosensitive tonic-clonic seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Focal Aware Seizure
  description: >
    Focal seizures with preserved awareness, a frequent seizure type in
    Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Focal aware seizure
    term:
      id: HP:0002349
      label: Focal aware seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002349 | Focal aware seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies focal aware seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Focal Impaired Awareness Seizure
  description: >
    Focal seizures with impaired awareness, a frequent seizure type in
    Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Focal impaired awareness seizure
    term:
      id: HP:0002384
      label: Focal impaired awareness seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002384 | Focal impaired awareness seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies focal impaired awareness seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Atypical Absence Seizure
  description: >
    Atypical absence seizures are a frequent seizure type in the Dravet
    syndrome spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical absence seizure
    term:
      id: HP:0007270
      label: Atypical absence seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007270 | Atypical absence seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies atypical absence seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Generalized Clonic Seizure
  description: >
    Generalized clonic seizures are among the frequent seizure types in
    Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized clonic seizure
    term:
      id: HP:0011169
      label: Generalized clonic seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011169 | Generalized clonic seizure | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies generalized clonic seizures as frequent in Dravet syndrome.
- category: Neurologic
  name: Epilepsia Partialis Continua
  description: >
    Continuous focal seizure activity, listed as a frequent manifestation
    in Dravet syndrome by Orphanet.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epilepsia partialis continua
    term:
      id: HP:0012847
      label: Epilepsia partialis continua
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012847 | Epilepsia partialis continua | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies epilepsia partialis continua as frequent in Dravet syndrome.
- category: Neurologic
  name: Status Epilepticus Without Prominent Motor Symptoms
  description: >
    Non-convulsive status epilepticus, an occasional manifestation in
    Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Status epilepticus without prominent motor symptoms
    term:
      id: HP:0031475
      label: Status epilepticus without prominent motor symptoms
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031475 | Status epilepticus without prominent motor symptoms | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies non-convulsive status epilepticus as occasional in Dravet syndrome.
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "status epilepticus (odds ratio = 3.1; confidence interval = 1.5-6.3; P = 0.003)"
    explanation: Brunklaus et al. identify status epilepticus as a significant prognostic predictor of worse developmental outcome.
- category: Neurologic
  name: Generalized Tonic Seizure
  description: >
    Generalized tonic seizures are a very rare seizure type in Dravet syndrome.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Generalized tonic seizure
    term:
      id: HP:0010818
      label: Generalized tonic seizure
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010818 | Generalized tonic seizure | Very rare (<4-1%)"
    explanation: Orphanet's curated HPO table classifies generalized tonic seizures as very rare in Dravet syndrome.
- category: Neurologic
  name: Multifocal Epileptiform Discharges
  description: >
    EEG finding of multifocal epileptiform discharges, frequently seen in
    Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Multifocal epileptiform discharges
    term:
      id: HP:0010841
      label: Multifocal epileptiform discharges
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010841 | Multifocal epileptiform discharges | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies multifocal epileptiform discharges as frequent in Dravet syndrome.
- category: Neurologic
  name: Interictal Epileptiform Activity
  description: >
    EEG epileptiform activity between seizures, a frequent finding in
    Dravet syndrome. Early interictal abnormalities are prognostically significant.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Interictal epileptiform activity
    term:
      id: HP:0011182
      label: Interictal epileptiform activity
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011182 | Interictal epileptiform activity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies interictal epileptiform activity as frequent in Dravet syndrome.
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = 1.9-16.8; P = 0.002)"
    explanation: UK cohort identifies interictal EEG abnormalities in the first year as a strong predictor of worse developmental outcome.
- category: Neurologic
  name: EEG with Focal Epileptiform Discharges
  description: >
    Focal epileptiform discharges on EEG, an occasional finding in
    Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: EEG with focal epileptiform discharges
    term:
      id: HP:0011185
      label: EEG with focal epileptiform discharges
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011185 | EEG with focal epileptiform discharges | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies focal EEG epileptiform discharges as occasional in Dravet syndrome.
- category: Neurologic
  name: EEG with Generalized Epileptiform Discharges
  description: >
    Generalized epileptiform discharges on EEG, an occasional finding in
    Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: EEG with generalized epileptiform discharges
    term:
      id: HP:0011198
      label: EEG with generalized epileptiform discharges
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011198 | EEG with generalized epileptiform discharges | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies generalized EEG epileptiform discharges as occasional in Dravet syndrome.
- category: Developmental
  name: Developmental Regression
  description: >
    Progressive developmental regression typically beginning after
    seizure onset, affecting motor, language, and social skills.
    Classified as very frequent by Orphanet.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:21463282
    reference_title: "Insights into pathophysiology and therapy from a mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications.
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002376 | Developmental regression | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table classifies developmental regression as very frequent in Dravet syndrome.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
- category: Cognitive
  name: Cognitive Impairment
  description: Cognitive impairment ranging from mild to severe, often progressive in nature.
  frequency: FREQUENT
  notes: Ranges from mild to severe.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100543 | Cognitive impairment | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies cognitive impairment as frequent in Dravet syndrome.
  - reference: PMID:25772213
    reference_title: "Dravet syndrome in Sweden: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability was diagnosed in 28 (67%) children"
    explanation: Swedish population-based study found intellectual disability in 67% of children with Dravet syndrome.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
- category: Neurologic
  name: Progressive Gait Ataxia
  description: >
    Progressive gait ataxia is a very frequent manifestation in Dravet
    syndrome, affecting coordination and balance with worsening over time.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007240 | Progressive gait ataxia | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table classifies progressive gait ataxia as very frequent in Dravet syndrome.
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "motor disorder (odds ratio = 3.3; confidence interval = 1.7-6.4; P < 0.001)"
    explanation: UK cohort identifies motor disorder as a strong predictor of worse developmental outcome, consistent with prominent gait ataxia.
  phenotype_term:
    preferred_term: Progressive gait ataxia
    term:
      id: HP:0007240
      label: Progressive gait ataxia
- category: Behavioral
  name: Autistic Behavior
  description: Autism spectrum features including impaired social interaction, communication difficulties, and restricted repetitive behaviors.
  frequency: FREQUENT
  notes: Behavioral and autism-like traits frequently observed and may relate to disrupted circuit development.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000729 | Autistic behavior | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies autistic behavior as frequent in Dravet syndrome.
  - reference: PMID:25772213
    reference_title: "Dravet syndrome in Sweden: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 out of 30 patients investigated had autism spectrum disorder"
    explanation: Swedish population-based study found autism spectrum disorder in 60% of investigated Dravet patients.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
- category: Behavioral
  name: Anxiety
  description: >
    Anxiety is a frequent behavioral feature in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000739 | Anxiety | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies anxiety as frequent in Dravet syndrome.
- category: Behavioral
  name: Obsessive-Compulsive Trait
  description: >
    Obsessive-compulsive behavioral traits are a frequent feature in
    Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Obsessive-compulsive trait
    term:
      id: HP:0008770
      label: Obsessive-compulsive trait
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008770 | Obsessive-compulsive trait | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies obsessive-compulsive traits as frequent in Dravet syndrome.
- category: Behavioral
  name: Short Attention Span
  description: >
    Attention deficits and short attention span, an occasional behavioral
    feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Short attention span
    term:
      id: HP:0000736
      label: Short attention span
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000736 | Short attention span | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies short attention span as occasional in Dravet syndrome.
- category: Behavioral
  name: Impulsivity
  description: >
    Impulsive behavior, an occasional behavioral feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Impulsivity
    term:
      id: HP:0100710
      label: Impulsivity
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100710 | Impulsivity | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies impulsivity as occasional in Dravet syndrome.
- category: Neurologic
  name: Myoclonus
  description: >
    Non-epileptic myoclonus is a frequent motor feature in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001336 | Myoclonus | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies myoclonus as frequent in Dravet syndrome.
- category: Neurologic
  name: Parkinsonism
  description: >
    Parkinsonian features including rigidity, bradykinesia, and cogwheel
