{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:36:07Z","timestamp":1787506567428,"version":"build-2736575974"},"reference-count":27,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["7R01FD006071-02 and 5R01FD006071-05"],"award-info":[{"award-number":["7R01FD006071-02 and 5R01FD006071-05"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003975","name":"Myotonic Dystrophy Foundation","doi-asserted-by":"publisher","award":["DMCRN 001"],"award-info":[{"award-number":["DMCRN 001"]}],"id":[{"id":"10.13039\/100003975","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Avidity Biosciences","award":["FP00013850"],"award-info":[{"award-number":["FP00013850"]}]},{"name":"Dyne Therapeutics","award":["FP00011118"],"award-info":[{"award-number":["FP00011118"]}]},{"DOI":"10.13039\/100011022","name":"Vertex Pharmaceuticals","doi-asserted-by":"publisher","award":["PO 7571439"],"award-info":[{"award-number":["PO 7571439"]}],"id":[{"id":"10.13039\/100011022","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007723","name":"Takeda Pharmaceuticals U.S.A.","doi-asserted-by":"publisher","award":["FP00019070"],"award-info":[{"award-number":["FP00019070"]}],"id":[{"id":"10.13039\/100007723","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PepGen Inc","award":["FP00019245"],"award-info":[{"award-number":["FP00019245"]}]},{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"publisher","award":["E005477258"],"award-info":[{"award-number":["E005477258"]}],"id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["FP00019023"],"award-info":[{"award-number":["FP00019023"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Arthex Biotech","award":["FP00021773"],"award-info":[{"award-number":["FP00021773"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited multi-system disorder that affects skeletal muscles but also many other organ systems. Molecular targets have been identified and targeted therapies are being developed and tested in first-in-human clinical trials. However, insufficient knowledge of the phenotypic heterogeneity and natural course of the disease, together with a lack of reliable biomarkers, complicate the design of clinical trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The main objectives of this study are to 1) characterize the phenotypic heterogeneity and disease progression of DM1 in a large cohort; 2) identify baseline characteristics that predict subsequent progression; 3) validate RNA biomarkers of disease severity. This is a prospective, multi-site observational study with a follow-up period of 24 months including approximately 700 adult DM1 patients. Visits will occur at baseline, and months 12 and 24. All patients will undergo strength testing, myotonia assessment, a battery of functional outcome assessments, spirometry, and complete various questionnaires and cognitive tests. Blood and urine samples will be taken at each visit for biomarker studies. A subset of 60 patients will undergo a muscle biopsy at baseline and at an additional 3-month visit. The sensitivity to disease progression and minimally clinically important differences will be determined for the various clinical outcome measures. Associations between baseline patient characteristics and the rate of disease progression will be evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The results of this large international study on DM1 will contribute to optimizing clinical trial design. Both data and biological samples will be collected for future research as well.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      Clinicaltrials.gov\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03981575\" xlink:type=\"simple\">NCT03981575<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0331163","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T18:26:57Z","timestamp":1765477617000},"page":"e0331163","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Establishing biomarkers and clinical endpoints in myotonic dystrophy type 1 (END-DM1): Protocol of an international natural history study"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8487-9478","authenticated-orcid":true,"given":"Karlien","family":"Mul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Eichinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria A.","family":"Sansone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Gagnon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sub","family":"Subramony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H.","family":"Roxburgh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Hamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Statland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakri","family":"Elsheikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacinda","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ragole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-8131","authenticated-orcid":true,"given":"Benedikt","family":"Schoser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Swenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chamindra","family":"Laverty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry","family":"Shieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3053-4057","authenticated-orcid":true,"given":"Ericka P.","family":"Greene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Wicklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Dekdebrun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Raymond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"DeSpain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Thornton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas E.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Myotonic Dystrophy Clinical Research Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"issue":"3","key":"pone.0331163.ref001","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1159\/000524734","article-title":"Global Prevalence of Myotonic Dystrophy: An Updated Systematic Review and Meta-Analysis","volume":"56","author":"Q Liao","year":"2022","journal-title":"Neuroepidemiology"},{"issue":"2","key":"pone.0331163.ref002","first-page":"385","article-title":"Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3\u2019 end of a transcript encoding a protein kinase family member","volume":"69","author":"JD Brook","year":"1992","journal-title":"Cell"},{"issue":"5049","key":"pone.0331163.ref003","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1126\/science.1546325","article-title":"Myotonic dystrophy mutation: an unstable CTG repeat in the 3\u2019 untranslated region of the gene","volume":"255","author":"M Mahadevan","year":"1992","journal-title":"Science"},{"issue":"3","key":"pone.0331163.ref004","doi-asserted-by":"crossref","first-page":"103489","DOI":"10.1016\/j.drudis.2023.103489","article-title":"The myotonic dystrophy type 1 drug development pipeline: 2022 edition","volume":"28","author":"M Pascual-Gilabert","year":"2023","journal-title":"Drug Discov Today"},{"issue":"16","key":"pone.0331163.ref005","doi-asserted-by":"crossref","first-page":"3558","DOI":"10.1093\/hmg\/dds185","article-title":"Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity","volume":"21","author":"F