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000281517 0247_ $$2ISSN$$a1460-2156
000281517 037__ $$aDZNE-2025-01136
000281517 041__ $$aEnglish
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000281517 1001_ $$aHirano, Yoko$$b0
000281517 245__ $$aBiallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
000281517 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000281517 520__ $$aMonoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture of LGI1-ADAM22/23 pathway-related diseases remains incompletely understood. Through international genetic data sharing, we identified the first ultra-rare biallelic LGI1 variants in six individuals from four consanguineous families. Affected individuals presented DEE with neonatal/infantile-onset epilepsy (n = 6/6), global developmental delay/intellectual disability (n = 6/6) and infant/premature death (n = 5/6). Brain MRI showed mild cerebral atrophy in a subset of patients (n = 3/6). Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes. Further, we observed epileptic discharges from the isolated whole hippocampus of Lgi1-/- knockout mice, experimentally modelling the hippocampal origin of LGI1-related epilepsy. Automated behavioural analysis of a mouse model for ADAM22-related DEE revealed its impaired cognitive function. Furthermore, we report the first ADAM23 variant associated with lethal neonatal-onset epilepsy and myopathy. Collectively, this study defines the LGI1-ADAM22/23 pathway-related disease spectrum.
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000281517 650_7 $$2Other$$aADAM22
000281517 650_7 $$2Other$$aADAM23
000281517 650_7 $$2Other$$aLGI1
000281517 650_7 $$2Other$$aMAGUK
000281517 650_7 $$2Other$$adevelopmental and epileptic encephalopathy
000281517 650_7 $$2Other$$adrug-resistant seizures
000281517 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aADAM Proteins
000281517 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aADAM22 protein, human
000281517 650_7 $$2NLM Chemicals$$aLGI1 protein, human
000281517 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aADAM23 protein, human
000281517 650_7 $$2NLM Chemicals$$aIntracellular Signaling Peptides and Proteins
000281517 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000281517 650_2 $$2MeSH$$aHumans
000281517 650_2 $$2MeSH$$aAnimals
000281517 650_2 $$2MeSH$$aADAM Proteins: genetics
000281517 650_2 $$2MeSH$$aADAM Proteins: metabolism
000281517 650_2 $$2MeSH$$aMale
000281517 650_2 $$2MeSH$$aFemale
000281517 650_2 $$2MeSH$$aHippocampus: metabolism
000281517 650_2 $$2MeSH$$aHippocampus: physiopathology
000281517 650_2 $$2MeSH$$aMice
000281517 650_2 $$2MeSH$$aIntracellular Signaling Peptides and Proteins: genetics
000281517 650_2 $$2MeSH$$aInfant
000281517 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000281517 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000281517 650_2 $$2MeSH$$aChild, Preschool
000281517 650_2 $$2MeSH$$aChild
000281517 650_2 $$2MeSH$$aEpilepsy: genetics
000281517 650_2 $$2MeSH$$aPedigree
000281517 650_2 $$2MeSH$$aSignal Transduction: genetics
000281517 650_2 $$2MeSH$$aAdolescent
000281517 650_2 $$2MeSH$$aMice, Knockout
000281517 7001_ $$aMiyazaki, Yuri$$b1
000281517 7001_ $$aIshikawa, Daisuke$$b2
000281517 7001_ $$aInahashi, Hiroki$$b3
000281517 7001_ $$aAl-Hassnan, Zuhair Nasser$$b4
000281517 7001_ $$aZifarelli, Giovanni$$b5
000281517 7001_ $$aBauer, Peter$$b6
000281517 7001_ $$aAlvi, Javeria Raza$$b7
000281517 7001_ $$aSultan, Tipu$$b8
000281517 7001_ $$aThompson, Michelle L$$b9
000281517 7001_ $$aSezer, Abdullah$$b10
000281517 7001_ $$aKonuşkan, Bahadır$$b11
000281517 7001_ $$aHajir, Razan S$$b12
000281517 7001_ $$aEl-Hattab, Ayman W$$b13
000281517 7001_ $$00000-0003-4900-9877$$aEfthymiou, Stephanie$$b14
000281517 7001_ $$aIshida, Ayuki$$b15
000281517 7001_ $$aYokoi, Norihiko$$b16
000281517 7001_ $$0P:(DE-2719)2811900$$aKornau, Hans-Christian$$b17$$udzne
000281517 7001_ $$0P:(DE-2719)2810725$$aSchmitz, Dietmar$$b18$$udzne
000281517 7001_ $$0P:(DE-2719)2810931$$aPrüss, Harald$$b19$$udzne
000281517 7001_ $$00000-0002-2866-7777$$aHoulden, Henry$$b20
000281517 7001_ $$aIkegaya, Yuji$$b21
000281517 7001_ $$aFukata, Yuko$$b22
000281517 7001_ $$aFukata, Masaki$$b23
000281517 7001_ $$00000-0001-6763-1542$$aMaroofian, Reza$$b24
000281517 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awaf202$$gVol. 148, no. 10, p. 3514 - 3522$$n10$$p3514 - 3522$$tBrain$$v148$$x0006-8950$$y2025
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