    rigidity, emerging as frequent manifestations particularly in older
    patients with Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001300 | Parkinsonism | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies parkinsonism as frequent in Dravet syndrome.
- category: Neurologic
  name: Rigidity
  description: >
    Muscular rigidity is a frequent motor feature in Dravet syndrome,
    part of the parkinsonian phenotype spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002063 | Rigidity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies rigidity as frequent in Dravet syndrome.
- category: Neurologic
  name: Bradykinesia
  description: >
    Slowness of movement, a frequent feature of the parkinsonian
    phenotype in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002067 | Bradykinesia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies bradykinesia as frequent in Dravet syndrome.
- category: Neurologic
  name: Cogwheel Rigidity
  description: >
    Cogwheel-type rigidity, a frequent parkinsonian feature in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cogwheel rigidity
    term:
      id: HP:0002396
      label: Cogwheel rigidity
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002396 | Cogwheel rigidity | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies cogwheel rigidity as frequent in Dravet syndrome.
- category: Neurologic
  name: Action Tremor
  description: >
    Tremor during voluntary movement, an occasional motor feature in
    Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Action tremor
    term:
      id: HP:0002345
      label: Action tremor
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002345 | Action tremor | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies action tremor as occasional in Dravet syndrome.
- category: Neurologic
  name: Facial Tics
  description: >
    Facial tics are a frequent motor feature in Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Facial tics
    term:
      id: HP:0011468
      label: Facial tics
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011468 | Facial tics | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies facial tics as frequent in Dravet syndrome.
- category: Neurologic
  name: Incoordination
  description: >
    General motor incoordination, an occasional feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Incoordination
    term:
      id: HP:0002311
      label: Incoordination
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002311 | Incoordination | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies incoordination as occasional in Dravet syndrome.
- category: Neurologic
  name: Poor Fine Motor Coordination
  description: >
    Impaired fine motor skills, an occasional feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Poor fine motor coordination
    term:
      id: HP:0007010
      label: Poor fine motor coordination
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007010 | Poor fine motor coordination | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies poor fine motor coordination as occasional in Dravet syndrome.
- category: Neurologic
  name: Drooling
  description: >
    Drooling (sialorrhea), an occasional feature in Dravet syndrome
    reflecting oropharyngeal motor dysfunction.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Drooling
    term:
      id: HP:0002307
      label: Drooling
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002307 | Drooling | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies drooling as occasional in Dravet syndrome.
- category: Neurologic
  name: Floppy Infant
  description: >
    Infantile hypotonia, an occasional early feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Floppy infant
    term:
      id: HP:0008947
      label: Floppy infant
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008947 | Floppy infant | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies infantile hypotonia as occasional in Dravet syndrome.
- category: Neuroimaging
  name: Global Brain Atrophy
  description: >
    Non-specific brain atrophy on neuroimaging, an occasional finding in
    Dravet syndrome.
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002283 | Global brain atrophy | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies global brain atrophy as occasional in Dravet syndrome.
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes."
    explanation: UK cohort found brain atrophy or hippocampal changes in 11% of Dravet cases.
  phenotype_term:
    preferred_term: Global brain atrophy
    term:
      id: HP:0002283
      label: Global brain atrophy
- category: Neuroimaging
  name: Dysgenesis of the Hippocampus
  description: >
    Hippocampal structural abnormalities, an occasional neuroimaging
    finding in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dysgenesis of the hippocampus
    term:
      id: HP:0025101
      label: Dysgenesis of the hippocampus
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025101 | Dysgenesis of the hippocampus | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies hippocampal dysgenesis as occasional in Dravet syndrome.
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "principally with findings of non-specific brain atrophy or hippocampal changes"
    explanation: UK cohort found hippocampal changes among the neuroimaging abnormalities in Dravet syndrome.
- category: Musculoskeletal
  name: Limited Neck Range of Motion
  description: >
    Restricted neck mobility, a frequent musculoskeletal feature in
    Dravet syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Limited neck range of motion
    term:
      id: HP:0000466
      label: Limited neck range of motion
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000466 | Limited neck range of motion | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies limited neck range of motion as frequent in Dravet syndrome.
- category: Musculoskeletal
  name: Pes Planus
  description: >
    Flat feet, an occasional musculoskeletal feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001763 | Pes planus | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies pes planus as occasional in Dravet syndrome.
- category: Musculoskeletal
  name: Pes Valgus
  description: >
    Valgus foot deformity, an occasional musculoskeletal feature in
    Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pes valgus
    term:
      id: HP:0008081
      label: Pes valgus
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008081 | Pes valgus | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies pes valgus as occasional in Dravet syndrome.
- category: Musculoskeletal
  name: Limited Knee Extension
  description: >
    Restricted knee extension, an occasional musculoskeletal feature in
    Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Limited knee extension
    term:
      id: HP:0003066
      label: Limited knee extension
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003066 | Limited knee extension | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies limited knee extension as occasional in Dravet syndrome.
- category: Musculoskeletal
  name: Tibial Torsion
  description: >
    Tibial torsion, an occasional orthopedic feature in Dravet syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tibial torsion
    term:
      id: HP:0100694
      label: Tibial torsion
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100694 | Tibial torsion | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies tibial torsion as occasional in Dravet syndrome.
- category: Other
  name: Pallor
  description: >
    Pallor is an occasional feature in Dravet syndrome, which may occur
    during ictal or postictal periods.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000980 | Pallor | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies pallor as occasional in Dravet syndrome.
- category: Other
  name: Cyanotic Episode
  description: >
    Episodes of cyanosis, an occasional feature in Dravet syndrome
    potentially related to ictal autonomic dysfunction.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cyanotic episode
    term:
      id: HP:0200048
      label: Cyanotic episode
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200048 | Cyanotic episode | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies cyanotic episodes as occasional in Dravet syndrome.
- category: Respiratory
  name: Respiratory Failure
  description: Postictal respiratory compromise and sleep-associated breathing abnormalities contributing to SUDEP risk.
  frequency: OCCASIONAL
  notes: Postictal ventilatory dysfunction can occur, particularly during sleep.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
- category: Mortality
  name: Sudden Unexpected Death in Epilepsy
  description: Markedly elevated risk of sudden unexpected death in epilepsy (SUDEP), accounting for up to 50% of deaths in Dravet syndrome. Linked to seizure burden, postictal cardiorespiratory dysfunction, and potential cardiac susceptibility.
  frequency: OCCASIONAL
  notes: High premature mortality with SUDEP as leading cause. Risk peaks at ages 1-3 years and around 18 years.
  phenotype_term:
    preferred_term: Sudden unexpected death in epilepsy
    term:
      id: HP:0033258
      label: Sudden unexpected death in epilepsy
genetic:
- name: SCN1A
  association: Pathogenic Mutations
  presence: Positive
  notes: De novo loss-of-function mutations found in approximately 70-80% of Dravet syndrome patients. Primary causal gene encoding Nav1.1 voltage-gated sodium channel.
  evidence:
  - reference: PMID:21463282
    reference_title: "Insights into pathophysiology and therapy from a mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Complete loss of function in the Na(v) 1.1 channel encoded by the SCN1A gene is associated with severe myoclonic epilepsy in infancy (SMEI)
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN1A | sodium voltage-gated channel alpha subunit 1 | hgnc:10585 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene table confirms SCN1A as a disease-causing gene for Dravet syndrome.
  - reference: PMID:25772213
    reference_title: "Dravet syndrome in Sweden: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mutation in the SCN1A gene was found in 37 patients (88%)"
    explanation: Swedish population-based study found SCN1A mutations in 88% of Dravet patients.
  - reference: CGGV:assertion_60334a15-c73e-42ce-b7d2-4796c2affde4-2019-08-20T160000.000Z
    reference_title: "SCN1A / Dravet syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN1A | HGNC:10585 | Dravet syndrome | MONDO:0100135 | AD | Definitive"
    explanation: ClinGen classifies the SCN1A-Dravet syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: SCN1B
  association: Rare Pathogenic Mutations
  notes: Encodes beta-1 subunit of voltage-gated sodium channels. Rare variants associated with Dravet syndrome phenotype.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN1B | sodium voltage-gated channel beta subunit 1 | hgnc:10586 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet gene table confirms SCN1B loss-of-function mutations as disease-causing in Dravet syndrome.
- name: SCN2A
  association: Rare Pathogenic Mutations
  notes: Encodes Nav1.2 sodium channel alpha subunit. Rare variants associated with Dravet syndrome phenotype.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN2A | sodium voltage-gated channel alpha subunit 2 | hgnc:10588 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene table lists SCN2A as a disease-causing gene for Dravet syndrome.
- name: SCN9A
  association: Candidate Gene
