{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:02:26Z","timestamp":1791928946227,"version":"4.3.4"},"reference-count":16,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Disinhibition of the mechanistic target of rapamycin (mTOR) pathway has been observed in patients with loss\u2010of\u2010function variants in the <jats:italic>disheveled<\/jats:italic>, Egl\u201010, and pleckstrin domain\u2010containing protein 5 (<jats:italic>DEPDC5<\/jats:italic>), and nitrogen permease regulator\u2010like proteins 2 and 3 (<jats:italic>NPRL2<\/jats:italic>, <jats:italic>and NPRL3<\/jats:italic>) genes, which encode\u00a0the components of GTPase activating protein Activity Toward Rags Complex 1 (GATOR1) complex. Everolimus, a synthetic mTOR inhibitor, has shown efficacy in treating seizures in patients with <jats:italic>DEPDC5<\/jats:italic> epilepsy, but seemed to worsen seizures in the one published patient with <jats:italic>NPRL3<\/jats:italic> epilepsy. We studied four patients with <jats:italic>NPRL2\u2010<\/jats:italic> and <jats:italic>NPRL3<\/jats:italic>\u2010related epilepsies with intractable focal seizures treated with everolimus as add\u2010on therapy. Age at treatment initiation was between 1\u2009month and 26\u2009years; patients had baseline seizure frequencies ranging from 15 to 301 per month and had failed 6\u201314 antiseizure medications. Daily doses ranged between 3.75 and 11.5\u2009mg with trough levels between 5 and 8.7\u2009ng\/mL. Two patients became seizure\u2010free by 2\u2009months of treatment. In one of them, seizures recurred at levels below 4\u2009ng\/mL, and seizure freedom was regained with increased levels. The other two patients experienced a clinically meaningful seizure reduction of 52% and 86%, respectively. Two patients experienced stomatitis, resulting in everolimus discontinuation in one; one patient had hyperlipidemia and another had recurrent respiratory infections, which resolved with dose reduction. In conclusion, everolimus add\u2010on may be effective in substantially reducing seizures in patients with <jats:italic>NPRL2\u2010<\/jats:italic> and <jats:italic>NPRL3<\/jats:italic>\u2010related epilepsies. However, strict surveillance is required, especially in young patients.<\/jats:p>","DOI":"10.1111\/epi.18543","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T14:59:32Z","timestamp":1752332372000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Everolimus precision therapy in <i>NPRL2<\/i>\u2010 and <i>NPRL3<\/i>\u2010related epilepsy"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-3078","authenticated-orcid":false,"given":"Evelina","family":"Carapancea","sequence":"first","affiliation":[{"name":"Institute of NeuroScience (IoNS) Universit\u00e9 Catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1902-4865","authenticated-orcid":false,"given":"Erik A.","family":"Eklund","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Clinical Sciences Sk\u00e5ne University Hospital, Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9433-7998","authenticated-orcid":false,"given":"Helene","family":"Verhelst","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics Ghent University Hospital, University of Ghent  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2481-8053","authenticated-orcid":false,"given":"Maria Roberta","family":"Cilio","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Department of Pediatrics, Cliniques Universitaires Saint\u2010Luc, Institute of Neuroscience (IoNS) Universit\u00e9 Catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcab222"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010018\u20100060\u20102"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12798"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(16)31419\u20102"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15975"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1055\/a\u20102104\u20101614"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2019.10.007"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010017\u20100581\u20109"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12770"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1113747"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2023.03.004"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200345"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2599"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.722"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab451"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.18543","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T08:48:15Z","timestamp":1758617295000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.18543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,12]]},"references-count":16,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1111\/epi.18543"],"URL":"https:\/\/doi.org\/10.1111\/epi.18543","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,12]]},"assertion":[{"value":"2025-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}