{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:55:27Z","timestamp":1785491727303,"version":"3.56.0"},"reference-count":25,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS099452"],"award-info":[{"award-number":["R01NS099452"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R37NS125632"],"award-info":[{"award-number":["R37NS125632"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Pathogenic variants in Kaptin (KPTN) cause KPTN\u2010related disorder (KRD). KPTN modulates mTOR signaling activation within the KICSTOR complex in response to cellular amino acid levels. We define the clinical spectrum and investigate the developmental pathogenesis of KRD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We report the genotype and clinical phenotype of 71 KRD individuals (28 female subjects, ages 1 to 55\u2009years) including 48 newly identified KRD individuals. The effects of Kptn knockout on brain development were assayed in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We defined 15 novel\n                      <jats:italic>KPTN<\/jats:italic>\n                      variants. Intellectual disability (ID) was identified in all KRD individuals. Macrocephaly and epilepsy were observed in 46% and 47%, respectively. Neuroimaging revealed megalencephaly but no overt structural abnormalities. Ketotic hypoglycemia and endocrinopathies were identified in KRD. Increased head size was detected in unaffected parents heterozygous for\n                      <jats:italic>KPTN<\/jats:italic>\n                      variants. Two KRD individuals with drug\u2010resistant epilepsy were treated with the mTOR inhibitor sirolimus but did not exhibit improved seizure control. CRISPR\/Cas9 Kptn knockout in vitro induced mTOR activation and an mTOR\u2010dependent increase in cell size.\n                      <jats:italic>Kptn\u2212\/\u2212<\/jats:italic>\n                      mice exhibited increased cortical mTOR signaling that was reduced by rapamycin. Heterotopic neurons were identified in the subcortical white matter in the\n                      <jats:italic>Kptn \u2212\/\u2212<\/jats:italic>\n                      mouse. Focal CRISPR\/Cas9 Kptn knockout in cortex via in utero electroporation resulted in white matter heterotopic neurons. Electroencephalogram (EEG) did not detect ictal or inter\u2010ictal abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>KRD is a multisystem neurodevelopmental disorder associated with ID, macrocephaly, epilepsy, mTOR signaling hyperactivation, and in a mouse model, subtle structural alterations in cerebral cortical cytoarchitecture. ANN NEUROL 2026;99:1287\u20131302<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78159","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T11:45:44Z","timestamp":1771242344000},"page":"1287-1302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Clinical Spectrum and Neurodevelopmental Pathogenesis of\n                    <scp>\n                      <i>KPTN<\/i>\n                    <\/scp>\n                    \u2010Related Disorder in a Mouse Model"],"prefix":"10.1002","volume":"99","author":[{"given":"Lettie E.","family":"Rawlins","sequence":"first","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"},{"name":"Peninsula Clinical Genetics Service  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2203-188X","authenticated-orcid":false,"suffix":"II","given":"Philip H.","family":"Iffland","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Page","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Z.","family":"Flessner","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soad M.","family":"Elziny","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Sbornova","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice K.","family":"Babus","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie R.","family":"Bruckmeier","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Parikh","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merel","family":"Verhoeven","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7614-9202","authenticated-orcid":false,"given":"James","family":"Fasham","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"},{"name":"Peninsula Clinical Genetics Service  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Leslie","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0713-4602","authenticated-orcid":false,"given":"Richard","family":"Caswell","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishanka","family":"Ubeyratna","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Wenger","sequence":"additional","affiliation":[{"name":"New Leaf Center, Clinic for Special Children  Mount Eaton OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan M.","family":"Scott","sequence":"additional","affiliation":[{"name":"New Leaf Center, Clinic for Special Children  Mount Eaton OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-2497","authenticated-orcid":false,"given":"John","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Children's National Medical Center  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Syrbe","sequence":"additional","affiliation":[{"name":"Center for Child and Adolescent Medicine, Heidelberg University  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annick","family":"Klabunde\u2010Cherwon","sequence":"additional","affiliation":[{"name":"Center for Child and Adolescent Medicine, Heidelberg University  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Owens","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory (NHS South West Genomic Laboratory Hub), Royal Devon University Healthcare NHS Foundation Trust  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew H.","family":"Crosby","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6637-3411","authenticated-orcid":false,"given":"Emma L.","family":"Baple","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School  Exeter UK"},{"name":"Peninsula Clinical Genetics Service  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-3740","authenticated-orcid":false,"given":"Peter B.","family":"Crino","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the KPTN Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-1809.2000.6430189.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.10.001"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21423"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16370"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37105"},{"key":"e_1_2_9_7_1","first-page":"1","article-title":"Pathogenic variants in KPTN gene identified by clinical whole whole\u2010genome sequencing","volume":"1","author":"Thiffault I","year":"2018","journal-title":"J Gen Hereditary Case Stud"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61492"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61778"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-0610-3"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.1113811"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14390"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jdn.10231"},{"key":"e_1_2_9_14_1","volume-title":"GeneReviews((R))","author":"Rawlins LE","year":"1993"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad231"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19980228)17:4<407::AID-SIM742>3.0.CO;2-L"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-444-9_15"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005271"},{"key":"e_1_2_9_20_1","unstructured":"Data from: Allen Mouse Brain Atlas 2011. Available at:http:\/\/mouse.brain-map.org. Deposited 2004."},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm100"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.11.031"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41592"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38717"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2017.08.003"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.12.019"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78159","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78159","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78159","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:48:26Z","timestamp":1777092506000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,16]]},"references-count":25,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/ana.78159"],"URL":"https:\/\/doi.org\/10.1002\/ana.78159","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,16]]},"assertion":[{"value":"2025-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}