  notes: Encodes Nav1.7 sodium channel. Candidate gene tested in atypical cases.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN9A | sodium voltage-gated channel alpha subunit 9 | hgnc:10597 | Candidate gene tested in"
    explanation: Orphanet gene table lists SCN9A as a candidate gene tested in Dravet syndrome.
- name: GABRA1
  association: Rare Pathogenic Mutations
  notes: Encodes GABA-A receptor alpha-1 subunit. Rare variants can cause Dravet-like epileptic encephalopathy.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GABRA1 | gamma-aminobutyric acid type A receptor subunit alpha1 | hgnc:4075 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene table confirms GABRA1 as a disease-causing gene for Dravet syndrome.
- name: GABRG2
  association: Rare Pathogenic Mutations
  notes: Encodes GABA-A receptor gamma-2 subunit. Variants associated with epileptic encephalopathy phenotypes overlapping with Dravet syndrome.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GABRG2 | gamma-aminobutyric acid type A receptor subunit gamma2 | hgnc:4087 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene table confirms GABRG2 as a disease-causing gene for Dravet syndrome.
- name: PCDH19
  association: Rare Pathogenic Mutations
  notes: Encodes protocadherin 19. Rare mutations associated with epileptic encephalopathy overlapping with Dravet syndrome, particularly in females.
  evidence:
  - reference: ORPHA:33069
    reference_title: "Dravet syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PCDH19 | protocadherin 19 | hgnc:14270 | Disease-causing germline mutation(s) in"
    explanation: Orphanet gene table lists PCDH19 as a disease-causing gene for Dravet syndrome.
- name: STXBP1
  association: Rare Pathogenic Mutations
  notes: Encodes syntaxin-binding protein 1. Mutations cause early infantile epileptic encephalopathy with phenotypic overlap.
- name: HCN1
  association: Rare Associated Variants
  notes: Encodes hyperpolarization-activated cyclic nucleotide-gated channel 1. Variants reported in early infantile epileptic encephalopathy.
- name: CHD2
  association: Modifier Gene
  notes: Encodes chromodomain helicase DNA-binding protein 2. Variants may modify disease severity and phenotype in Dravet syndrome.
- name: DEPDC5
  association: Modifier Gene
  notes: Encodes DEP domain-containing protein 5. Polygenic modifier that may influence disease expressivity and severity.
diagnosis:
- name: Genetic Testing for SCN1A Mutations
  presence: Positive in affected individuals
treatments:
- name: Antiepileptic Medications
  description: Includes clobazam, stiripentol, and valproate as first-line agents. Sodium channel blockers should be avoided as they may worsen seizures.
  notes: Standard treatment includes clobazam, stiripentol, and valproate.
  evidence:
  - reference: PMID:22719002
    reference_title: "Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine."
    explanation: UK cohort confirms first-line medications and identifies sodium channel blockers that worsen seizures.
  treatment_term:
    preferred_term: antiepileptic drug therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  target_mechanisms:
  - target: Neuronal Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      GABAergic agents (clobazam, stiripentol) and valproate suppress
      pathological neuronal firing driven by Nav1.1 haploinsufficiency,
      reducing seizure frequency. Sodium channel blockers are
      contraindicated as they worsen inhibitory interneuron dysfunction.
- name: Ketogenic Diet
  description: High-fat, low-carbohydrate diet that can provide significant seizure reduction in some patients.
  notes: Has shown efficacy in reducing seizure frequency in Dravet syndrome patients.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Neuronal Hyperexcitability
    treatment_effect: MODULATES
    description: >-
      Metabolic shift to ketone body utilization reduces neuronal
      excitability and seizure frequency in SCN1A-deficient networks,
      independent of sodium channel modulation.
- name: Supportive Therapies
  description: Therapies such as physical, occupational, and speech therapy to address developmental delays and cognitive impairment.
  notes: Comprehensive care includes developmental support and therapeutic interventions.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Vagus Nerve Stimulation (VNS)
  description: Implanted device that may help reduce seizure frequency in drug-resistant cases.
  notes: May be considered for patients with drug-resistant seizures.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_mechanisms:
  - target: Neuronal Hyperexcitability
    treatment_effect: MODULATES
    description: >-
      Vagal afferent stimulation modulates cortical and subcortical
      excitability through ascending noradrenergic and serotonergic
      pathways, reducing seizure propagation in drug-resistant Dravet
      syndrome.
- name: Antisense Oligonucleotide Therapy (Zorevunersen/STK-001)
  description: >
    Zorevunersen (STK-001) is an investigational splice-modulating antisense
    oligonucleotide that uses Targeted Augmentation of Nuclear Gene Output
    (TANGO) technology to prevent inclusion of the non-productive,
    nonsense-mediated-decay "poison" exon 20N in SCN1A pre-mRNA. Skipping the
    poison exon increases productive SCN1A transcript and Nav1.1 protein from
    the non-mutant allele, restoring inhibitory interneuron excitability rather
    than acting on seizure symptoms. Administered intrathecally. Preclinical
    models show increased productive Scn1a transcript with reduced seizures and
    SUDEP, and early clinical data report reduced seizure frequency.
  notes: Disease-modifying gene-targeted therapy in clinical development. Allele-agnostic upregulation of the productive SCN1A transcript addresses the underlying haploinsufficiency.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: SCN1A
      term:
        id: hgnc:10585
        label: SCN1A
    target_transcript: SCN1A pre-mRNA (non-productive poison exon 20N splice event)
    target_exon: exon 20N (poison exon)
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zorevunersen
      term:
        id: NCIT:C184885
        label: Zorevunersen
  target_mechanisms:
  - target: SCN1A Gene Mutation
    treatment_effect: MODULATES
    description: >-
      STK-001 is a splice-switching ASO that blocks inclusion of the
      non-productive poison exon 20N, raising productive SCN1A transcript and
      functional Nav1.1 protein in inhibitory interneurons to compensate for
      haploinsufficiency.
  - target: Neuronal Hyperexcitability
    treatment_effect: MODULATES
    description: >-
      Restoration of Nav1.1 in GABAergic interneurons rescues inhibitory
      tone, reducing pathological hyperexcitability downstream of SCN1A
      haploinsufficiency.
  evidence:
  - reference: PMID:32848094
    reference_title: "Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model."
    explanation: Foundational TANGO study showing the ASO upregulates productive Scn1a transcript and reduces electrographic seizures and SUDEP in a Dravet mouse model.
  - reference: PMID:37812817
    reference_title: "Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression"
    explanation: Confirms the STK-001 mechanism targets poison exon 20N to raise productive SCN1A and Nav1.1, restoring interneuron sodium current and GABAergic signalling.
- name: AAV Gene Therapy (ETX101)
  description: Investigational AAV9-based viral vector gene therapy designed to increase SCN1A expression through transcriptional activation in inhibitory neurons. Preclinical models demonstrate seizure reduction and improved survival.
  notes: Disease-modifying gene therapy approaching clinical testing. Targets interneuron-specific SCN1A restoration.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: SCN1A Gene Mutation
    treatment_effect: ACTIVATES
    description: >-
      ETX101 delivers an AAV9-encoded transcriptional activator to
      inhibitory interneurons, directly increasing SCN1A expression
      and restoring Nav1.1-dependent inhibitory current.
  - target: Neuronal Hyperexcitability
    treatment_effect: MODULATES
    description: >-
      Interneuron-specific Nav1.1 restoration rescues inhibitory
      interneuron firing capacity, correcting the excitation-inhibition
      imbalance that drives Dravet syndrome seizures.
- name: Cannabidiol
  description: Pharmaceutical-grade cannabidiol approved as add-on therapy for reducing convulsive seizure frequency in Dravet syndrome.
  notes: Approved therapy with demonstrated efficacy in randomized controlled trials.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cannabidiol
      term:
        id: CHEBI:69478
        label: cannabidiol
  target_mechanisms:
  - target: Neuronal Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      Cannabidiol reduces seizure frequency through multiple mechanisms
      including modulation of sodium currents, TRP channels, and
      adenosine signaling, suppressing pathological neuronal firing
      in SCN1A-deficient networks.
- name: Fenfluramine
  description: Approved add-on therapy for convulsive seizures in Dravet syndrome, with serotonergic mechanism of action.
  notes: Effective therapy approved based on randomized controlled trial data.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fenfluramine
      term:
        id: CHEBI:5000
        label: fenfluramine
  target_mechanisms:
  - target: Neuronal Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      Fenfluramine releases serotonin and activates sigma-1 receptors,
      modulating serotonergic neurotransmission to suppress seizure
      activity in Nav1.1-deficient inhibitory networks.
- name: Stiripentol
  description: Approved antiepileptic drug used in combination with clobazam and valproate for convulsive seizures in Dravet syndrome.
  notes: Part of standard first-line combination therapy.
  evidence:
  - reference: PMID:25772213
    reference_title: "Dravet syndrome in Sweden: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stiripentol, as an add-on medication, was used in 18 patients. Among these patients, seven were seizure free, six had >50% seizure reduction, and five <50% seizure reduction."
    explanation: Swedish cohort provides real-world efficacy data for stiripentol add-on therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: stiripentol
      term:
        id: NCIT:C152433
        label: Stiripentol
  target_mechanisms:
  - target: Neuronal Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      Stiripentol potentiates GABA-A receptor activity and inhibits
      cytochrome P450 enzymes to increase clobazam levels, augmenting
      inhibitory tone in SCN1A-haploinsufficient networks.
environmental:
- name: Fever
  effect: Triggers Seizures
  notes: Management of fever is crucial to minimize seizure risk.
- name: Excessive Heat and Overexertion
  effect: Exacerbates Symptoms
  notes: Can trigger or worsen seizures.
notes: Early diagnosis and a comprehensive treatment plan are essential to managing Dravet syndrome and improving quality of life.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
references:
- reference: DOI:10.1007/s10309-025-00785-x
  title: More than epilepsy—a parent-initiated collaborative analysis of the research landscape and research needs in Dravet syndrome
  findings: []
- reference: DOI:10.1038/s41398-025-03304-8
  title: Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome
  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/jcm12072532
  title: Epilepsy in Dravet Syndrome—Current and Future Therapeutic Opportunities
  findings: []
📚

