Details of Disease

General Information of Disease (ID: DISJF7LY)

• Disease Name: Dravet syndrome
• Synonyms: myoclonic epilepsy, severe, of infancy; SME; DS; Dravet syndrome
• Disease Class: 8A61-8A6Z: Epilepsy/seizure
• Definition: Dravet syndrome is a channelopathy with epilepsy of with onset during the first year of life, typically 4-5 months, characterized by status epilepticus and a variety of drug-resistant seizures often induced by fever, presenting in previously healthy children, and which frequently leads to cognitive and motor impairment. Dravet differs from other channelopathies usually due to a mutation in SCN1A.|This is a distinct class from MONDO:0100079 epileptic encephalopathy, early infantile 6. See https://github.com/monarch-initiative/mondo/issues/745
• Disease Hierarchy:
  DISZOCA3: Epileptic encephalopathy
  DISJF7LY: Dravet syndrome
• ICD Code:
  ICD-11: ICD-11: 8A61.11
  Expand ICD-11: '8A61.11
• Disease Identifiers:
  MONDO ID: MONDO_0100135
  MESH ID: D004831
  UMLS CUI: C0751122
  OMIM ID: 607208
  MedGen ID: 148243
  Orphanet ID: 33069
  SNOMED CT ID: 230437002

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 2 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Cannabidiol	DM0659E	Approved	Small molecular drug	[1]
Stiripentol	DMMSDOY	Approved	Small molecular drug	[2]

This Disease is Treated as An Indication in 6 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Ataluren	DM4GXW3	Phase 3	Small molecular drug	[3]
E2023	DMCUNZL	Phase 3	Small molecule	[4]
Fenfluramine	DM0762O	Phase 3	Small molecular drug	[3]
EPX-200	DMWK26Q	Phase 2	NA	[3]
TAK-935	DMOZAMN	Phase 2	NA	[3]
EPX-100	DMXI9P4	Phase 1	NA	[3]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 13 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
GABRD	TTGXH6N	Limited	Biomarker	[5]
SLC12A5	TTH6UZY	Limited	Altered Expression	[6]
ADRA1D	TT34BHT	moderate	Genetic Variation	[7]
KCNQ2	TTPXI3S	moderate	Biomarker	[8]
KCNQ3	TTIVDM3	moderate	Genetic Variation	[9]
CACNA1G	TT729IR	Strong	Biomarker	[10]
EPHA5	TTV9KOD	Strong	Biomarker	[11]
GABRA1	TT1MPAY	Strong	Genetic Variation	[12]
GABRA2	TTBMV1G	Strong	Biomarker	[13]
GPR55	TTNET8J	Strong	Biomarker	[14]
SCN2A	TTLJTUF	Strong	Genetic Variation	[15]
SCN8A	TT54ERL	Strong	Genetic Variation	[16]
SCN9A	TT4G2JS	Strong	Biomarker	[17]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
CACNB4	DTV8E46	Strong	Genetic Variation	[18]
SCN1A	DTN0M1I	Definitive	Autosomal dominant	[19]

This Disease Is Related to 18 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
GABRB3	OT80C3D4	moderate	Biomarker	[20]
PVALB	OTZW1WVQ	moderate	Biomarker	[21]
ARX	OTBGYH25	Strong	Biomarker	[22]
B3GNT2	OTE69HV8	Strong	Genetic Variation	[23]
B3GNTL1	OTYWGHF1	Strong	Genetic Variation	[23]
CHD2	OTRKL6YC	Strong	Genetic Variation	[24]
CPLX1	OT7UIGTP	Strong	Genetic Variation	[25]
EPM2A	OTJU4IAG	Strong	Biomarker	[26]
GPHN	OTAKK1SV	Strong	Genetic Variation	[27]
OPN1MW	OTPJ7LX4	Strong	Biomarker	[28]
PMP22	OTXWYWCZ	Strong	Biomarker	[29]
RAPGEF2	OTZWX2AA	Strong	Biomarker	[30]
SAMD12	OTIFG9O6	Strong	Biomarker	[30]
SCN7A	OTK05PXY	Strong	Biomarker	[31]
STXBP1	OTRYA8C3	Strong	Genetic Variation	[32]
TNRC6A	OT493IOM	Strong	Biomarker	[30]
TSPYL4	OTHCX9RH	Strong	Genetic Variation	[33]
SCN1A	OTJ9ZTYI	Definitive	Autosomal dominant	[19]

