TY  - JOUR
AU  - Hirano, Yoko
AU  - Miyazaki, Yuri
AU  - Ishikawa, Daisuke
AU  - Inahashi, Hiroki
AU  - Al-Hassnan, Zuhair Nasser
AU  - Zifarelli, Giovanni
AU  - Bauer, Peter
AU  - Alvi, Javeria Raza
AU  - Sultan, Tipu
AU  - Thompson, Michelle L
AU  - Sezer, Abdullah
AU  - Konuşkan, Bahadır
AU  - Hajir, Razan S
AU  - El-Hattab, Ayman W
AU  - Efthymiou, Stephanie
AU  - Ishida, Ayuki
AU  - Yokoi, Norihiko
AU  - Kornau, Hans-Christian
AU  - Schmitz, Dietmar
AU  - Prüss, Harald
AU  - Houlden, Henry
AU  - Ikegaya, Yuji
AU  - Fukata, Yuko
AU  - Fukata, Masaki
AU  - Maroofian, Reza
TI  - Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.
JO  - Brain
VL  - 148
IS  - 10
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2025-01136
SP  - 3514 - 3522
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Animals
KW  - ADAM Proteins: genetics
KW  - ADAM Proteins: metabolism
KW  - Male
KW  - Female
KW  - Hippocampus: metabolism
KW  - Hippocampus: physiopathology
KW  - Mice
KW  - Intracellular Signaling Peptides and Proteins: genetics
KW  - Infant
KW  - Nerve Tissue Proteins: genetics
KW  - Nerve Tissue Proteins: metabolism
KW  - Child, Preschool
KW  - Child
KW  - Epilepsy: genetics
KW  - Pedigree
KW  - Signal Transduction: genetics
KW  - Adolescent
KW  - Mice, Knockout
KW  - ADAM22 (Other)
KW  - ADAM23 (Other)
KW  - LGI1 (Other)
KW  - MAGUK (Other)
KW  - developmental and epileptic encephalopathy (Other)
KW  - drug-resistant seizures (Other)
KW  - ADAM Proteins (NLM Chemicals)
KW  - ADAM22 protein, human (NLM Chemicals)
KW  - LGI1 protein, human (NLM Chemicals)
KW  - ADAM23 protein, human (NLM Chemicals)
KW  - Intracellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40455867
C2  - pmc:PMC12493049
DO  - DOI:10.1093/brain/awaf202
UR  - https://pub.dzne.de/record/281517
ER  -