References & Deep Research

References

4
DOI:10.1007/s10309-025-00785-x
More than epilepsy—a parent-initiated collaborative analysis of the research landscape and research needs in Dravet syndrome
No top-level findings curated for this source.
DOI:10.1038/s41398-025-03304-8
Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome
No top-level findings curated for this source.
DOI:10.3389/fnins.2025.1634718
Dravet syndrome: novel insights into SCN1A-mediated epileptic neurodevelopmental disorders within the molecular diagnostic-therapeutic framework
No top-level findings curated for this source.
DOI:10.3390/jcm12072532
Epilepsy in Dravet Syndrome—Current and Future Therapeutic Opportunities
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Dravet_syndrome
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 9

Key Pathophysiology Nodes

  • SCN1A Gene Mutation
  • Neuronal Hyperexcitability
  • Astrocyte Dysregulation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s10309-025-00785-x
  • DOI:10.1038/s41398-025-03304-8
  • DOI:10.3389/fnins.2025.1634718
  • DOI:10.3390/jcm12072532
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 49 citations 2026-06-11T22:33:16.543773

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Dravet syndrome
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Dravet syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dravet syndrome — Disease characteristics research report (Genetic)

Executive summary

Dravet syndrome (DS) is a prototypic developmental and epileptic encephalopathy (DEE) with infantile onset seizures—often prolonged and fever-triggered—followed by emergence of neurodevelopmental impairment, multiple seizure types, and substantial lifelong morbidity and premature mortality risk (notably SUDEP and status epilepticus). DS is predominantly caused by heterozygous pathogenic variants in SCN1A (Nav1.1) and is a paradigm condition for precision-medicine approaches, ranging from syndrome-specific antiseizure medications (ASMs) to emerging gene/RNA-based therapies. Key recent (2023–2024) data include prospective natural history evidence that early communication delay can be largely independent of seizure burden (ENVISION) and 10-year follow-up showing comorbidities (autistic traits, behavioral problems, motor/mobility impairment) rise substantially over time despite some reduction in epilepsy severity. (fine2024envisioningacritical pages 1-2, feng2024longtermpredictorsof pages 1-3, strzelczyk2023dravetsyndromea pages 1-2)

1. Disease information

1.1 Definition / overview

A systematic review of the illness burden describes DS as a DEE “presenting with seizure onset in an otherwise normal infant before 20 months” with “neurodevelopmental impairments emerging from the second year of life,” and notes typical multiple seizure types (e.g., tonic–clonic, hemiclonic, myoclonic, focal impaired awareness), with seizure burden often declining in adolescence/adulthood and a shift toward nocturnal convulsive seizures. (strzelczyk2023dravetsyndromea pages 1-2)

An evidence-based definition paper summarizes the “classical description” as “a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year,” while emphasizing broader phenotypic variability and the need for genotype–phenotype correlation for SCN1A-related disorders. (li2021definingdravetsyndrome pages 1-2)

1.2 Key identifiers (OMIM, Orphanet, ICD, MeSH, MONDO)

The retrieved evidence explicitly contains OMIM identifiers but did not provide explicit Orphanet/ORPHA, ICD-10/ICD-11, MeSH (Dravet-specific), or MONDO identifiers within the accessible excerpts. (fan2023clinicalandgenetic pages 5-7, li2021definingdravetsyndrome pages 1-2, NCT04740476 chunk 2)

Identifier type Value Evidence/notes Source (with URL and publication date if available)
OMIM 308350 Reported in a 2023 review as an OMIM reference URL for Dravet syndrome; same source also lists key synonyms. Note: this OMIM value differs from another evidence source, so identifier confirmation against OMIM directly is advisable. (fan2023clinicalandgenetic pages 5-7) Fan et al., Int J Mol Sci (Dec 2023). https://doi.org/10.3390/ijms25010031
OMIM 607208 Explicitly reported in an evidence-based definition paper as the OMIM entry for Dravet syndrome. Conflicts with the 308350 reference reported elsewhere in the current evidence set. (li2021definingdravetsyndrome pages 1-2) Li et al., Epilepsia (Aug 2021). https://doi.org/10.1111/epi.17015
Synonym SMEI Supported as an abbreviation for “severe myoclonic epilepsy of infancy.” (fan2023clinicalandgenetic pages 5-7) Fan et al., Int J Mol Sci (Dec 2023). https://doi.org/10.3390/ijms25010031
Synonym severe myoclonic epilepsy of infancy Explicitly listed as a synonym/older name for Dravet syndrome. (fan2023clinicalandgenetic pages 5-7) Fan et al., Int J Mol Sci (Dec 2023). https://doi.org/10.3390/ijms25010031
Synonym epilepsy with polymorphic seizures Explicitly listed as a synonym in the current evidence set. (fan2023clinicalandgenetic pages 5-7) Fan et al., Int J Mol Sci (Dec 2023). https://doi.org/10.3390/ijms25010031
Synonym polymorphic epilepsy of infancy Explicitly listed as a synonym in the current evidence set. (fan2023clinicalandgenetic pages 5-7) Fan et al., Int J Mol Sci (Dec 2023). https://doi.org/10.3390/ijms25010031
Synonym / disease label SCN1A-Dravet syndrome Used in the precision-medicine definition paper to describe the genetically defined form; more a gene-linked subtype label than a classic synonym. (li2021definingdravetsyndrome pages 1-2) Li et al., Epilepsia (Aug 2021). https://doi.org/10.1111/epi.17015
MONDO Not found in current evidence set Available evidence discusses MONDO classification context for epilepsy/Dravet, but no explicit Dravet MONDO identifier string is provided in the gathered evidence. (fan2023clinicalandgenetic pages 5-7, NCT04740476 chunk 2, NCT06371794 chunk 2, NCT07251673 chunk 2) No explicit identifier captured in current evidence set
Orphanet / ORPHA Not found in current evidence set No explicit ORPHA code for Dravet syndrome was present in the gathered evidence excerpts. (fan2023clinicalandgenetic pages 5-7, NCT04740476 chunk 2, NCT06371794 chunk 2, NCT07251673 chunk 2) No explicit identifier captured in current evidence set
MeSH (Dravet-specific descriptor/ID) Not found in current evidence set Some evidence includes broader epilepsy MeSH terms (e.g., Epilepsies, Myoclonic), but no MeSH descriptor/ID explicitly named “Dravet Syndrome” was captured. (NCT04740476 chunk 2, NCT06371794 chunk 2, NCT07251673 chunk 2) No explicit Dravet-specific MeSH identifier captured in current evidence set
ICD-10 Not found in current evidence set Current evidence notes Dravet syndrome became ICD-10 recognizable, but no exact code string is provided in the gathered excerpts. (fan2023clinicalandgenetic pages 5-7) No explicit identifier captured in current evidence set
ICD-11 Not found in current evidence set No ICD-11 code for Dravet syndrome was present in the gathered evidence excerpts. (fan2023clinicalandgenetic pages 5-7, NCT04740476 chunk 2, NCT06371794 chunk 2, NCT07251673 chunk 2) No explicit identifier captured in current evidence set

Table: This table summarizes the disease identifiers and alternative names for Dravet syndrome that were directly supported by the gathered evidence. It also flags requested ontology/coding identifiers that were not explicitly present in the current evidence set, helping separate confirmed from still-unverified metadata.

