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However, so far, only two affected individuals have been described and many features of this disorder are unknown.<\/jats:p>\n                  <jats:p>We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay\/intellectual disability (20\/20), hypotonia (12\/20) and delayed motor development (19\/20). Brain MRI findings included cerebral atrophy (13\/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5\/20), and callosal hypoplasia (4\/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and\/or (iii) impaired interaction with the postsynaptic density protein PSD-95.<\/jats:p>\n                  <jats:p>We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.<\/jats:p>","DOI":"10.1093\/brain\/awac116","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T08:01:13Z","timestamp":1649059273000},"page":"2301-2312","source":"Crossref","is-referenced-by-count":24,"title":["Biallelic\n                    <i>ADAM22<\/i>\n                    pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8721-6300","authenticated-orcid":false,"given":"Marieke M","family":"van der Knoop","sequence":"first","affiliation":[{"name":"Department of Child Neurology, Sophia Children\u2019s Hospital, Erasmus University Medical Center , 3015 CN Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Fukata","sequence":"additional","affiliation":[{"name":"Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences , Okazaki, Aichi 444-8787 , Japan"},{"name":"Department of 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Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki , Helsinki 00290 , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Muona","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki , Helsinki 00290 , Finland"},{"name":"Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Finland, 00100 Helsinki , Finland"},{"name":"Blueprint Genetics , 02150 Espoo , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Paetau","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medicum, University of Helsinki , 00100 Helsinki , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Division of Membrane Physiology, Department of Molecular and Cellular 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RC Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison J","family":"Eaton","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta , Edmonton, AB , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois D","family":"Morneau-Jacob","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, University of Alberta , Edmonton, AB , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Sagi-Dain","sequence":"additional","affiliation":[{"name":"Affiliated to the Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel Institute of Technology, Genetics Institute, Carmel Medical Center, Haifa , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilach","family":"Shemer-Meiri","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Carmel Medical Center , Haifa , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Peleg","sequence":"additional","affiliation":[{"name":"Affiliated to the Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel Institute of Technology, Genetics Institute, Carmel Medical Center, Haifa , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumana","family":"Haddad-Halloun","sequence":"additional","affiliation":[{"name":"Department of Biology, Technion-Israel Institute of Technology , Haifa 3200003 , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan J","family":"Kamphuis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Reinier de Graaf Hospital , 2625 AD Delft , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cacha M P C D","family":"Peeters-Scholte","sequence":"additional","affiliation":[{"name":"Department of Neurology, Leiden University Medical Center , 2300 RA Leiden , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Semra Hiz","family":"Kurul","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus , Izmir , Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eylul University , Izmir , Turkey"},{"name":"Department of Paediatric Neurology, School of Medicine, Dokuz Eylul University , Izmir , Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-170X","authenticated-orcid":false,"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge , Cambridge Biomedical Campus, Cambridge , UK"},{"name":"Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge , Cambridge , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology , Barcelona , Spain"},{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, University of Ottawa , Ottawa , Canada"},{"name":"Department of Neuropediatrics and Muscle Disorders, Medical Center\u2013University of Freiburg, Faculty of Medicine , Freiburg , Germany"},{"name":"Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa , Ottawa , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , 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Seattle Children\u2019s Hospital , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aboulfazl","family":"Rad","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology - Head and Neck Surgery, T\u00fcbingen Hearing Research Centre, Eberhard Karls University T\u00fcbingen , T\u00fcbingen 72076 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6719-3447","authenticated-orcid":false,"given":"Barbara","family":"Vona","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology - Head and Neck Surgery, T\u00fcbingen Hearing Research Centre, Eberhard Karls University T\u00fcbingen , T\u00fcbingen 72076 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firdous","family":"Abdulwahad","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , 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