{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T20:20:22Z","timestamp":1773346822830,"version":"3.50.1"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In children with Rett syndrome, this study aimed to (1) describe gross motor skill trajectories; and (2) analyse the influences of genetic variant and comorbidities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a prospective longitudinal study conducted at the Danish National Center for Rett Syndrome 2008 to 2022. The Rett Syndrome Gross Motor Scale (RSGMS) was administered, and clinical data collected at each visit. Mixed-effects linear regression models were used to analyze the effects of age, genetic variant and comorbidities on gross motor skills. Clinical records data were reviewed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Data for 33 children with a mean age of 7.3\u202fyears (SD 1.2) at first visit were followed for a mean duration of 6.8\u202fyears (SD 2.1). The mean RSGMS score was 24.0 (SD 13.2, total of 45) at baseline. Adjusting for age and genetic variant, all severity levels of epilepsy, autonomic breathing dysfunction and scoliosis, except for surgically corrected scoliosis, were associated with a 4-point decrease in RSGMS score every 5 years. Acute escalation of seizures, change in muscle tone, orthopedic surgeries and bone fracture could be associated capacity to maintain gross motor skills.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We identified decline in gross motor skills during childhood. This novel natural history data can assist with interpretation of changes in gross motor skills following the administration of new therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2025.1702703","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:23:05Z","timestamp":1769664185000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Longitudinal trajectory of gross motor skills in school-aged children with Rett syndrome"],"prefix":"10.3389","volume":"16","author":[{"given":"Anne-Marie","family":"Bisgaard","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Center for Rett Syndrome, Rigshospitalet","place":["Copenhagen, Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kingsley","family":"Wong","sequence":"additional","affiliation":[{"name":"The Kids Research Institute Australia, University of Western Australia","place":["Perth, WA, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Katrine","family":"H\u00f8jfeldt","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Center for Rett Syndrome, Rigshospitalet","place":["Copenhagen, Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Stahlhut","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Center for Rett Syndrome, Rigshospitalet","place":["Copenhagen, Denmark"]},{"name":"Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital","place":["Copenhagen, Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny","family":"Downs","sequence":"additional","affiliation":[{"name":"The Kids Research Institute Australia, University of Western Australia","place":["Perth, WA, Australia"]},{"name":"Curtin School of Allied Health, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1203\/PDR.0b013e3182242461","article-title":"Trends in the diagnosis of Rett syndrome in Australia","volume":"70","author":"Fehr","year":"2011","journal-title":"Pediatr Res"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1111\/cge.13473","article-title":"Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements","volume":"95","author":"Schonewolf-Greulich","year":"2019","journal-title":"Clin Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/s41431-019-0508-0","article-title":"Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database","volume":"28","author":"Nguengang Wakap","year":"2020","journal-title":"Eur J Hum Genet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/1096-8628(200022)97:2<147::AID-AJMG6>3.0.CO;2-O","article-title":"Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations","volume":"97","author":"Amir","year":"2000","journal-title":"Am J Med Genet"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"Rett syndrome: revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann Neurol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.ejpn.2015.07.004","article-title":"Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012","volume":"19","author":"Bisgaard","year":"2015","journal-title":"Eur J Paediatr Neurol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1080\/17518423.2017.1323970","article-title":"Early development in Rett syndrome - the benefits and difficulties of a birth cohort approach","volume":"21","author":"Marschik","year":"2018","journal-title":"Dev Neurorehabil"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nrneurol.2016.186","article-title":"Clinical and biological progress over 50 years in Rett syndrome","volume":"13","author":"Leonard","year":"2017","journal-title":"Nat Rev Neurol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1016\/S1474-4422(15)00199-4","article-title":"A roadmap for precision medicine in the