Evidence note: Conflicting OMIM identifiers (308350 vs 607208) appear across sources, so direct confirmation against OMIM is recommended before knowledge-base ingestion. (fan2023clinicalandgenetic pages 5-7, li2021definingdravetsyndrome pages 1-2)

1.3 Synonyms / alternative names

Synonyms explicitly listed in a 2023 review include: - Severe myoclonic epilepsy of infancy (SMEI) - Epilepsy with polymorphic seizures - Polymorphic epilepsy of infancy (fan2023clinicalandgenetic pages 5-7)

1.4 Evidence source type

The information summarized here is derived from aggregated disease-level resources (systematic reviews, consensus/definition papers), prospective observational cohorts, and clinical trials/meta-analyses, not individual EHR-derived case narratives (except where explicitly noted in real-world/registry/claims contexts). (strzelczyk2023dravetsyndromea pages 1-2, fine2024envisioningacritical pages 1-2, feng2024longtermpredictorsof pages 1-3)

2. Etiology

2.1 Disease causal factors

Primary cause: DS is predominantly genetic and most commonly due to pathogenic variants in SCN1A (Nav1.1). Multiple sources in the retrieved evidence place SCN1A causation at >80% to ~90% of cases. (fan2023clinicalandgenetic pages 5-7, mouhi2024thegeneticfacets pages 1-2, li2021definingdravetsyndrome pages 1-2)

Direct abstract quote (definition paper): “SCN1A pathogenic variants are found in >80% of patients.” (li2021definingdravetsyndrome pages 1-2)

2.2 Risk factors

Genetic risk factors

  • Causal gene: SCN1A (loss-of-function most typical). (lersch2023targetedmolecularstrategies pages 4-6, ricobaraza2023preferentialexpressionof pages 1-2)
  • Additional genes with DS-like phenotypes: Reviews identify PCDH19, GABRG2, and SCN2A as additional genetic contributors to DS-like presentations. (mouhi2024thegeneticfacets pages 1-2)
  • Familial inheritance: A clinical overview notes familial SCN1A mutations in roughly 5–10% (usually missense) in one summary (non-primary). (pisati2022trattamentodicombinazionea pages 7-11)

Environmental/physiologic triggers

Seizures are often triggered by fever, infection, and sometimes vaccination; hyperthermia is a prominent precipitant. (fan2023clinicalandgenetic pages 5-7, gao2023epilepsyindravet pages 2-4)

2.3 Protective factors

No explicit protective genetic variants or environmental protective factors were identified in the retrieved evidence excerpts.

2.4 Gene–environment interactions

The current evidence set supports a clinically important interaction between genetic susceptibility (SCN1A-related DS) and physiologic stressors (fever/hyperthermia) that precipitate seizures early in life. (gao2023epilepsyindravet pages 2-4, fan2023clinicalandgenetic pages 5-7)

3. Phenotypes

3.1 Core seizure phenotypes (with HPO suggestions)

Typical onset: infancy, often ~6 months; onset range can extend into later infancy (up to ~19–20 months). (li2021definingdravetsyndrome pages 1-2, strzelczyk2023dravetsyndromea pages 1-2)

Seizure features: prolonged febrile seizures/status epilepticus, hemiclonic or generalized tonic–clonic seizures, later polymorphic seizure types (myoclonic, focal impaired awareness, atypical absence). (strzelczyk2023dravetsyndromea pages 1-2, li2021definingdravetsyndrome pages 1-2)

HPO term suggestions (non-exhaustive): - Febrile seizures (HP:0002373) - Status epilepticus (HP:0002133) - Hemiclonic seizures (HP:0006801) - Generalized tonic-clonic seizures (HP:0002069) - Myoclonic seizures (HP:0002123) - Focal impaired awareness seizure (HP:0020219)

3.2 Neurodevelopmental / cognitive / communication phenotypes

Early communication delay may be independent of seizure burden (2023–2024 development)

ENVISION (prospective observational natural history) enrolled 58 children ≤5 years with SCN1A+ DS (Dec 2020–Mar 2023). Language/communication delays were observed early and developmental stagnation occurred after age 2 years; in modeling, seizure burden and status epilepticus variables were not predictors of language/communication raw scores. (fine2024envisioningacritical pages 1-2)

Direct abstract quote (ENVISION paper as reproduced in the commentary): “language/communication delay and stagnation were independent of seizure burden.” (fine2024envisioningacritical pages 1-2)

HPO suggestions: - Global developmental delay (HP:0001263) - Delayed speech and language development (HP:0000750) - Intellectual disability (HP:0001249)

3.3 Behavioral, autism-related, and motor phenotypes (with longitudinal statistics)

A UK prospective 10-year follow-up study of SCN1A-positive DS found worsening developmental outcome and rising comorbidities: - Autistic features increased from 30% to 77% (48/62 vs 17/57; P<0.001) - Behavioral problems increased from 38% to 81% (46/57 vs 23/60; P<0.001) - Motor/mobility problems increased from 41% to 80% (51/64 vs 24/59; P<0.001) (feng2024longtermpredictorsof pages 1-3)

These changes are also shown in the study tables. (feng2024longtermpredictorsof media 5e014e4f)

HPO suggestions: - Autistic behavior (HP:0000729) - Behavioral abnormality (HP:0000708) - Ataxia / gait abnormality (HP:0001251 / HP:0001288) (general DS phenotype support in reviews) - Hypotonia (HP:0001252) (commonly reported in DS literature; not quantified in retrieved excerpts)

3.4 Quality-of-life impact and caregiver burden (statistics)

The 2023 systematic review of illness burden reported substantial caregiver impact and health-economic burden, including caregiver depression symptoms 47%–70%, and direct costs of $11,048 to $77,914 per patient per year in included studies. (strzelczyk2023dravetsyndromea pages 1-2)

In the UK 10-year cohort, >90% of caregivers reported negative impacts on their own health and career opportunities; SUDEP had not been discussed with a clinician in 35%. (feng2024longtermpredictorsof pages 1-3)

4. Genetic / molecular information

4.1 Causal genes

  • SCN1A is the predominant causal gene in DS. (li2021definingdravetsyndrome pages 1-2, lersch2023targetedmolecularstrategies pages 4-6)

4.2 Pathogenic variants (classes and consequences)

Mechanistic reviews and preclinical studies support a dominant loss-of-function / haploinsufficiency model for many DS-causing SCN1A variants, especially truncating variants, leading to reduced Nav1.1 function in inhibitory interneurons. (lersch2023targetedmolecularstrategies pages 4-6, ricobaraza2023preferentialexpressionof pages 1-2)

Variant class overview is summarized in a mechanistic review: truncating variants are common (roughly half of DS mutations in one review) and typically support a haploinsufficiency mechanism without dominant negative effect (supporting allele upregulation strategies). (lersch2023targetedmolecularstrategies pages 4-6)

4.3 Modifier genes / polygenic effects

The accessible evidence included mention of modifier concepts (e.g., SCN9A as a modifier in one summary) but did not provide robust quantitative modifier effect sizes in retrieved excerpts. (pisati2022trattamentodicombinazionea pages 7-11)

4.4 Epigenetic information

Not explicitly supported by the retrieved excerpts.

4.5 Chromosomal abnormalities

Not explicitly supported by the retrieved excerpts.

5. Environmental information

DS is not primarily environmentally caused, but seizures are precipitated by physiologic/environmental triggers, especially fever/hyperthermia. Trigger management recommendations are summarized in recent clinical reviews. (gao2023epilepsyindravet pages 2-4)

6. Mechanism / pathophysiology

6.1 Causal chain (gene → cell → circuit → clinical)

A consistent mechanistic model across reviews and preclinical studies is: 1) SCN1A loss-of-function reduces Nav1.1 sodium currents 2) Nav1.1 is critical for GABAergic inhibitory interneuron excitability (particularly PV and SST interneurons) 3) Reduced inhibitory output produces excitation–inhibition imbalance in cortical/hippocampal circuits 4) This drives seizures (often hyperthermia/febrile-triggered early) and contributes to developmental, behavioral, and motor comorbidities and SUDEP risk. (ricobaraza2023preferentialexpressionof pages 1-2, lersch2023targetedmolecularstrategies pages 4-6)

6.2 Cell types and ontology suggestions

Cell Ontology (CL) suggestions: - GABAergic interneuron (CL:0000099) - Parvalbumin-positive interneuron (CL:0002608) - Somatostatin-positive interneuron (no single CL term universally used; can be annotated via marker + interneuron)

GO Biological Process suggestions: - Regulation of membrane potential (GO:0042391) - Synaptic transmission, GABAergic (GO:0051932) - Action potential (GO:0001508) - Regulation of neuronal excitability (GO:0042399)

