Journal Article

DZNE-2025-01136

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.

Hirano, Y. ; Miyazaki, Y. ; Ishikawa, D. ; Inahashi, H. ; Al-Hassnan, Z. N. ; Zifarelli, G. ; Bauer, P. ; Alvi, J. R. ; Sultan, T. ; Thompson, M. L. ; Sezer, A. ; Konuşkan, B. ; Hajir, R. S. ; El-Hattab, A. W. ; Efthymiou, S. ; Ishida, A. ; Yokoi, N. ; Kornau, H.-C.DZNE* ; Schmitz, D.DZNE* ; Prüss, H.DZNE* ; Houlden, H. ; Ikegaya, Y. ; Fukata, Y. ; Fukata, M. ; Maroofian, R.

2025
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf202

Abstract: 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.

Keyword(s): Humans (MeSH) ; Animals (MeSH) ; ADAM Proteins: genetics (MeSH) ; ADAM Proteins: metabolism (MeSH) ; Male (MeSH) ; Female (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: physiopathology (MeSH) ; Mice (MeSH) ; Intracellular Signaling Peptides and Proteins: genetics (MeSH) ; Infant (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Child, Preschool (MeSH) ; Child (MeSH) ; Epilepsy: genetics (MeSH) ; Pedigree (MeSH) ; Signal Transduction: genetics (MeSH) ; Adolescent (MeSH) ; Mice, Knockout (MeSH) ; ADAM22 ; ADAM23 ; LGI1 ; MAGUK ; developmental and epileptic encephalopathy ; drug-resistant seizures ; ADAM Proteins ; ADAM22 protein, human ; LGI1 protein, human ; ADAM23 protein, human ; Intracellular Signaling Peptides and Proteins ; Nerve Tissue Proteins

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Contributing Institute(s):

1. Network Dysfunction (AG Schmitz)
2. Autoimmune Encephalopathies (AG Prüß)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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