Home > Publications Database > Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway. > print

001     281517
005     20251029111228.0
024 7 _ |a 10.1093/brain/awaf202
|2 doi
024 7 _ |a pmid:40455867
|2 pmid
024 7 _ |a pmc:PMC12493049
|2 pmc
024 7 _ |a 0006-8950
|2 ISSN
024 7 _ |a 1460-2156
|2 ISSN
037 _ _ |a DZNE-2025-01136
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Hirano, Yoko
|b 0
245 _ _ |a Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
260 _ _ |a Oxford
|c 2025
|b Oxford Univ. Press
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1761732473_30623
|2 PUB:(DE-HGF)
336 7 _ |a ARTICLE
|2 BibTeX
336 7 _ |a JOURNAL_ARTICLE
|2 ORCID
336 7 _ |a Journal Article
|0 0
|2 EndNote
520 _ _ |a Monoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture of LGI1-ADAM22/23 pathway-related diseases remains incompletely understood. Through international genetic data sharing, we identified the first ultra-rare biallelic LGI1 variants in six individuals from four consanguineous families. Affected individuals presented DEE with neonatal/infantile-onset epilepsy (n = 6/6), global developmental delay/intellectual disability (n = 6/6) and infant/premature death (n = 5/6). Brain MRI showed mild cerebral atrophy in a subset of patients (n = 3/6). Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes. Further, we observed epileptic discharges from the isolated whole hippocampus of Lgi1-/- knockout mice, experimentally modelling the hippocampal origin of LGI1-related epilepsy. Automated behavioural analysis of a mouse model for ADAM22-related DEE revealed its impaired cognitive function. Furthermore, we report the first ADAM23 variant associated with lethal neonatal-onset epilepsy and myopathy. Collectively, this study defines the LGI1-ADAM22/23 pathway-related disease spectrum.
536 _ _ |a 351 - Brain Function (POF4-351)
|0 G:(DE-HGF)POF4-351
|c POF4-351
|f POF IV
|x 0
536 _ _ |a 353 - Clinical and Health Care Research (POF4-353)
|0 G:(DE-HGF)POF4-353
|c POF4-353
|f POF IV
|x 1
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a ADAM22
|2 Other
650 _ 7 |a ADAM23
|2 Other
650 _ 7 |a LGI1
|2 Other
650 _ 7 |a MAGUK
|2 Other
650 _ 7 |a developmental and epileptic encephalopathy
|2 Other
650 _ 7 |a drug-resistant seizures
|2 Other
650 _ 7 |a ADAM Proteins
|0 EC 3.4.24.-
|2 NLM Chemicals
650 _ 7 |a ADAM22 protein, human
|0 EC 3.4.24.-
|2 NLM Chemicals
650 _ 7 |a LGI1 protein, human
|2 NLM Chemicals
650 _ 7 |a ADAM23 protein, human
|0 EC 3.4.24.-
|2 NLM Chemicals
650 _ 7 |a Intracellular Signaling Peptides and Proteins
|2 NLM Chemicals
650 _ 7 |a Nerve Tissue Proteins
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a ADAM Proteins: genetics
|2 MeSH
650 _ 2 |a ADAM Proteins: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Hippocampus: metabolism
|2 MeSH
650 _ 2 |a Hippocampus: physiopathology
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Intracellular Signaling Peptides and Proteins: genetics
|2 MeSH
650 _ 2 |a Infant
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: genetics
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins: metabolism
|2 MeSH
650 _ 2 |a Child, Preschool
|2 MeSH
650 _ 2 |a Child
|2 MeSH
650 _ 2 |a Epilepsy: genetics
|2 MeSH
650 _ 2 |a Pedigree
|2 MeSH
650 _ 2 |a Signal Transduction: genetics
|2 MeSH
650 _ 2 |a Adolescent
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
700 1 _ |a Miyazaki, Yuri
|b 1
700 1 _ |a Ishikawa, Daisuke
|b 2
700 1 _ |a Inahashi, Hiroki
|b 3
700 1 _ |a Al-Hassnan, Zuhair Nasser
|b 4
700 1 _ |a Zifarelli, Giovanni
|b 5
700 1 _ |a Bauer, Peter
|b 6
700 1 _ |a Alvi, Javeria Raza
|b 7
700 1 _ |a Sultan, Tipu
|b 8
700 1 _ |a Thompson, Michelle L
|b 9
700 1 _ |a Sezer, Abdullah
|b 10
700 1 _ |a Konuşkan, Bahadır
|b 11