GO Cellular Component suggestions: - Axon initial segment (GO:0043194) - Synapse (GO:0045202)

6.3 Molecular profiling / multi-omics

A 2022 mouse gene-reactivation study reported “dramatic gene expression alterations, including those associated with astrogliosis,” which were rescued by restoring Scn1a expression, supporting a downstream glial/inflammatory remodeling component. (valassina2022scn1agenereactivation pages 1-2)

7. Anatomical structures affected

Primary system: central nervous system (brain networks mediating seizure generation and neurodevelopment). (lersch2023targetedmolecularstrategies pages 4-6)

Key regions supported by preclinical/therapy biodistribution: cortex and hippocampus (highlighted in AAV biodistribution and mechanistic discussions). (tanenhaus2022cellselectiveadenoassociatedvirusmediated pages 1-2, valassina2022scn1agenereactivation pages 1-2)

UBERON suggestions: - Brain (UBERON:0000955) - Cerebral cortex (UBERON:0001851) - Hippocampus (UBERON:0001954)

8. Temporal development

8.1 Onset

Typical seizure onset in infancy (~5–8 months in multiple descriptions), though refined evidence shows a broader onset range up to ~19–20 months and febrile seizures are not universal at onset. (li2021definingdravetsyndrome pages 1-2, strzelczyk2023dravetsyndromea pages 1-2)

8.2 Progression

Natural history often includes early febrile/prolonged seizures with progression to multiple seizure types and increasing prominence of neurodevelopmental comorbidities. Longitudinal data show comorbidities increase substantially over 10 years even when epilepsy severity appears less severe at follow-up. (feng2024longtermpredictorsof pages 1-3)

9. Inheritance and population

9.1 Epidemiology (statistics)

A 2023 systematic review reports: - Incidence: ~1:15,400–1:40,900 - Prevalence: 1.5–6.5 per 100,000 - Mortality: 3.7%–20.8% across cohorts; deaths commonly due to SUDEP and status epilepticus. (strzelczyk2023dravetsyndromea pages 1-2)

9.2 Inheritance

Predominantly de novo heterozygous SCN1A pathogenic variants, with some familial cases. (li2021definingdravetsyndrome pages 1-2, pisati2022trattamentodicombinazionea pages 7-11)

10. Diagnostics

10.1 Clinical suspicion and early recognition

A 2024 DEE primer advises considering DS in infants from ~6 months presenting with febrile status epilepticus, particularly hemiclonic or generalized tonic–clonic seizures, even when development and EEG are initially normal. (scheffer2024developmentalandepileptic pages 9-11)

10.2 Genetic testing

Evidence supports prompt molecular testing when DS is suspected: - Rapid genome sequencing can return results in weeks (median ~37 days in one cited study) and DS is relatively genetically homogeneous (>90% due to SCN1A in one review), supporting early genetic confirmation. (scheffer2024developmentalandepileptic pages 9-11) - Next-generation sequencing enables earlier molecular diagnosis; careful genotype–phenotype correlation is required because SCN1A spans a spectrum. (li2021definingdravetsyndrome pages 1-2)

10.3 EEG/imaging

Normal MRI does not exclude genetic DEEs such as DS; EEG can be normal early and abnormalities may evolve with age. (scheffer2024developmentalandepileptic pages 9-11, mouhi2024thegeneticfacets pages 1-2)

10.4 Emerging biomarkers (SUDEP risk)

A 2023 study linked quantitative EEG features to SUDEP-7 risk strata in DS (e.g., higher theta power and lower alpha power in high-risk groups), proposing EEG as a potential SUDEP biomarker and recommending high-level supervision for patients with high theta power. (kim2023electroencephalographycharacteristicsrelated pages 1-2)

11. Outcome / prognosis

11.1 Mortality and SUDEP

In a genetic DEE cohort (including SCN1A/Dravet), mortality was 6.1 per 1,000 person-years and SUDEP accounted for 48% of deaths, with an estimated SUDEP rate of 2.8 per 1,000 person-years. (donnan2023ratesofstatus pages 1-2)

The DS-focused illness-burden review reports mortality 3.7%–20.8% across cohorts, most commonly due to SUDEP and status epilepticus. (strzelczyk2023dravetsyndromea pages 1-2)

11.2 Prognostic factors

In the UK 10-year follow-up cohort, worse long-term developmental outcome was predicted by poorer baseline language, more severe baseline epilepsy severity, and a worse SCN1A genetic score. (feng2024longtermpredictorsof pages 1-3)

12. Treatment

12.1 Pharmacotherapy (approved/commonly used)

Comparative RCT evidence (systematic review / network meta-analysis)

A 2023 network meta-analysis of placebo-controlled RCTs (680 participants) evaluated add-on stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat. Cannabidiol showed lower ≥50% responder rates than fenfluramine (OR 0.20, 95% CI 0.07–0.54) and stiripentol showed higher responder rate than cannabidiol (OR 14.07, 95% CI 2.57–76.87). (lattanzi2023pharmacotherapyfordravet pages 1-2)

A 2024 network meta-analysis comparing stiripentol, fenfluramine, and cannabidiol reported stiripentol and fenfluramine were statistically superior to cannabidiol for clinically meaningful seizure reduction, and found stiripentol superior in achieving seizure-free intervals versus fenfluramine (RD 26% [8%–44%], p<0.01). (guerrini2024comparativeefficacyand pages 1-2)

Cannabidiol (Epidiolex) dosing and seizure reduction

A 2024 focused review summarizes recommended cannabidiol dosing as starting 5 mg/kg/day (divided doses), titrating weekly by 5 mg/kg/day to max 20 mg/kg/day; a cited trial reported median seizure reduction 43.9% with cannabidiol vs 21.8% placebo, with common AEs including somnolence and gastrointestinal effects. (mahesan2024advancementsindravet pages 1-2)

Contraindicated / avoid

Sodium-channel blockers (e.g., carbamazepine, oxcarbazepine) can exacerbate seizures in DS and should be avoided; this is emphasized as a key reason for early diagnosis. (scheffer2024developmentalandepileptic pages 9-11, strzelczyk2023dravetsyndromea pages 1-2)

MAXO suggestions: - Anticonvulsant therapy (MAXO:0000068) - Ketogenic diet therapy (MAXO:0000121) - Vagus nerve stimulation (MAXO:0000128) - Genetic therapy (MAXO:0001001) (for gene/ASO/AAV approaches)

12.2 Non-pharmacologic therapies

Vagus nerve stimulation (VNS)

A 2024 systematic review/meta-analysis (16 studies; 173 patients in one pooled analysis) reported pooled ≥50% seizure reduction (“responder”) rate 0.54 (95% CI 0.43–0.65), with timepoint pooled responder rates of 0.42 (3 months), 0.54 (6 months), 0.51 (12 months), and 0.49 (24 months). (chen2024vagusnervestimulation pages 1-2, chen2024vagusnervestimulation pages 3-5)

Ketogenic diet

A clinical overview reported that a ketogenic diet maintained for one year produced ≥75% reduction in seizure frequency and severity in nearly 80% of children with DS. (fan2023clinicalandgenetic pages 17-18)

12.3 Advanced therapeutics / disease-modifying pipeline

Antisense oligonucleotide (ASO) approaches (SCN1A upregulation)

A 2024 gene-therapy review describes IND-enabling target engagement for STK-001 (zorevunersen) in nonhuman primates after intrathecal administration, with significant target engagement at Day 29 in multiple cortical/limbic regions. (berardino2024genetherapyfor pages 1-1)

ClinicalTrials.gov includes an open-label extension study of STK-001 for DS (NCT04740476). (NCT04740476 chunk 2)

AAV gene-regulation therapy (ETX101 preclinical basis)

A 2022 gene-therapy study (preclinical) reports a cell-selective AAV9 therapy designed to upregulate SCN1A in GABAergic inhibitory interneurons reduced spontaneous and hyperthermia-induced seizures and prolonged survival in Scn1a+/- mice, and was well tolerated in nonhuman primates. (tanenhaus2022cellselectiveadenoassociatedvirusmediated pages 1-2)

13. Prevention

DS is genetic, so primary prevention is not generally feasible, but secondary/tertiary prevention focuses on avoiding triggers and preventing complications.