epilepsies","volume":"14","year":"2015","journal-title":"Lancet Neurol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s13023-022-02240-w","article-title":"Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome","volume":"17","author":"Leonard","year":"2022","journal-title":"Orphanet J Rare Dis"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1186\/s13063-024-08678-6","article-title":"International workshop: what is needed to ensure outcome measures for Rett syndrome are fit-for-purpose for clinical trials? June 7, 2023, Nashville, USA","volume":"25","author":"Downs","year":"2024","journal-title":"Trials"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1177\/0883073811402688","article-title":"Change in gross motor abilities of girls and women with rett syndrome over a 3- to 4-year period","volume":"26","author":"Foley","year":"2011","journal-title":"J Child Neurol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"3683","DOI":"10.1002\/ajmg.a.62429","article-title":"Decline in gross motor skills in adult Rett syndrome; results from a Danish longitudinal study","volume":"185","author":"Bisgaard","year":"2021","journal-title":"Am J Med Genet A"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e0147555","DOI":"10.1371\/journal.pone.0147555","article-title":"Validating the Rett syndrome gross motor scale","volume":"11","author":"Downs","year":"2016","journal-title":"PLoS One"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13023-016-0418-y","article-title":"Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome","volume":"11","author":"Mangatt","year":"2016","journal-title":"Orphanet J Rare Dis"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/j.braindev.2018.03.010","article-title":"The course of awake breathing disturbances across the lifespan in Rett syndrome","volume":"40","author":"Tarquinio","year":"2018","journal-title":"Brain Dev"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1097\/BRS.0000000000001399","article-title":"The natural history of scoliosis in females with Rett syndrome","volume":"41","author":"Downs","year":"2016","journal-title":"Spine (Phila Pa 1976)"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1017\/cjn.2016.8","article-title":"The incidence and evolution of parkinsonian rigidity in Rett syndrome: a pilot study","volume":"43","author":"Humphreys","year":"2016","journal-title":"Can J Neurol Sci"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e000717","DOI":"10.1136\/bmjpo-2020-000717","article-title":"Consensus guidelines on managing Rett syndrome across the lifespan","volume":"4","author":"Fu","year":"2020","journal-title":"BMJ Paediatr Open"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1136\/jmedgenet-2013-102113","article-title":"Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome","volume":"51","author":"Cuddapah","year":"2014","journal-title":"J Med Genet"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/mrdd.10020","article-title":"Clinical manifestations and stages of Rett syndrome","volume":"8","author":"Hagberg","year":"2002","journal-title":"Ment Retard Dev Disabil Res Rev"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1111\/cge.12110","article-title":"Early development and regression in Rett syndrome","volume":"84","author":"Lee","year":"2013","journal-title":"Clin Genet"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.jpeds.2021.06.060","article-title":"Longitudinal evaluation of the stability of hand function in Rett syndrome","volume":"237","author":"Downs","year":"2021","journal-title":"J Pediatr"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1111\/cch.12243","article-title":"Spinal fusion in girls with Rett syndrome: post-operative recovery and family experiences","volume":"41","author":"Marr","year":"2015","journal-title":"Child Care Health Dev"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1093\/ptj\/pzz138","article-title":"Feasibility and effectiveness of an individualized 12-week \"uptime\" participation (U-PART) intervention in girls and women with Rett syndrome","volume":"100","author":"Stahlhut","year":"2020","journal-title":"Phys Ther"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1111\/dmcn.15436","article-title":"Can telehealth increase physical activity in individuals with Rett syndrome? A multicentre randomized controlled trial","volume":"65","author":"Downs","year":"2023","journal-title":"Dev Med Child Neurol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1152\/physiol.00008.2020","article-title":"The pathophysiology of Rett syndrome with a focus on breathing dysfunctions","volume":"35","author":"Ramirez","year":"2020","journal-title":"Physiology (Bethesda)"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1702703\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:15:31Z","timestamp":1771924531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1702703\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":27,"alternative-id":["10.3389\/fneur.2025.1702703"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1702703","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,29]]},"article-number":"1702703"}}