Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy
Brain, vol. 145, pp. 2301–2312
Abstract
Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. 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. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.
Authors 47
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Child Neurology, Sophia Children’s Hospital, Erasmus University Medical Center , 3015 CN Rotterdam , The Netherlands
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK
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National Institutes of Natural Sciences · The Graduate University for Advanced Studies, SOKENDAI · National Institute for Physiological Sciences
Affiliation as printed
Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies) , Okazaki, Aichi 444-8585 , Japan
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
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Affiliation as printed
Department of Clinical Genetics, Erasmus University Medical Center , 3015 CN Rotterdam , The Netherlands
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St George's, University of London
Affiliation as printed
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George’s University , London SW17 0RE , UK
Next Generation Genetic Polyclinic, Razavi International Hospital , Mashhad , Iran
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Affiliation as printed
Folkhälsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki , Helsinki 00290 , Finland
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University of Helsinki · Blueprint Genetics (Finland)
Affiliation as printed
Blueprint Genetics , 02150 Espoo , Finland
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Finland, 00100 Helsinki , Finland
Folkhälsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki , Helsinki 00290 , Finland
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Affiliation as printed
Department of Pathology, Medicum, University of Helsinki , 00100 Helsinki , Finland
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National Institutes of Natural Sciences · The Graduate University for Advanced Studies, SOKENDAI · National Institute for Physiological Sciences
Affiliation as printed
Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies) , Okazaki, Aichi 444-8585 , Japan
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
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Cairo University · Cairo University hospitals
Affiliation as printed
Division of Neurology and Metabolism, Kasr Al Ainy School of Medicine, Cairo University Children Hospital , Cairo , Egypt
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Universidade de São Paulo · Universidade Federal de São Paulo
Affiliation as printed
Department of Morphology and Genetics, Clinical Center of Medical Genetics Federal, University of São Paulo , São Paulo , Brazil
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Universidade de São Paulo · Universidade Federal de São Paulo
Affiliation as printed
Department of Morphology and Genetics, Clinical Center of Medical Genetics Federal, University of São Paulo , São Paulo , Brazil
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Affiliation as printed
Centogene GmbH , 18055 Rostock , Germany
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center , 2300 RC Leiden , The Netherlands
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Affiliation as printed
Department of Medical Genetics, University of Alberta , Edmonton, AB , Canada
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Affiliation as printed
Division of Pediatric Neurology, University of Alberta , Edmonton, AB , Canada
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Technion – Israel Institute of Technology · Carmel Medical Center
Affiliation as printed
Affiliated to the Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel Institute of Technology, Genetics Institute, Carmel Medical Center, Haifa , Israel
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Affiliation as printed
Pediatric Neurology Unit, Carmel Medical Center , Haifa , Israel
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Technion – Israel Institute of Technology · Carmel Medical Center
Affiliation as printed
Affiliated to the Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel Institute of Technology, Genetics Institute, Carmel Medical Center, Haifa , Israel
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Technion – Israel Institute of Technology
Affiliation as printed
Department of Biology, Technion-Israel Institute of Technology , Haifa 3200003 , Israel
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Affiliation as printed
Department of Neurology, Reinier de Graaf Hospital , 2625 AD Delft , The Netherlands
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Cacha M. P. C. D. Peeters‐Scholte Aachen Department of Neurology, Leiden University Medical Center (LUMC)
Leiden University Medical Center
Affiliation as printed
Department of Neurology, Leiden University Medical Center , 2300 RA Leiden , The Netherlands
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Dokuz Eylül University · Izmir Biomedicine and Genome Center
Affiliation as printed
Department of Paediatric Neurology, School of Medicine, Dokuz Eylul University , Izmir , Turkey
Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus , Izmir , Turkey
Izmir International Biomedicine and Genome Institute, Dokuz Eylul University , Izmir , Turkey
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Affiliation as printed
Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge , Cambridge , UK
Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge , Cambridge Biomedical Campus, Cambridge , UK
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University of Ottawa · University of Freiburg · Children's Hospital of Eastern Ontario · Ottawa Hospital · University Medical Center Freiburg · Barcelona Institute of Science and Technology · Centre for Genomic Regulation · uOttawa Brain and Mind Research Institute
Affiliation as printed
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology , Barcelona , Spain
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa , Ottawa , Canada
Department of Neuropediatrics and Muscle Disorders, Medical Center–University of Freiburg, Faculty of Medicine , Freiburg , Germany
Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa , Ottawa , Canada
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK
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Affiliation as printed
Institute of Medical Genetics and Applied Genomics, University of Tübingen , Tübingen 72076 , Germany
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Praxis für Humangenetik · Klinikum Bremen-Mitte
Affiliation as printed
Praxis für Humangenetik, Klinikum Bremen-Mitte , Bremen 28209 , Germany
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Affiliation as printed
Department of Pediatrics, Klinikum Bremen-Mitte , Bremen 28205 , Germany
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Seattle Children's Hospital · University of Washington
Affiliation as printed
Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital , Seattle, WA 98195 , USA
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Affiliation as printed
Department of Otolaryngology - Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen , Tübingen 72076 , Germany
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Affiliation as printed
Department of Otolaryngology - Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen , Tübingen 72076 , Germany
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , Saudi Arabia
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , Saudi Arabia
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Pirogov Russian National Research Medical University · Ministry of Health of the Russian Federation
Affiliation as printed
Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health , Moscow , Russia
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Pirogov Russian National Research Medical University · Ministry of Health of the Russian Federation · Mental Health Research Center of Russian Academy of Medical Sciences
Affiliation as printed
Mental Health Research Center , Moscow 107076 , Russia
Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health , Moscow , Russia
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Indira Gandhi Institute of Child Health
Affiliation as printed
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health , Bangalore , India
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Indira Gandhi Institute of Child Health
Affiliation as printed
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health , Bangalore , India
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King Faisal Specialist Hospital & Research Centre
Affiliation as printed
Department of Translational Genomics, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , Saudi Arabia
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Seattle Children's Hospital · University of Washington
Affiliation as printed
Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital , Seattle, WA 98195 , USA
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King Saud bin Abdulaziz University for Health Sciences · King Abdulaziz Medical City · King Abdullah International Medical Research Center · National Guard Health Affairs
Affiliation as printed
Genetics and Precision Medicine Department, King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNG-HA) , Riyadh , Saudi Arabia
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King AbdulAziz Medical City, Ministry of National Guard Health Affairs , Riyadh , Saudi Arabia
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Affiliation as printed
Centre for Rare Diseases, University of Tübingen , Tübingen 72076 , Germany
Institute of Medical Genetics and Applied Genomics, University of Tübingen , Tübingen 72076 , Germany
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova , Genova , Italy
IRCCS Istituto Giannina Gaslini , 16147 Genoa , Italy
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Affiliation as printed
IRCCS Istituto Giannina Gaslini , 16147 Genoa , Italy
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Masaki Fukata corresponding
National Institutes of Natural Sciences · The Graduate University for Advanced Studies, SOKENDAI · National Institute for Physiological Sciences
Affiliation as printed
Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies) , Okazaki, Aichi 444-8585 , Japan
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
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center , 2300 RC Leiden , The Netherlands
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Henry Houlden corresponding
UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK
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