{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T13:58:54Z","timestamp":1747144734094,"version":"3.40.5"},"reference-count":47,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>We created WiTNNess as a hybrid prospective\/cross\u2010sectional observational study to simulate a clinical trial for infantile\u2010onset TNNT1 myopathy. Our aims were to identify populations for future trial enrollment, rehearse outcome assessments, specify endpoints, and refine trial logistics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eligible participants had biallelic pathogenic variants of <jats:italic>TNNT1<\/jats:italic> and infantile\u2010onset proximal weakness without confounding conditions. The primary endpoint was ventilator\u2010free survival. \u201cThriving\u201d was a secondary endpoint defined as the ability to swallow and grow normally without non\u2010oral feeding support. Endpoints of gross motor function included independent sitting and standing as defined by the Word Health Organization, a novel TNNT1 abbreviated motor score, and video mapping of limb movement. We recorded adverse events, concomitant medications, and indices of organ function to serve as comparators of safety in future trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sixteen children were enrolled in the aggregate cohort (6 prospective, 10 cross\u2010sectional; median census age 2.3\u2009years, range 0.5\u201313.8). Median ventilator\u2010free survival was 20.2\u2009months and probability of death or permanent mechanical ventilation was 100% by age 60\u2009months. All six children (100%) in the prospective arm failed to thrive by age 12\u2009months. Only 2 of 16 (13%) children in the aggregate cohort sat independently and none stood alone. Novel exploratory motor assessments also proved informative. Laboratory and imaging data suggest that primary manifestations of TNNT1 deficiency are restricted to skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>WiTNNess allowed us to streamline and economize the collection of historical control data without compromising scientific rigor, and thereby establish a sound operational framework for future clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51884","type":"journal-article","created":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T05:16:58Z","timestamp":1693027018000},"page":"1972-1984","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>WiTNNess<\/scp>: An international natural history study of infantile\u2010onset <scp>TNNT1<\/scp> myopathy"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-8657","authenticated-orcid":false,"given":"Kevin A.","family":"Strauss","sequence":"first","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"},{"name":"Department of Pediatrics Penn Medicine\u2010Lancaster General Hospital  Pennsylvania Lancaster USA"},{"name":"Department of Pediatrics UMass Chan Medical School  Worcester Massachusetts USA"},{"name":"Department of Molecular, Cell &amp; Cancer Biology UMass Chan Medical School  Worcester Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent J.","family":"Carson","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"},{"name":"Department of Pediatrics Penn Medicine\u2010Lancaster General Hospital  Pennsylvania Lancaster USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilienne","family":"Bolettieri","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariah","family":"Everett","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashton","family":"Bollinger","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren E.","family":"Bowser","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keturah","family":"Beiler","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Millie","family":"Young","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Edvardson","sequence":"additional","affiliation":[{"name":"ALYN Hospital Pediatric and Adolescent Rehabilitation Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nitay","family":"Fraenkel","sequence":"additional","affiliation":[{"name":"ALYN Hospital Pediatric and Adolescent Rehabilitation Center  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2438-2624","authenticated-orcid":false,"given":"Adele","family":"D'Amico","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Disorders, Department of Neurosciences IRCCS Bambino Ges\u00f9 Children's Hospital  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-4590","authenticated-orcid":false,"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Disorders, Department of Neurosciences IRCCS Bambino Ges\u00f9 Children's Hospital  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lokesh","family":"Lingappa","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Rainbow Children's Hospital  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devyani","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Cardiology Care for Children  Lancaster Pennsylvania USA"},{"name":"Department of Cardiology Nemours Children's Health  Wilmington Delaware USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda P.","family":"Lowes","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Iammarino","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2263-7569","authenticated-orcid":false,"given":"Lindsay N.","family":"Alfano","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karlla W.","family":"Brigatti","sequence":"additional","affiliation":[{"name":"Clinic for Special Children  Strasburg Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.01.006"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1086\/303089"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy233"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2022.01.014"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106714"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.09.005"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24885"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24528"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.52"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25685"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2021.03.001"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.325"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2016.08.004"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2019.199"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.02.013"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/mthe.1999.0019"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300246"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn4704"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19230-w"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.268177"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-01017-1"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2019.01.004"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011458"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32032"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI75199"},{"key":"e_1_2_8_27_1","first-page":"86","article-title":"WHO motor development study: windows of achievement for six gross motor development milestones","volume":"450","author":"Group WHOMGRS","year":"2006","journal-title":"Acta Paediatr Suppl"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1177\/15648265040251S106"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2021.05.021"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14230"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073813495959"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4962"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200056"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000140"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000010237"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14012"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-021-01022-5"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-021-00193-6"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.2c00589"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/03630269.2022.2099285"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00001-6"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01866-4"},{"key":"e_1_2_8_43_1","first-page":"47","article-title":"Reliability of motor development data in the WHO multicentre growth reference study","volume":"450","author":"Group WHOMGRS","year":"2006","journal-title":"Acta Paediatr Suppl"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01867-3"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.09.007"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2009.11.014"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0156696"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51884","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T21:22:22Z","timestamp":1700083342000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":47,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/acn3.51884"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51884","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"type":"print","value":"2328-9503"},{"type":"electronic","value":"2328-9503"}],"subject":[],"published":{"date-parts":[[2023,8,25]]},"assertion":[{"value":"2023-05-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}