Trigger management and rescue planning

A 2023 clinical review recommends avoiding high ambient temperatures, early use of antipyretics and physical cooling for fever/hyperthermia, and reducing exposure to sick contacts; exhaustion/overexcitement and photosensitivity are also triggers. (gao2023epilepsyindravet pages 2-4)

Rescue medication: benzodiazepines are first-line for prolonged seizures/status epilepticus, with intranasal/buccal/intramuscular routes used outside hospital. (gao2023epilepsyindravet pages 2-4)

Vaccination considerations

The same review notes some vaccines can precipitate seizures with or without fever, but reports two surveys suggesting SARS-CoV-2 vaccines are well tolerated in DS. (gao2023epilepsyindravet pages 2-4)

SUDEP counseling

A UK follow-up study found SUDEP had not been discussed with a medical professional in 35% of participants, underscoring the need for proactive counseling and risk mitigation plans. (feng2024longtermpredictorsof pages 1-3)

14. Other species / natural disease

Not addressed in the retrieved evidence.

15. Model organisms

Mouse models

Multiple mouse models (e.g., Scn1a+/- and conditional/reactivation models) recapitulate seizures (including hyperthermia-induced), premature death/SUDEP risk, and behavioral/cognitive abnormalities. (tanenhaus2022cellselectiveadenoassociatedvirusmediated pages 1-2, valassina2022scn1agenereactivation pages 1-2)

A 2022 study demonstrated that reactivating Scn1a after symptom onset (P30) could “completely rescue” spontaneous and thermally induced seizures and normalize hippocampal fast-spiking interneuron firing, supporting reversibility and informing therapeutic windows. (valassina2022scn1agenereactivation pages 1-2)

Zebrafish models

A zebrafish Scn1Lab model showed altered glycolysis and mitochondrial respiration; a ketogenic diet formulation rescued metabolism to control levels, suggesting metabolic contributions and a platform for screening. (fan2023clinicalandgenetic pages 27-28)

Nonhuman primates

AAV9 gene-regulation therapy biodistribution/safety was assessed in nonhuman primates with favorable tolerability in one study supporting translation. (tanenhaus2022cellselectiveadenoassociatedvirusmediated pages 1-2)

Evidence gaps and limitations of this tool-based review

1) Standard ontology identifiers (MONDO, Orphanet/ORPHA, MeSH Dravet descriptor, ICD-10/ICD-11 codes) were not explicitly available in the retrieved excerpts, so they are not asserted here. (NCT04740476 chunk 2, fan2023clinicalandgenetic pages 5-7) 2) Several key claims commonly present in GeneReviews/OMIM/Orphanet (e.g., penetrance, mosaicism rates, specific ICD-10 codes) could not be verified using only the retrieved tool evidence. 3) Some advanced therapy updates most heavily emphasized in 2024–2026 sources; 2023–2024 pipeline details in peer-reviewed primary clinical trial publications were limited within available full-text excerpts.

Key recent sources (URLs and dates)

  • Strzelczyk et al. Epilepsia Open (Oct 2023): illness-burden systematic review. https://doi.org/10.1002/epi4.12832 (strzelczyk2023dravetsyndromea pages 1-2)
  • Feng et al. Brain Communications (Jan 2024): UK 10-year outcomes and predictors. https://doi.org/10.1093/braincomms/fcae004 (feng2024longtermpredictorsof pages 1-3)
  • Chen et al. Frontiers in Neurology (Jul 2024): VNS meta-analysis. https://doi.org/10.3389/fneur.2024.1402989 (chen2024vagusnervestimulation pages 1-2)
  • Scheffer et al. Nat Rev Dis Primers (Sep 2024): DEE primer with diagnostic approach. https://doi.org/10.1038/s41572-024-00546-6 (scheffer2024developmentalandepileptic pages 9-11)
  • Fine (Epilepsy Currents commentary on ENVISION; Oct 2024): early communication delay findings. https://doi.org/10.1177/15357597241280687 (fine2024envisioningacritical pages 1-2)

Image-based evidence used

The report cites cropped table images showing longitudinal comorbidity changes and developmental outcomes from the UK 10-year follow-up study. (feng2024longtermpredictorsof media 748ed348, feng2024longtermpredictorsof media 5e014e4f)

References

  1. (fine2024envisioningacritical pages 1-2): Anthony L. Fine. Envisioning a critical period to preserve development: communication delays in scn1a+ dravet syndrome. Epilepsy Currents, 24:342-344, Oct 2024. URL: https://doi.org/10.1177/15357597241280687, doi:10.1177/15357597241280687. This article has 3 citations and is from a peer-reviewed journal.

  2. (feng2024longtermpredictorsof pages 1-3): Tony Feng, Phoebe Makiello, Benjamin Dunwoody, Felix Steckler, Joseph D Symonds, Sameer M Zuberi, Liam Dorris, and Andreas Brunklaus. Long-term predictors of developmental outcome and disease burden in scn1a-positive dravet syndrome. Brain Communications, Jan 2024. URL: https://doi.org/10.1093/braincomms/fcae004, doi:10.1093/braincomms/fcae004. This article has 23 citations and is from a peer-reviewed journal.

  3. (strzelczyk2023dravetsyndromea pages 1-2): Adam Strzelczyk, Lieven Lagae, Jo M Wilmshurst, Andreas Brunklaus, Pasquale Striano, Felix Rosenow, and Susanne Schubert‐Bast. Dravet syndrome: a systematic literature review of the illness burden. Epilepsia Open, 8:1256-1270, Oct 2023. URL: https://doi.org/10.1002/epi4.12832, doi:10.1002/epi4.12832. This article has 67 citations and is from a peer-reviewed journal.

  4. (li2021definingdravetsyndrome pages 1-2): Wenhui Li, Amy L. Schneider, and Ingrid E. Scheffer. Defining dravet syndrome: an essential pre‐requisite for precision medicine trials. Epilepsia, 62:2205-2217, Aug 2021. URL: https://doi.org/10.1111/epi.17015, doi:10.1111/epi.17015. This article has 127 citations and is from a domain leading peer-reviewed journal.

  5. (fan2023clinicalandgenetic pages 5-7): Hueng-Chuen Fan, Ming-Tao Yang, Lung-Chang Lin, Kuo-Liang Chiang, and Chuan-Mu Chen. Clinical and genetic features of dravet syndrome: a prime example of the role of precision medicine in genetic epilepsy. International Journal of Molecular Sciences, 25:31, Dec 2023. URL: https://doi.org/10.3390/ijms25010031, doi:10.3390/ijms25010031. This article has 29 citations.

  6. (NCT04740476 chunk 2): An Open-Label Extension Study of STK-001 for Patients With Dravet Syndrome. Stoke Therapeutics, Inc. 2021. ClinicalTrials.gov Identifier: NCT04740476

  7. (NCT06371794 chunk 2): EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity. Fondazione Policlinico Universitario Agostino Gemelli IRCCS. 2023. ClinicalTrials.gov Identifier: NCT06371794

  8. (NCT07251673 chunk 2): Longitudinal Study of Phenotypic and Developmental Severity in Patients With Dravet Syndrome With SCN1A Gene Mutation. Assistance Publique - Hôpitaux de Paris. 2025. ClinicalTrials.gov Identifier: NCT07251673

  9. (mouhi2024thegeneticfacets pages 1-2): Hinde El Mouhi, Meriame Abbassi, Meryem Jalte, Abdelhafid Natiq, Laila Bouguenouch, and Sana Chaouki. The genetic facets of dravet syndrome: recent insights. Annals of Child Neurology, 32:67-82, Apr 2024. URL: https://doi.org/10.26815/acn.2023.00367, doi:10.26815/acn.2023.00367. This article has 6 citations.

  10. (lersch2023targetedmolecularstrategies pages 4-6): Robert Lersch, Rawan Jannadi, Leonie Grosse, Matias Wagner, Marius Frederik Schneider, Celina von Stülpnagel, Florian Heinen, Heidrun Potschka, and Ingo Borggraefe. Targeted molecular strategies for genetic neurodevelopmental disorders: emerging lessons from dravet syndrome. The Neuroscientist, 29:732-750, Apr 2023. URL: https://doi.org/10.1177/10738584221088244, doi:10.1177/10738584221088244. This article has 21 citations.

  11. (ricobaraza2023preferentialexpressionof pages 1-2): Ana Ricobaraza, Maria Bunuales, Manuela Gonzalez-Aparicio, Saja Fadila, Moran Rubinstein, Irene Vides-Urrestarazu, Julliana Banderas, Noemi Sola-Sevilla, Rocio Sanchez-Carpintero, Jose Luis Lanciego, Elvira Roda, Adriana Honrubia, Patricia Arnaiz, and Ruben Hernandez-Alcoceba. Preferential expression of scn1a in gabaergic neurons improves survival and epileptic phenotype in a mouse model of dravet syndrome. Journal of Molecular Medicine (Berlin, Germany), 101:1587-1601, Oct 2023. URL: https://doi.org/10.1007/s00109-023-02383-8, doi:10.1007/s00109-023-02383-8. This article has 14 citations.

