{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:04:00Z","timestamp":1788141840107,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T00:00:00Z","timestamp":1678492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1315"],"award-info":[{"award-number":["CRC1315"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FOR3004"],"award-info":[{"award-number":["FOR3004"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>WWOX<\/jats:italic>is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (<jats:italic>WWOX<\/jats:italic>\u2010DEE), also known as WOREE (<jats:italic>WWOX<\/jats:italic>\u2010related epileptic encephalopathy). We analyzed the epileptology and imaging features of<jats:italic>WWOX<\/jats:italic>\u2010DEE, and investigated genotype\u2013phenotype correlations, particularly with regard to survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied 13 patients from 12 families with<jats:italic>WWOX<\/jats:italic>\u2010DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic<jats:italic>WWOX<\/jats:italic>variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null\/null, (2) null\/missense, (3) missense\/missense. Differences in survival outcome were estimated using the Kaplan\u2013Meier method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All patients experienced multiple seizure types (median onset\u00a0=\u00a05\u2009weeks, range\u00a0=\u00a01\u00a0day\u201310\u00a0months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (<jats:italic>n<\/jats:italic>\u00a0=\u20095), myoclonic (<jats:italic>n<\/jats:italic>\u00a0=\u20092), epileptic spasms (<jats:italic>n<\/jats:italic>\u00a0=\u20092), focal (<jats:italic>n<\/jats:italic>\u00a0=\u20091), and migrating focal (<jats:italic>n<\/jats:italic>\u00a0=\u20091) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo\u2010occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout<jats:italic>WWOX<\/jats:italic>and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (<jats:italic>p<\/jats:italic>\u2010value\u00a0=\u00a0.0085, log\u2010rank test).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Biallelic<jats:italic>WWOX<\/jats:italic>pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null<jats:italic>WWOX<\/jats:italic>pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17542","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T08:29:33Z","timestamp":1676276973000},"page":"1351-1367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["<i>WWOX<\/i>developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-6153","authenticated-orcid":false,"given":"Karen L.","family":"Oliver","sequence":"first","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine University of Melbourne, Austin Health Heidelberg 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Medicine University of Melbourne, Austin Health Heidelberg Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Muir","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Washington Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apoorva","family":"Chowdhary","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Washington Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hertzberg","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Sozialp\u00e4diatrie und Neurop\u00e4diatrie (DBZ) Vivantes Hospital Neukoelln Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Goldhahn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neuropediatrics, DRK Klinikum Westend Berlin 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Research Parkville Victoria Australia"},{"name":"Department of Medical Biology University of Melbourne Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine University of Melbourne, Austin Health Heidelberg Victoria Australia"},{"name":"Murdoch Children's Research Institute Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather C.","family":"Mefford","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Washington Seattle Washington USA"},{"name":"Center for Pediatric Neurological Disease Research St. Jude Children's Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9454-206X","authenticated-orcid":false,"given":"Angela M.","family":"Kaindl","sequence":"additional","affiliation":[{"name":"Center for Chronically Sick Children (SPZ) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin Berlin Germany"},{"name":"Department of Pediatric Neurology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin Berlin Germany"},{"name":"Institute of Cell Biology and Neurobiology Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8120-0287","authenticated-orcid":false,"given":"Nicola","family":"Specchio","sequence":"additional","affiliation":[{"name":"Rare and Complex Epilepsy Unit, Department of Neuroscience Bambino Ges\u00f9 Children's Hospital IRCCS, full member of European Reference Network EpiCARE Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2311-2174","authenticated-orcid":false,"given":"Ingrid 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