%0 Journal Article
%A Hirano, Yoko
%A Miyazaki, Yuri
%A Ishikawa, Daisuke
%A Inahashi, Hiroki
%A Al-Hassnan, Zuhair Nasser
%A Zifarelli, Giovanni
%A Bauer, Peter
%A Alvi, Javeria Raza
%A Sultan, Tipu
%A Thompson, Michelle L
%A Sezer, Abdullah
%A Konuşkan, Bahadır
%A Hajir, Razan S
%A El-Hattab, Ayman W
%A Efthymiou, Stephanie
%A Ishida, Ayuki
%A Yokoi, Norihiko
%A Kornau, Hans-Christian
%A Schmitz, Dietmar
%A Prüss, Harald
%A Houlden, Henry
%A Ikegaya, Yuji
%A Fukata, Yuko
%A Fukata, Masaki
%A Maroofian, Reza
%T Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
%J Brain
%V 148
%N 10
%@ 0006-8950
%C Oxford
%I Oxford Univ. Press
%M DZNE-2025-01136
%P 3514 - 3522
%D 2025
%X 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.
%K Humans
%K Animals
%K ADAM Proteins: genetics
%K ADAM Proteins: metabolism
%K Male
%K Female
%K Hippocampus: metabolism
%K Hippocampus: physiopathology
%K Mice
%K Intracellular Signaling Peptides and Proteins: genetics
%K Infant
%K Nerve Tissue Proteins: genetics
%K Nerve Tissue Proteins: metabolism
%K Child, Preschool
%K Child
%K Epilepsy: genetics
%K Pedigree
%K Signal Transduction: genetics
%K Adolescent
%K Mice, Knockout
%K ADAM22 (Other)
%K ADAM23 (Other)
%K LGI1 (Other)
%K MAGUK (Other)
%K developmental and epileptic encephalopathy (Other)
%K drug-resistant seizures (Other)
%K ADAM Proteins (NLM Chemicals)
%K ADAM22 protein, human (NLM Chemicals)
%K LGI1 protein, human (NLM Chemicals)
%K ADAM23 protein, human (NLM Chemicals)
%K Intracellular Signaling Peptides and Proteins (NLM Chemicals)
%K Nerve Tissue Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40455867
%2 pmc:PMC12493049
%R 10.1093/brain/awaf202
%U https://pub.dzne.de/record/281517