Details of Disease

General Information of Disease (ID: DISOTGO5)

• Disease Name: LennoxGastaut syndrome
• Synonyms: epileptic encephalopathy Lennox-Gastaut type; encephalopathy of childhood; macrocephaly and epileptic encephalopathy; Lennox syndrome; LGS
• Disease Class: 8A62: Epileptic encephalopathy
• Definition: Lennox-Gastaut syndrome (LGS) belongs to the group of severe childhood epileptic encephalopathies.
• Disease Hierarchy:
  DIS6SVEE: Syndromic disease
  DIS9O5K5: Childhood electroclinical syndrome
  DISZOCA3: Epileptic encephalopathy
  DISYKM6G: Childhood-onset epilepsy syndrome
  DISOTGO5: LennoxGastaut syndrome
• ICD Code:
  ICD-11: ICD-11: 8A62.1
  Expand ICD-11: '8A62.1
• Disease Identifiers:
  MONDO ID: MONDO_0016532
  UMLS CUI: C0238111
  MedGen ID: 116044
  Orphanet ID: 2382
  SNOMED CT ID: 230418006

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

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

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

Drug Name	Drug ID	Highest Status	Drug Type	REF
Fenfluramine	DM0762O	Phase 3	Small molecular drug	[2]
TAK-935	DMOZAMN	Phase 2	NA	[2]

This Disease is Treated as An Indication in 1 Preclinical Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
AQST-120	DMB5K3S	Application submitted	NA	[2]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 10 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
MAPK10	TT056SO	Limited	Autosomal dominant	[3]
MAPK10	TT056SO	Limited	Biomarker	[4]
SCN1A	TTANOZH	Limited	Biomarker	[5]
ABAT	TTT2LD9	Strong	Genetic Variation	[6]
CYP46A1	TT4EB85	Strong	Biomarker	[7]
DNM1	TTE3JW9	Strong	GermlineCausalMutation	[8]
GABRB2	TTZA1NY	Strong	Genetic Variation	[9]
KCNT2	TTLU5FO	Strong	Genetic Variation	[10]
GABRA1	TT1MPAY	Definitive	Genetic Variation	[11]
SLC6A1	TTPRKM0	Definitive	Genetic Variation	[12]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
CACNA1A	DTYKGPB	Supportive	Autosomal dominant	[13]
SCN1A	DTN0M1I	Supportive	Autosomal dominant	[14]

This Disease Is Related to 15 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
MAPK10	OTC46VX1	Limited	Autosomal dominant	[3]
CACNA1A	OTY08SIX	Supportive	Autosomal dominant	[13]
CHD2	OTRKL6YC	Supportive	Autosomal dominant	[15]
CUX2	OTDJTQAJ	Supportive	Autosomal dominant	[16]
DNM1	OTI8X2WQ	Supportive	Autosomal dominant	[17]
GABRB3	OT80C3D4	Supportive	Autosomal dominant	[18]
SCN1A	OTJ9ZTYI	Supportive	Autosomal dominant	[14]
ADGRG1	OTQBB8NT	Strong	Genetic Variation	[19]
ARFGEF1	OTPAU0L4	Strong	Biomarker	[20]
DGKD	OTNI8HAH	Strong	Biomarker	[21]
ND1	OTCLGIXV	Strong	Genetic Variation	[22]
NEXMIF	OT576F40	Strong	Genetic Variation	[6]
QDPR	OTSKOIUX	Strong	Genetic Variation	[23]
BCL9	OTRBIPR4	Definitive	Genetic Variation	[11]
LGSN	OTQG5Z82	Definitive	Genetic Variation	[11]

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients.Hum Genet. 2013 Apr;132(4):461-71. doi: 10.1007/s00439-012-1260-5. Epub 2013 Jan 18.
• [5] Adult motor phenotype differentiates Dravet syndrome from Lennox-Gastaut syndrome and links SCN1A to early onset parkinsonian features.Epilepsia. 2017 Mar;58(3):e44-e48. doi: 10.1111/epi.13692. Epub 2017 Feb 10.
• [6] Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability.JAMA Neurol. 2017 Nov 1;74(11):1301-1311. doi: 10.1001/jamaneurol.2017.1775.
• [7] Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases.Neurotherapeutics. 2019 Jul;16(3):635-648. doi: 10.1007/s13311-019-00731-6.
• [8] Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.
• [9] Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy.Prog Brain Res. 2014;213:55-85. doi: 10.1016/B978-0-444-63326-2.00003-X.
• [10] De novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy.Ann Neurol. 2018 Jun;83(6):1198-1204. doi: 10.1002/ana.25248.
• [11] Association of GABAA Receptor Gene with Epilepsy Syndromes.J Mol Neurosci. 2018 Jun;65(2):141-153. doi: 10.1007/s12031-018-1081-7. Epub 2018 May 21.
• [12] A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function.Exp Neurol. 2019 Oct;320:112973. doi: 10.1016/j.expneurol.2019.112973. Epub 2019 Jun 6.
• [13] Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome. Epilepsia. 2019 Sep;60(9):1881-1894. doi: 10.1111/epi.16316. Epub 2019 Aug 29.
• [14] The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain. 2007 Mar;130(Pt 3):843-52. doi: 10.1093/brain/awm002.
• [15] Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013 Jul;45(7):825-30. doi: 10.1038/ng.2646. Epub 2013 May 26.
• [16] The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. Ann Neurol. 2018 May;83(5):926-934. doi: 10.1002/ana.25222. Epub 2018 Apr 30.
• [17] De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014 Oct 2;95(4):360-70. doi: 10.1016/j.ajhg.2014.08.013. Epub 2014 Sep 25.
• [18] De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217-21. doi: 10.1038/nature12439. Epub 2013 Aug 11.
• [19] Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria.Brain Dev. 2014 Jun;36(6):528-31. doi: 10.1016/j.braindev.2013.07.015. Epub 2013 Aug 24.
• [20] Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABA(A) receptors. Neurobiol Dis. 2020 Feb;134:104632. doi: 10.1016/j.nbd.2019.104632. Epub 2019 Oct 31.
• [21] Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.Am J Hum Genet. 2007 Apr;80(4):792-9. doi: 10.1086/513019. Epub 2007 Feb 12.
• [22] Whole-exome sequencing identifies a variant of the mitochondrial MT-ND1 gene associated with epileptic encephalopathy: west syndrome evolving to Lennox-Gastaut syndrome.Hum Mutat. 2013 Dec;34(12):1623-7. doi: 10.1002/humu.22445. Epub 2013 Oct 10.
• [23] Experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation.J Child Neurol. 2011 Feb;26(2):142-6. doi: 10.1177/0883073810375116. Epub 2010 Sep 7.