700 1 _ |a Hajir, Razan S
|b 12
700 1 _ |a El-Hattab, Ayman W
|b 13
700 1 _ |a Efthymiou, Stephanie
|0 0000-0003-4900-9877
|b 14
700 1 _ |a Ishida, Ayuki
|b 15
700 1 _ |a Yokoi, Norihiko
|b 16
700 1 _ |a Kornau, Hans-Christian
|0 P:(DE-2719)2811900
|b 17
|u dzne
700 1 _ |a Schmitz, Dietmar
|0 P:(DE-2719)2810725
|b 18
|u dzne
700 1 _ |a Prüss, Harald
|0 P:(DE-2719)2810931
|b 19
|u dzne
700 1 _ |a Houlden, Henry
|0 0000-0002-2866-7777
|b 20
700 1 _ |a Ikegaya, Yuji
|b 21
700 1 _ |a Fukata, Yuko
|b 22
700 1 _ |a Fukata, Masaki
|b 23
700 1 _ |a Maroofian, Reza
|0 0000-0001-6763-1542
|b 24
773 _ _ |a 10.1093/brain/awaf202
|g Vol. 148, no. 10, p. 3514 - 3522
|0 PERI:(DE-600)1474117-9
|n 10
|p 3514 - 3522
|t Brain
|v 148
|y 2025
|x 0006-8950
856 4 _ |u https://pub.dzne.de/record/281517/files/DZNE-2025-01136%20SUP.pdf
856 4 _ |y OpenAccess
|u https://pub.dzne.de/record/281517/files/DZNE-2025-01136.pdf
856 4 _ |y OpenAccess
|x pdfa
|u https://pub.dzne.de/record/281517/files/DZNE-2025-01136.pdf?subformat=pdfa
856 4 _ |x pdfa
|u https://pub.dzne.de/record/281517/files/DZNE-2025-01136%20SUP.pdf?subformat=pdfa
910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
|0 I:(DE-588)1065079516
|k DZNE
|b 17
|6 P:(DE-2719)2811900
910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
|0 I:(DE-588)1065079516
|k DZNE
|b 18
|6 P:(DE-2719)2810725
910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
|0 I:(DE-588)1065079516
|k DZNE
|b 19
|6 P:(DE-2719)2810931
913 1 _ |a DE-HGF
|b Gesundheit
|l Neurodegenerative Diseases
|1 G:(DE-HGF)POF4-350
|0 G:(DE-HGF)POF4-351
|3 G:(DE-HGF)POF4
|2 G:(DE-HGF)POF4-300
|4 G:(DE-HGF)POF
|v Brain Function
|x 0
913 1 _ |a DE-HGF
|b Gesundheit
|l Neurodegenerative Diseases
|1 G:(DE-HGF)POF4-350
|0 G:(DE-HGF)POF4-353
|3 G:(DE-HGF)POF4
|2 G:(DE-HGF)POF4-300
|4 G:(DE-HGF)POF
|v Clinical and Health Care Research
|x 1
914 1 _ |y 2025
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0200
|2 StatID
|b SCOPUS
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0160
|2 StatID
|b Essential Science Indicators
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1050
|2 StatID
|b BIOSIS Previews
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1190
|2 StatID
|b Biological Abstracts
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0600
|2 StatID
|b Ebsco Academic Search
|d 2024-12-12
915 _ _ |a JCR
|0 StatID:(DE-HGF)0100
|2 StatID
|b BRAIN : 2022
|d 2024-12-12
915 _ _ |a IF >= 10
|0 StatID:(DE-HGF)9910
|2 StatID
|b BRAIN : 2022
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1030
|2 StatID
|b Current Contents - Life Sciences
|d 2024-12-12
915 _ _ |a WoS
|0 StatID:(DE-HGF)0113
|2 StatID
|b Science Citation Index Expanded
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0150
|2 StatID
|b Web of Science Core Collection
|d 2024-12-12
915 _ _ |a Creative Commons Attribution CC BY 4.0
|0 LIC:(DE-HGF)CCBY4
|2 HGFVOC
915 _ _ |a OpenAccess
|0 StatID:(DE-HGF)0510
|2 StatID
915 _ _ |a Peer Review
|0 StatID:(DE-HGF)0030
|2 StatID
|b ASC
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0300
|2 StatID
|b Medline
|d 2024-12-12
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1110
|2 StatID
|b Current Contents - Clinical Medicine
|d 2024-12-12
915 _ _ |a Nationallizenz
|0 StatID:(DE-HGF)0420
|2 StatID
|d 2024-12-12
|w ger
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0199
|2 StatID
|b Clarivate Analytics Master Journal List
|d 2024-12-12
920 1 _ |0 I:(DE-2719)1810004
|k AG Schmitz
|l Network Dysfunction
|x 0
920 1 _ |0 I:(DE-2719)1810003
|k AG Prüß
|l Autoimmune Encephalopathies
|x 1
980 _ _ |a journal
980 _ _ |a VDB
980 _ _ |a UNRESTRICTED
980 _ _ |a I:(DE-2719)1810004
980 _ _ |a I:(DE-2719)1810003
980 1 _ |a FullTexts

LibraryCollectionCLSMajorCLSMinorLanguageAuthor
Marc 21