Morales","year":"2012","journal-title":"Hum Mol Genet"},{"issue":"11","key":"pone.0331163.ref006","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1007\/s00415-020-09970-6","article-title":"Change over time in ability to perform activities of daily living in myotonic dystrophy type 1","volume":"267","author":"E Landfeldt","year":"2020","journal-title":"J Neurol"},{"issue":"1","key":"pone.0331163.ref007","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13023-019-1088-3","article-title":"The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care","volume":"14","author":"M De Antonio","year":"2019","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0331163.ref008","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.nmd.2024.08.005","article-title":"Comprehensive four-year disease progression assessment of myotonic dystrophy type 1","volume":"43","author":"LA la Fontaine","year":"2024","journal-title":"Neuromuscul Disord"},{"issue":"1","key":"pone.0331163.ref009","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1186\/s12916-022-02591-y","article-title":"Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood","volume":"20","author":"OPTIMISTIC consortium","year":"2022","journal-title":"BMC Med"},{"issue":"3","key":"pone.0331163.ref010","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1212\/WNL.39.3.420","article-title":"Criteria for establishing the validity of genetic recombination in myotonic dystrophy","volume":"39","author":"RC Griggs","year":"1989","journal-title":"Neurology"},{"key":"pone.0331163.ref011","volume-title":"Aids to the Investigation of Peripheral Nerve Injuries","author":"MR Council","year":"1976"},{"issue":"3","key":"pone.0331163.ref012","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/ptj\/74.3.253","article-title":"Facioscapulohumeral dystrophy natural history study: standardization of testing procedures and reliability of measurements. The FSH DY Group","volume":"74","author":"KE Personius","year":"1994","journal-title":"Phys Ther"},{"issue":"1","key":"pone.0331163.ref013","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00455-013-9486-5","article-title":"Reliability of measurements of tongue and hand strength and endurance using the Iowa Oral Performance Instrument with healthy adults","volume":"29","author":"V Adams","year":"2014","journal-title":"Dysphagia"},{"key":"pone.0331163.ref014","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.nmd.2007.08.003","article-title":"Reliability and feasibility of the six minute walk test in subjects with myotonic dystrophy","volume":"17","author":"M Kierkegaard","year":"2007","journal-title":"Neuromuscul Disord"},{"issue":"2","key":"pone.0331163.ref015","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1519\/00139143-200608000-00004","article-title":"Reference values for the timed up and go test: a descriptive meta-analysis","volume":"29","author":"RW Bohannon","year":"2006","journal-title":"J Geriatr Phys Ther"},{"issue":"3","key":"pone.0331163.ref016","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/mus.27559","article-title":"Remote assessment of myotonic dystrophy type 1: A feasibility study","volume":"66","author":"J Hamel","year":"2022","journal-title":"Muscle Nerve"},{"issue":"11","key":"pone.0331163.ref017","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.nmd.2018.08.011","article-title":"Validation of the Nine Hole Peg Test as a measure of dexterity in myotonic dystrophy type 1","volume":"28","author":"C Cutell\u00e8","year":"2018","journal-title":"Neuromuscul Disord"},{"issue":"6","key":"pone.0331163.ref018","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1002\/mus.24097","article-title":"Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure","volume":"49","author":"C Heatwole","year":"2014","journal-title":"Muscle Nerve"},{"issue":"5","key":"pone.0331163.ref019","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.nmd.2010.03.010","article-title":"Rasch-built myotonic dystrophy type 1 activity and participation scale (DM1-Activ)","volume":"20","author":"MCE Hermans","year":"2010","journal-title":"Neuromuscul Disord"},{"issue":"1","key":"pone.0331163.ref020","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s00455-022-10486-6","article-title":"Diagnostic Accuracy of the Eating Assessment Tool-10 (EAT-10) in Screening Dysphagia: A Systematic Review and Meta-Analysis","volume":"38","author":"P-P Zhang","year":"2023","journal-title":"Dysphagia"},{"issue":"1","key":"pone.0331163.ref021","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/s12883-019-1452-x","article-title":"Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study","volume":"19","author":"S LoRusso","year":"2019","journal-title":"BMC Neurol"},{"issue":"5","key":"pone.0331163.ref022","doi-asserted-by":"crossref","first-page":"353","DOI":"10.2165\/00019053-199304050-00006","article-title":"The validity and reproducibility of a work productivity and activity impairment instrument","volume":"4","author":"MC Reilly","year":"1993","journal-title":"Pharmacoeconomics"},{"issue":"3","key":"pone.0331163.ref023","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0168-8510(90)90421-9","article-title":"EuroQol--a new facility for the measurement of health-related quality of life","volume":"16","author":"Group EuroQol","year":"1990","journal-title":"Health Policy"},{"issue":"4","key":"pone.0331163.ref024","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1097\/WAD.0000000000000587","article-title":"Mild Cognitive Impairment Subtype Performance in Comparison to Healthy Older Controls on the NIH Toolbox and Cogstate","volume":"37","author":"S Garcia","year":"2023","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"12","key":"pone.0331163.ref025","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1001\/archneur.61.12.1943","article-title":"Characterization of the pattern of cognitive impairment in myotonic dystrophy type 1","volume":"61","author":"A Modoni","year":"2004","journal-title":"Arch Neurol"},{"issue":"6","key":"pone.0331163.ref026","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1002\/ana.23992","article-title":"Splicing biomarkers of disease severity in myotonic dystrophy","volume":"74","author":"M Nakamori","year":"2013","journal-title":"Ann Neurol"},{"issue":"5","key":"pone.0331163.ref027","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1097\/00005650-199905000-00006","article-title":"Linking clinical relevance and statistical significance in evaluating intra-individual changes in health-related quality of life","volume":"37","author":"KW Wyrwich","year":"1999","journal-title":"Med Care"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331163","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T18:27:01Z","timestamp":1765477621000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331163"}},"subtitle":[],"editor":[{"given":"Julie","family":"Dumonceaux","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":27,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0331163","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]}}}