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] The effects of stiripentol on GABA(A) receptors.Epilepsia. 2011 Apr;52 Suppl 2:76-8.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] ClinicalTrials.gov (NCT04572243) A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study With Open-Label Extension Phase of Lorcaserin as Adjunctive Treatment in Subjects With Dravet Syndrome. U.S.National Institutes of Health.
• [5] Mutations in GABAA receptor subunits associated with genetic epilepsies.J Physiol. 2010 Jun 1;588(Pt 11):1861-9. doi: 10.1113/jphysiol.2010.186999. Epub 2010 Mar 22.
• [6] A novel GABAergic dysfunction in human Dravet syndrome.Epilepsia. 2018 Nov;59(11):2106-2117. doi: 10.1111/epi.14574. Epub 2018 Oct 11.
• [7] Deletions of SCN1A 5' genomic region with promoter activity in Dravet syndrome.Hum Mutat. 2010 Jul;31(7):820-9. doi: 10.1002/humu.21275.
• [8] Genetics of pediatric epilepsy.Pediatr Clin North Am. 2015 Jun;62(3):703-22. doi: 10.1016/j.pcl.2015.03.013.
• [9] Sodium and potassium channel dysfunctions in rare and common idiopathic epilepsy syndromes.Brain Dev. 2009 Aug;31(7):515-20. doi: 10.1016/j.braindev.2009.04.012. Epub 2009 May 22.
• [10] Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome.Epilepsia. 2017 Aug;58(8):e111-e115. doi: 10.1111/epi.13811. Epub 2017 May 28.
• [11] Molecular aspects of Dravet syndrome patients in Taiwan.Clin Chim Acta. 2013 Jun 5;421:34-40. doi: 10.1016/j.cca.2013.02.015. Epub 2013 Feb 26.
• [12] De novo GABRA1 mutations in Ohtahara and West syndromes.Epilepsia. 2016 Apr;57(4):566-73. doi: 10.1111/epi.13344. Epub 2016 Feb 25.
• [13] Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq.PLoS Genet. 2016 Oct 21;12(10):e1006398. doi: 10.1371/journal.pgen.1006398. eCollection 2016 Oct.
• [14] Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11229-11234. doi: 10.1073/pnas.1711351114. Epub 2017 Oct 2.
• [15] Ketogenic diet as a successful early treatment modality for SCN2A mutation.Brain Dev. 2019 Apr;41(4):389-391. doi: 10.1016/j.braindev.2018.10.015. Epub 2018 Nov 8.
• [16] Identifying mutations in epilepsy genes: Impact on treatment selection.Epilepsy Res. 2019 May;152:18-30. doi: 10.1016/j.eplepsyres.2019.03.001. Epub 2019 Mar 4.
• [17] SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine.Neurosci Bull. 2020 Jan;36(1):11-24. doi: 10.1007/s12264-019-00413-5. Epub 2019 Aug 1.
• [18] A CACNB4 mutation shows that altered Ca(v)2.1 function may be a genetic modifier of severe myoclonic epilepsy in infancy.Neurobiol Dis. 2008 Dec;32(3):349-54. doi: 10.1016/j.nbd.2008.07.017. Epub 2008 Aug 3.
• [19] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [20] A mutation in GABRB3 associated with Dravet syndrome.Am J Med Genet A. 2017 Aug;173(8):2126-2131. doi: 10.1002/ajmg.a.38282. Epub 2017 May 24.
• [21] Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Na(v)1.1 activators.Bioorg Med Chem Lett. 2019 Mar 15;29(6):815-820. doi: 10.1016/j.bmcl.2019.01.023. Epub 2019 Jan 23.
• [22] CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy.Epilepsy Res. 2009 Nov;87(1):25-30. doi: 10.1016/j.eplepsyres.2009.07.004. Epub 2009 Sep 5.
• [23] A homozygous mutation of voltage-gated sodium channel (I) gene SCN1B in a patient with Dravet syndrome.Epilepsia. 2012 Dec;53(12):e200-3. doi: 10.1111/epi.12040. Epub 2012 Nov 13.
• [24] De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.Am J Hum Genet. 2013 Nov 7;93(5):967-75. doi: 10.1016/j.ajhg.2013.09.017. Epub 2013 Oct 24.
• [25] Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID. Eur J Hum Genet. 2017 Jun;25(7):889-893. doi: 10.1038/ejhg.2017.52. Epub 2017 Apr 19.
• [26] Debate: Does genetic information in humans help us treat patients PRO--genetic information in humans helps us treat patients. CON--genetic information does not help at all. Epilepsia. 2008 Dec;49 Suppl 9:13-24.
• [27] Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy.EMBO Mol Med. 2015 Dec;7(12):1580-94. doi: 10.15252/emmm.201505323.
• [28] The potential role of cannabinoids in epilepsy treatment.Expert Rev Neurother. 2017 Nov;17(11):1069-1079. doi: 10.1080/14737175.2017.1373019. Epub 2017 Sep 4.
• [29] Myoclonic seizures in a patient with Charcot-Marie-tooth disease.Pediatr Neurol. 2007 Feb;36(2):118-20. doi: 10.1016/j.pediatrneurol.2006.09.006.
• [30] Expansions?of?intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet. 2018 Apr;50(4):581-590. doi: 10.1038/s41588-018-0067-2. Epub 2018 Mar 5.
• [31] Epilepsy phenotype associated with a chromosome 2q24.3 deletion involving SCN1A: Migrating partial seizures of infancy or atypical Dravet syndrome?.Epilepsy Res. 2015 Jan;109:34-9. doi: 10.1016/j.eplepsyres.2014.10.008. Epub 2014 Oct 28.
• [32] The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment.Seizure. 2018 Aug;60:68-70. doi: 10.1016/j.seizure.2018.06.010. Epub 2018 Jun 13.
• [33] Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.PLoS One. 2012;7(7):e41802. doi: 10.1371/journal.pone.0041802. Epub 2012 Jul 25.