{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:13:37Z","timestamp":1791213217848,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,2,6]],"date-time":"2014-02-06T00:00:00Z","timestamp":1391644800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Children with neurofibromatosis\u20101 (NF1) are at risk for developing numerous nervous system abnormalities, including cognitive problems and brain tumors (optic pathway glioma). Currently, there are few prognostic factors that predict clinical manifestations or outcomes in patients, even in families with an identical <jats:italic>NF1<\/jats:italic> gene mutation. In this study, we leveraged <jats:italic>Nf1<\/jats:italic> genetically engineered mice (GEM) to define the potential role of sex as a clinically relevant modifier of NF1\u2010associated neuronal dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Deidentified clinical data were analyzed to determine the impact of sex on optic glioma\u2013associated visual decline in children with NF1. In addition, <jats:italic>Nf1<\/jats:italic> GEM were employed as experimental platforms to investigate sexually dimorphic differences in learning\/memory, visual acuity, retinal ganglion cell (RGC) death, and <jats:italic>Nf1<\/jats:italic> protein (neurofibromin)\u2010regulated signaling pathway function (Ras activity, cyclic adenosine monophosphate [cAMP], and dopamine levels).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Female patients with NF1\u2010associated optic glioma were twice as likely to undergo brain magnetic resonance imaging for visual symptoms and 3\u00d7 more likely to require treatment for visual decline than their male counterparts. As such, only female <jats:italic>Nf1<\/jats:italic> GEM exhibited a decrement in optic glioma\u2013associated visual acuity, shorter RGC axons, and attenuated cAMP levels. In contrast, only male <jats:italic>Nf1<\/jats:italic> GEM showed spatial learning\/memory deficits, increased Ras activity, and reduced dopamine levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Collectively, these observations establish sex as a major prognostic factor underlying neuronal dysfunction in NF1, and suggest that sex should be considered when interpreting future preclinical and clinical study results. Ann Neurol 2014;75:309\u2013316<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24093","type":"journal-article","created":{"date-parts":[[2013,12,28]],"date-time":"2013-12-28T03:38:49Z","timestamp":1388201929000},"page":"309-316","source":"Crossref","is-referenced-by-count":137,"title":["Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1"],"prefix":"10.1002","volume":"75","author":[{"given":"Kelly A.","family":"Diggs\u2010Andrews","sequence":"first","affiliation":[{"name":"Departments of Neurology Washington University School of Medicine Box 8111, 660 South Euclid Avenue St Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Departments of Neurology Washington University School of Medicine Box 8111, 660 South Euclid Avenue St Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Gianino","sequence":"additional","affiliation":[{"name":"Departments of Neurology Washington University School of Medicine Box 8111, 660 South Euclid Avenue St Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua B.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Pediatrics Washington University School of Medicine Box 8111, 660 South Euclid Avenue St Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David F.","family":"Wozniak","sequence":"additional","affiliation":[{"name":"Psychiatry Washington University School of Medicine Box 8111, 660 South Euclid Avenue St Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Gutmann","sequence":"additional","affiliation":[{"name":"Departments of Neurology Washington University School of Medicine Box 8111, 660 South Euclid Avenue St Louis MO"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,2,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.12.002"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(89)80137-4"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(94)70122-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/09297041003761993"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000179303.72345.ce"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2006.tb01268.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-011-9380-0"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-009-9179-4"},{"key":"e_1_2_8_10_1","first-page":"575","article-title":"Conference statement. 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