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@ARTICLE{Hirano:281517,
      author       = {Hirano, Yoko and Miyazaki, Yuri and Ishikawa, Daisuke and
                      Inahashi, Hiroki and Al-Hassnan, Zuhair Nasser and
                      Zifarelli, Giovanni and Bauer, Peter and Alvi, Javeria Raza
                      and Sultan, Tipu and Thompson, Michelle L and Sezer,
                      Abdullah and Konuşkan, Bahadır and Hajir, Razan S and
                      El-Hattab, Ayman W and Efthymiou, Stephanie and Ishida,
                      Ayuki and Yokoi, Norihiko and Kornau, Hans-Christian and
                      Schmitz, Dietmar and Prüss, Harald and Houlden, Henry and
                      Ikegaya, Yuji and Fukata, Yuko and Fukata, Masaki and
                      Maroofian, Reza},
      title        = {{B}iallelic {LGI}1 and {ADAM}23 variants cause hippocampal
                      epileptic encephalopathy via the {LGI}1-{ADAM}22/23
                      pathway.},
      journal      = {Brain},
      volume       = {148},
      number       = {10},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2025-01136},
      pages        = {3514 - 3522},
      year         = {2025},
      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.},
      keywords     = {Humans / Animals / ADAM Proteins: genetics / ADAM Proteins:
                      metabolism / Male / Female / Hippocampus: metabolism /
                      Hippocampus: physiopathology / Mice / Intracellular
                      Signaling Peptides and Proteins: genetics / Infant / Nerve
                      Tissue Proteins: genetics / Nerve Tissue Proteins:
                      metabolism / Child, Preschool / Child / Epilepsy: genetics /
                      Pedigree / Signal Transduction: genetics / Adolescent /
                      Mice, Knockout / ADAM22 (Other) / ADAM23 (Other) / LGI1
                      (Other) / MAGUK (Other) / developmental and epileptic
                      encephalopathy (Other) / drug-resistant seizures (Other) /
                      ADAM Proteins (NLM Chemicals) / ADAM22 protein, human (NLM
                      Chemicals) / LGI1 protein, human (NLM Chemicals) / ADAM23
                      protein, human (NLM Chemicals) / Intracellular Signaling
                      Peptides and Proteins (NLM Chemicals) / Nerve Tissue
                      Proteins (NLM Chemicals)},
      cin          = {AG Schmitz / AG Prüß},
      ddc          = {610},
      cid          = {I:(DE-2719)1810004 / I:(DE-2719)1810003},
      pnm          = {351 - Brain Function (POF4-351) / 353 - Clinical and Health
                      Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40455867},
      pmc          = {pmc:PMC12493049},
      doi          = {10.1093/brain/awaf202},
      url          = {https://pub.dzne.de/record/281517},
}