{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T08:02:27Z","timestamp":1768896147447,"version":"3.49.0"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Protein\u2010activated kinases mediate spine morphogenesis and synaptic plasticity. PAK3 is part of the p21\u2010activated kinases (PAKs) family of Ras\u2010signaling serine\/threonine kinases. Pathogenic variants in the X\u2010linked gene <jats:italic>PAK3<\/jats:italic> have been described in patients with neurodevelopmental syndromes. We analyzed an Italian family with sleep\u2010related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel <jats:italic>PAK3<\/jats:italic> c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. The male proband had drug\u2010resistant hypermotor seizures and moderate intellectual disability. His brother had drug\u2010responsive hypermotor seizures and mild intellectual disability. Both brothers were hemizygous and had psychiatric and behavioral problems as well as dysmorphic facial features. Their mother had never had seizures but was shown to be mosaic for the <jats:italic>PAK3<\/jats:italic> pathogenic variant. She had normal intellect but did have short stature and dysmorphic facial features similar to her sons. This is the first reported association of a <jats:italic>PAK3<\/jats:italic> pathogenic variant with sleep\u2010related hypermotor epilepsy. <jats:italic>PAK3<\/jats:italic> testing should be considered in families with suspected X\u2010linked sleep\u2010related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain Language Summary<\/jats:title><jats:p>We studied an Italian family with sleep\u2010related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel <jats:italic>PAK3<\/jats:italic> c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. This is the first reported association of a <jats:italic>PAK3<\/jats:italic> pathogenic variant with sleep\u2010related hypermotor epilepsy. <jats:italic>PAK3<\/jats:italic> testing should be considered in families with suspected X\u2010linked sleep\u2010related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.13124","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T05:42:53Z","timestamp":1736833373000},"page":"593-601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp><i>PAK3<\/i><\/scp> pathogenic variant associated with sleep\u2010related hypermotor epilepsy in a family with parental mosaicism"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7384-3074","authenticated-orcid":false,"given":"Antonio","family":"Gambardella","sequence":"first","affiliation":[{"name":"Institute of Neurology, Department of Medical and Surgical Sciences Magna Graecia University  Catanzaro Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine The University of Melbourne, Austin Health  Heidelberg Victoria Australia"},{"name":"Population Health and Immunity Division The Walter and Eliza Hall Institute of Medical Research  Parkville Victoria Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark F.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, 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