{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:22:06Z","timestamp":1773008526758,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2024\u2010160022OB\u2010100"],"award-info":[{"award-number":["PID2024\u2010160022OB\u2010100"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2021\u2010122201OB\u2010C21"],"award-info":[{"award-number":["PID2021\u2010122201OB\u2010C21"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["EFA031\/01 NEURO\u2010COOP"],"award-info":[{"award-number":["EFA031\/01 NEURO\u2010COOP"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["AC21_2\/00024"],"award-info":[{"award-number":["AC21_2\/00024"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["AC21_2\/00032"],"award-info":[{"award-number":["AC21_2\/00032"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013278","name":"EU Joint Programme \u2013 Neurodegenerative Disease Research","doi-asserted-by":"publisher","award":["JPND\u20102021\u2010650\u2010130"],"award-info":[{"award-number":["JPND\u20102021\u2010650\u2010130"]}],"id":[{"id":"10.13039\/100013278","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Inherited prion diseases follow autosomal dominant inheritance with a theoretical 50% transmission risk per pregnancy. Transmission ratio distortion (TRD)\u2014deviation from expected Mendelian ratios\u2014has been documented in other genetic disorders but never systematically studied in prionopathies. We aimed to determine whether TRD occurs in families with inherited prion diseases\u2014specifically familial Creutzfeldt\u2010Jakob disease due to the p.E200K variant and fatal familial insomnia caused by the p.D178N variant\u2014and to assess whether transmission patterns differ by parent sex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 24 pedigrees (12 per variant) comprising 65 nuclear families with 151 offspring. Transmission ratios were calculated and compared to expected 50% Mendelian inheritance using generalized estimating equations. Sex\u2010specific transmission patterns were evaluated for both maternal and paternal carriers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Overall transmission rates were 67.1% for p.D178N (95% CI: 56.3%\u201377.9%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and 70.5% for p.E200K (95% CI: 60.4%\u201380.6%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), representing deviations from expected Mendelian ratios. Sex\u2010specific analysis revealed maternal transmission of 67.5% for p.D178N (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and 67.3% for p.E200K (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Paternal transmission showed 66.7% for p.D178N (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.056) and 78.3% for p.E200K (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), with the latter showing pronounced paternal bias.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides the first systematic evidence of TRD in inherited prion diseases, with both variants showing clinically meaningful deviations from Mendelian inheritance. These findings challenge current genetic counseling assumptions of 50% inheritance risk and suggest that actual transmission probabilities are 17%\u201321% higher than traditionally estimated. Risk assessment protocols for prion diseases require updating to incorporate variant\u2010specific and sex\u2010specific transmission patterns, particularly the strong paternal bias observed with p.E200K.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70455","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T07:49:01Z","timestamp":1765007341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Risk of Transmission of Genetic Prion Diseases is Greater Than 50%"],"prefix":"10.1111","volume":"32","author":[{"given":"Izaro","family":"Kortazar\u2010Zubizarreta","sequence":"first","affiliation":[{"name":"Department of Neurology, Bioaraba Health Research Institute Araba University Hospital \u2010Txagorritxu  Vitoria\u2010Gasteiz Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Africa","family":"Manero\u2010Azua","sequence":"additional","affiliation":[{"name":"Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute Araba University Hospital  Vitoria\u2010Gasteiz Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hasier","family":"Era\u00f1a","sequence":"additional","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Prion Research Lab  Derio Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Carlos III National Health Institute  Madrid Spain"},{"name":"ATLAS Molecular Pharma S. L. Bizkaia Technology Park  Derio Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urko","family":"Aguire","sequence":"additional","affiliation":[{"name":"Research Unit, Osakidetza Basque Health Service, Barrualde\u2010Galdakao Integrated Health Organisation, Galdakao\u2010Usansolo Hospital  Galdakao Spain"},{"name":"Kronikgune Institute for Health Services Research  Barakaldo Spain"},{"name":"Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS)  Galdakao Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-1361","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Castilla","sequence":"additional","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Prion Research Lab  Derio Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Carlos III National Health Institute  Madrid Spain"},{"name":"IKERBASQUE, Basque Foundation for Science  Bilbao Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2424-5294","authenticated-orcid":false,"given":"Guiomar","family":"Perez de Nanclares","sequence":"additional","affiliation":[{"name":"Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute Araba University Hospital  Vitoria\u2010Gasteiz Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021600"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010genet\u2010112618\u2010043905"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390000437"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3948"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4221"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa042786"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2020.11574"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201559"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12719"},{"issue":"2","key":"e_1_2_12_11_1","first-page":"79","article-title":"Diseases Caused by Triplet Expansion","volume":"49","author":"Rosales\u2010Reynoso M. A.","year":"2009","journal-title":"Revue Neurologique"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1515\/tnsci\u20102022\u20100315"},{"issue":"1","key":"e_1_2_12_13_1","first-page":"109","article-title":"Segregation Distortion of the CTG Repeats at the Myotonic Dystrophy Locus","volume":"59","author":"Chakraborty R.","year":"1996","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35943"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad5169"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007745"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060376"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlac113"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1515\/sagmb\u20102015\u20100056"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1331390100"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.45.32153"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206357200"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.12.017"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/dnares\/dsaa019"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.4161\/pri.1.2.4346"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/380639a0"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211830200"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.4067\/s0716\u201097602006000100005"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmn004"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10815\u2010014\u20100344\u20107"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.4857.290"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105313442203"}],"container-title":["European Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.70455","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ene.70455","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.70455","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T08:04:09Z","timestamp":1771401849000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ene.70455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":31,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/ene.70455"],"URL":"https:\/\/doi.org\/10.1111\/ene.70455","archive":["Portico"],"relation":{},"ISSN":["1351-5101","1468-1331"],"issn-type":[{"value":"1351-5101","type":"print"},{"value":"1468-1331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70455"}}