Biallelic <i>LGI1</i> and <i>ADAM23</i> variants cause hippocampal epileptic encephalopathy via the LGI1–ADAM22/23 pathway

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.

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Journal
Brain
Published
2025-06-02
DOI
https://doi.org/10.1093/brain/awaf202
Citations
1
Primary Topic
Autoimmune Neurological Disorders and Treatments
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article
Field-Weighted Citation Impact
1.39

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article

Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1–ADAM22/23 pathway

Michelle L. Thompson, Ayako Ishida, Yoko Hirano, Ayman W. El‐Hattab et al.
1 citations
Brain
Autoimmune Neurological Disorders and Treatments
1.39
article

Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1–ADAM22/23 pathway

Michelle L. Thompson, Ayako Ishida, Yoko Hirano, Ayman W. El‐Hattab, Masaki Fukata, Giovanni Zifarelli, Stéphanie Efthymiou, Harald Prüß, Bahadır Konuşkan, Abdullah Sezer, Yuri Miyazaki, Hans‐Christian Kornau, Yuko Fukata, Javeria Raza Alvi, Henry Houlden, Hiroki Inahashi, Reza Maroofian, Zuhair Nasser Al-Hassnan, Dietmar Schmitz, Tipu Sultan, Daisuke Ishikawa, Norihiko Yokoi, Peter Bauer, Razan S Hajir
article en
1 citations

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.

BrainVol. 148(10)
Alfaisal University (SA), Wellcome Centre for Human Neuroimaging (GB), University of the Punjab (PK), National Institutes of Natural Sciences (JP), King Faisal Specialist Hospital & Research Centre (SA), Emirates Foundation (AE), German Center for Neurodegenerative Diseases (DE), University of Health Sciences Lahore (PK), University of Sharjah (AE), Humboldt-Universität zu Berlin (DE), Memorial Ankara Hospital (TR), University of Tokyo Hospital (JP), Medical Genetics Center (DE), Brain Innovation (Netherlands) (NL), Centogene (Germany) (DE), National Institute for Physiological Sciences (JP), HudsonAlpha Institute for Biotechnology (US), National Hospital for Neurology and Neurosurgery (GB), Genetic Analysis (Norway) (NO), University College London (GB), Nagoya University (JP), The University of Tokyo (JP), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), National Institute of Information and Communications Technology (JP)
Michael J. Fox Foundation for Parkinson's Research, Friedreich's Ataxia Research Alliance, Takeda Science Foundation, Japan Agency for Medical Research and Development, Wellcome Trust, Multiple System Atrophy Trust, Multiple System Atrophy Coalition, Dolby Family Ventures, Guarantors of Brain, Rosetrees Trust, Ministry of Education, Culture, Sports, Science and Technology, Alzheimer’s Research UK, European Academy of Neurology, Medical Research Centre, Cerebral Palsy Alliance, National Institutes of Health, Medical Research Council, University College London Hospitals Biomedical Research Centre, Instituto Nacional do Câncer, Ministério da Saúde, National Human Genome Research Institute, National Institute on Minority Health and Health Disparities, National Institute for Physiological Sciences
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Openalex Percentile: Top 19%
Autoimmune Neurological Disorders and Treatments
1.39
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