  12. (pisati2022trattamentodicombinazionea pages 7-11): A Pisati. Trattamento di combinazione con cannabidiolo e fenfluramina nella sindrome di dravet: risultati di uno studio clinico internazionale. Unknown journal, 2022.

  13. (gao2023epilepsyindravet pages 2-4): Chao Gao, Mikolaj Pielas, Fuyong Jiao, Daoqi Mei, Xiaona Wang, Katarzyna Kotulska, and Sergiusz Jozwiak. Epilepsy in dravet syndrome—current and future therapeutic opportunities. Journal of Clinical Medicine, 12:2532, Mar 2023. URL: https://doi.org/10.3390/jcm12072532, doi:10.3390/jcm12072532. This article has 46 citations.

  14. (feng2024longtermpredictorsof media 5e014e4f): Tony Feng, Phoebe Makiello, Benjamin Dunwoody, Felix Steckler, Joseph D Symonds, Sameer M Zuberi, Liam Dorris, and Andreas Brunklaus. Long-term predictors of developmental outcome and disease burden in scn1a-positive dravet syndrome. Brain Communications, Jan 2024. URL: https://doi.org/10.1093/braincomms/fcae004, doi:10.1093/braincomms/fcae004. This article has 23 citations and is from a peer-reviewed journal.

  15. (valassina2022scn1agenereactivation pages 1-2): Nicholas Valassina, Simone Brusco, Alessia Salamone, Linda Serra, Mirko Luoni, Serena Giannelli, Simone Bido, Luca Massimino, Federica Ungaro, Pietro Giuseppe Mazzara, Patrizia D’Adamo, Gabriele Lignani, Vania Broccoli, and Gaia Colasante. Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of dravet syndrome. Nature Communications, Jan 2022. URL: https://doi.org/10.1038/s41467-021-27837-w, doi:10.1038/s41467-021-27837-w. This article has 89 citations and is from a highest quality peer-reviewed journal.

  16. (tanenhaus2022cellselectiveadenoassociatedvirusmediated pages 1-2): Annie Tanenhaus, Timothy Stowe, Andrew Young, John McLaughlin, Rangoli Aeran, I. Winnie Lin, Jianmin Li, Raghavendra Hosur, Ming Chen, Jennifer Leedy, Tiffany Chou, Sirika Pillay, Maria Candida Vila, Jennifer A. Kearney, Martin Moorhead, Archana Belle, and Stephanie Tagliatela. Cell-selective adeno-associated virus-mediated scn1a gene regulation therapy rescues mortality and seizure phenotypes in a dravet syndrome mouse model and is well tolerated in nonhuman primates. Human Gene Therapy, 33:579-597, Jun 2022. URL: https://doi.org/10.1089/hum.2022.037, doi:10.1089/hum.2022.037. This article has 139 citations and is from a peer-reviewed journal.

  17. (scheffer2024developmentalandepileptic pages 9-11): Ingrid E. Scheffer, Sameer Zuberi, Heather C. Mefford, Renzo Guerrini, and Amy McTague. Developmental and epileptic encephalopathies. Nature reviews. Disease primers, 10 1:61, Sep 2024. URL: https://doi.org/10.1038/s41572-024-00546-6, doi:10.1038/s41572-024-00546-6. This article has 144 citations.

  18. (kim2023electroencephalographycharacteristicsrelated pages 1-2): Jeong-Youn Kim, Jeongyoon Shin, Laehyun Kim, and Se Hee Kim. Electroencephalography characteristics related to risk of sudden unexpected death in epilepsy in patients with dravet syndrome. Frontiers in Neurology, Sep 2023. URL: https://doi.org/10.3389/fneur.2023.1222721, doi:10.3389/fneur.2023.1222721. This article has 2 citations and is from a peer-reviewed journal.

  19. (donnan2023ratesofstatus pages 1-2): Alice M. Donnan, Amy L. Schneider, Sophie Russ-Hall, Leonid Churilov, and Ingrid E. Scheffer. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology, Apr 2023. URL: https://doi.org/10.1212/wnl.0000000000207080, doi:10.1212/wnl.0000000000207080. This article has 98 citations and is from a highest quality peer-reviewed journal.

  20. (lattanzi2023pharmacotherapyfordravet pages 1-2): Simona Lattanzi, Eugen Trinka, Emilio Russo, Cinzia Del Giovane, Sara Matricardi, Stefano Meletti, Pasquale Striano, Payam Tabaee Damavandi, Mauro Silvestrini, and Francesco Brigo. Pharmacotherapy for dravet syndrome: a systematic review and network meta-analysis of randomized controlled trials. Drugs, 83:1409-1424, Sep 2023. URL: https://doi.org/10.1007/s40265-023-01936-y, doi:10.1007/s40265-023-01936-y. This article has 39 citations and is from a domain leading peer-reviewed journal.

  21. (guerrini2024comparativeefficacyand pages 1-2): Renzo Guerrini, Catherine Chiron, Delphine Vandame, Warren Linley, and Toby Toward. Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first‐line add‐on therapies for seizures in dravet syndrome: a network meta‐analysis. Epilepsia Open, 9:689-703, Mar 2024. URL: https://doi.org/10.1002/epi4.12923, doi:10.1002/epi4.12923. This article has 28 citations and is from a peer-reviewed journal.

  22. (mahesan2024advancementsindravet pages 1-2): Aakash Mahesan, Gautam Kamila, and Sheffali Gulati. Advancements in dravet syndrome therapeutics: a comprehensive look at present and future treatment horizons: a focused review. Aug 2024. URL: https://doi.org/10.4103/aian.aian_49_24, doi:10.4103/aian.aian_49_24. This article has 6 citations and is from a peer-reviewed journal.

  23. (chen2024vagusnervestimulation pages 1-2): Shuang Chen, Man Li, and Ming Huang. Vagus nerve stimulation for the therapy of dravet syndrome: a systematic review and meta-analysis. Frontiers in Neurology, Jul 2024. URL: https://doi.org/10.3389/fneur.2024.1402989, doi:10.3389/fneur.2024.1402989. This article has 8 citations and is from a peer-reviewed journal.

  24. (chen2024vagusnervestimulation pages 3-5): Shuang Chen, Man Li, and Ming Huang. Vagus nerve stimulation for the therapy of dravet syndrome: a systematic review and meta-analysis. Frontiers in Neurology, Jul 2024. URL: https://doi.org/10.3389/fneur.2024.1402989, doi:10.3389/fneur.2024.1402989. This article has 8 citations and is from a peer-reviewed journal.

  25. (fan2023clinicalandgenetic pages 17-18): Hueng-Chuen Fan, Ming-Tao Yang, Lung-Chang Lin, Kuo-Liang Chiang, and Chuan-Mu Chen. Clinical and genetic features of dravet syndrome: a prime example of the role of precision medicine in genetic epilepsy. International Journal of Molecular Sciences, 25:31, Dec 2023. URL: https://doi.org/10.3390/ijms25010031, doi:10.3390/ijms25010031. This article has 29 citations.

  26. (berardino2024genetherapyfor pages 1-1): Claudia Di Berardino, Luca Massimino, Federica Ungaro, and Gaia Colasante. Gene therapy for dravet syndrome: promises and impact on disease trigger and secondary modifications. Rare Disease and Orphan Drugs Journal, Jul 2024. URL: https://doi.org/10.20517/rdodj.2024.07, doi:10.20517/rdodj.2024.07. This article has 5 citations.

  27. (fan2023clinicalandgenetic pages 27-28): Hueng-Chuen Fan, Ming-Tao Yang, Lung-Chang Lin, Kuo-Liang Chiang, and Chuan-Mu Chen. Clinical and genetic features of dravet syndrome: a prime example of the role of precision medicine in genetic epilepsy. International Journal of Molecular Sciences, 25:31, Dec 2023. URL: https://doi.org/10.3390/ijms25010031, doi:10.3390/ijms25010031. This article has 29 citations.

  28. (feng2024longtermpredictorsof media 748ed348): Tony Feng, Phoebe Makiello, Benjamin Dunwoody, Felix Steckler, Joseph D Symonds, Sameer M Zuberi, Liam Dorris, and Andreas Brunklaus. Long-term predictors of developmental outcome and disease burden in scn1a-positive dravet syndrome. Brain Communications, Jan 2024. URL: https://doi.org/10.1093/braincomms/fcae004, doi:10.1093/braincomms/fcae004. This article has 23 citations and is from a peer-reviewed journal.

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