{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T14:48:29Z","timestamp":1788187709552,"version":"build-2803163510"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Unidade Local de Sa\u00fade de Coimbra"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Rett syndrome (RTT) is a neurological disorder caused by mutations in the\n                    <jats:italic>MECP2<\/jats:italic>\n                    gene. It is characterized by apparently normal early neurodevelopment followed by psychomotor regression between 6 and 18\u00a0months. There is no cure, and treatment is multidisciplinary, focusing on improving quality of life and functionality. This study aims to characterize RTT patients and evaluate clinical patterns, interventions, and outcomes. A retrospective cohort study was conducted of children diagnosed with RTT and a pathogenic\n                    <jats:italic>MECP2<\/jats:italic>\n                    variant, followed at a Portuguese tertiary pediatric hospital from 2010 to 2024. Electronic medical records were reviewed, and epidemiological and clinical data were collected. Twelve RTT patients were followed (91.7% female). The median age at symptom onset was 15\u00a0months, and at diagnosis, 35\u00a0months. Seven patients (58.3%) had classic RTT. Molecular analysis identified 10 different\n                    <jats:italic>MECP2<\/jats:italic>\n                    variants, all de novo mutations. Epilepsy and constipation were the most common comorbidities. Five patients (41.7%) were wheelchair-dependent, and two required non-invasive respiratory support. Almost all patients received physical, occupational, and speech therapies. The median number of chronic medications per patient was two, primarily anticonvulsants. The median number of medical specialties per patient was two, with neuropediatrics and neurodevelopmental pediatrics being the most frequent.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusions<\/jats:italic>\n                    :\u00a0RTT prevalence remained stable over 20 years, with a decreased median age at diagnosis, likely due to increased awareness and genetic testing. No clear genotype\u2013phenotype correlation was found. RTT diagnosis remains based on clinical features, particularly neurodevelopmental regression. A multidisciplinary approach was critical, with patients receiving various therapies and support. This study provides valuable insights into RTT in Portugal, contributing to global knowledge.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:table-wrap>\n                      <jats:table>\n                        <jats:tbody>\n                          <jats:tr>\n                            <jats:td colspan=\"2\">\n                              <jats:bold>What is known:<\/jats:bold>\n                              \u2022\n                              <jats:italic>Rett syndrome is a rare neurodevelopmental disorder primarily affecting females, characterized by regression of motor and communication skills<\/jats:italic>\n                              .\u2022\n                              <jats:italic>Limited long-term data exist on clinical progression and functional outcomes in pediatric Rett syndrome<\/jats:italic>\n                              .\n                            <\/jats:td>\n                          <\/jats:tr>\n                          <jats:tr>\n                            <jats:td colspan=\"2\">\n                              <jats:bold>What is new:<\/jats:bold>\n                              \u2022\n                              <jats:italic>A decreasing age at diagnosis was observed, likely reflecting increased awareness and access to genetic testing<\/jats:italic>\n                              .\u2022\n                              <jats:italic>In an era of promising clinical trials for potential curative treatments, an individualized, multidisciplinary approach remains the standard of care in most countries, including Portugal<\/jats:italic>\n                              .\n                            <\/jats:td>\n                          <\/jats:tr>\n                        <\/jats:tbody>\n                      <\/jats:table>\n                    <\/jats:table-wrap>\n                  <\/jats:p>","DOI":"10.1007\/s00431-025-06291-6","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T10:47:45Z","timestamp":1751539665000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Clinical and functional outcomes in pediatric patients with Rett syndrome: a 15-year retrospective study"],"prefix":"10.1007","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1556-9737","authenticated-orcid":false,"given":"Mariana Cortez","family":"Ferreira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7442-354X","authenticated-orcid":false,"given":"Joana","family":"De Beir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1856-5355","authenticated-orcid":false,"given":"Maria In\u00eas","family":"Barreto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5712-3106","authenticated-orcid":false,"given":"Joana Afonso","family":"Ribeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5895-0242","authenticated-orcid":false,"given":"Cristina","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-1277","authenticated-orcid":false,"given":"Guiomar","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"6291_CR1","doi-asserted-by":"publisher","unstructured":"Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S (2023) Global prevalence of Rett syndrome: systematic review and meta-analysis. Syst Rev 12. https:\/\/doi.org\/10.1186\/s13643-023-02169-6","DOI":"10.1186\/s13643-023-02169-6"},{"key":"6291_CR2","unstructured":"Santos MJP (2007) Pathogenesis of rett syndrome and study of the role of MeCP2 protein in neuronal function. Universidade do Porto (Portugal). Available at: https:\/\/hdl.handle.net\/10216\/7217"},{"key":"6291_CR3","doi-asserted-by":"publisher","unstructured":"Ivy AS, Standridge SM (2021) Rett syndrome: a timely review from recognition to current clinical approaches and clinical study updates. Semin Pediatr Neurol 37. https:\/\/doi.org\/10.1016\/j.spen.2021.100881","DOI":"10.1016\/j.spen.2021.100881"},{"key":"6291_CR4","doi-asserted-by":"publisher","unstructured":"Vashi N, Justice MJ (2019) Treating rett syndrome: from mouse models to human therapies. Mamm Genome 30. https:\/\/doi.org\/10.1007\/s00335-019-09793-5","DOI":"10.1007\/s00335-019-09793-5"},{"key":"6291_CR5","doi-asserted-by":"publisher","unstructured":"Huppke P, Held M, Hanefeld F et al (2002) Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. Neuropediatrics 33. https:\/\/doi.org\/10.1055\/s-2002-32365","DOI":"10.1055\/s-2002-32365"},{"key":"6291_CR6","doi-asserted-by":"publisher","unstructured":"May DM, Neul JL, Satija A et al (2023) Real-world clinical management of individuals with Rett syndrome: a physician survey. J Med Econ 26. https:\/\/doi.org\/10.1080\/13696998.2023.2286778","DOI":"10.1080\/13696998.2023.2286778"},{"key":"6291_CR7","doi-asserted-by":"publisher","unstructured":"Neul JL, Kaufmann WE, Glaze DG et al (2010) Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 68. https:\/\/doi.org\/10.1002\/ana.22124","DOI":"10.1002\/ana.22124"},{"key":"6291_CR8","doi-asserted-by":"publisher","unstructured":"Amoako AN, Hare DJ (2020) Non-medical interventions for individuals with Rett syndrome: a systematic review. J Appl Res Intellect Disabil 33.https:\/\/doi.org\/10.1111\/jar.12694","DOI":"10.1111\/jar.12694"},{"key":"6291_CR9","doi-asserted-by":"publisher","unstructured":"Fehr S, Bebbington A, Nassar N et al (2011) Trends in the diagnosis of rett syndrome in Australia. Pediatr Res 70. https:\/\/doi.org\/10.1203\/PDR.0b013e3182242461","DOI":"10.1203\/PDR.0b013e3182242461"},{"key":"6291_CR10","doi-asserted-by":"publisher","unstructured":"Vilvarajan S, McDonald M, Douglas L et al (2023) Multidisciplinary management of Rett syndrome: twenty years\u2019 experience. Genes (Basel) 14. https:\/\/doi.org\/10.3390\/genes14081607","DOI":"10.3390\/genes14081607"},{"key":"6291_CR11","doi-asserted-by":"publisher","unstructured":"Top\u00e7u M, Akyerli C, Sayi A et al (2002) Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. Eur J Hum Genet 10. https:\/\/doi.org\/10.1038\/sj.ejhg.5200745","DOI":"10.1038\/sj.ejhg.5200745"},{"key":"6291_CR12","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.pediatrneurol.2024.09.022","volume":"161","author":"A Ananth","year":"2024","unstructured":"Ananth A, Fu C, Neul JL et al (2024) MECP2 variants in males: more common than previously appreciated. Pediatr Neurol 161:263\u2013267. https:\/\/doi.org\/10.1016\/j.pediatrneurol.2024.09.022","journal-title":"Pediatr Neurol"},{"key":"6291_CR13","doi-asserted-by":"publisher","unstructured":"Haymond M, Kappelgaard AM, Czernichow P et al (2013) Early recognition of growth abnormalities permitting early intervention. Acta Paediatr 102. https:\/\/doi.org\/10.1111\/apa.12266","DOI":"10.1111\/apa.12266"},{"key":"6291_CR14","doi-asserted-by":"publisher","unstructured":"Hanzlik E, Gigante J (2017) Microcephaly. Children 4. https:\/\/doi.org\/10.3390\/children4060047","DOI":"10.3390\/children4060047"},{"key":"6291_CR15","doi-asserted-by":"publisher","unstructured":"Fisher RS, Acevedo C, Arzimanoglou A et al (2014) ILAE Official Report: a practical clinical definition of epilepsy. Epilepsia 55. https:\/\/doi.org\/10.1111\/epi.12550","DOI":"10.1111\/epi.12550"},{"key":"6291_CR16","doi-asserted-by":"publisher","unstructured":"Lord C, Rutter M, Le Couteur A (1994) Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24. https:\/\/doi.org\/10.1007\/BF02172145","DOI":"10.1007\/BF02172145"},{"key":"6291_CR17","doi-asserted-by":"publisher","unstructured":"Lord C, Rutter M, Goode S et al (1989) Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 19. https:\/\/doi.org\/10.1007\/BF02211841","DOI":"10.1007\/BF02211841"},{"key":"6291_CR18","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association","DOI":"10.1176\/appi.books.9780890425596"},{"key":"6291_CR19","doi-asserted-by":"publisher","unstructured":"Tarquinio DC, Hou W, Neul JL et al (2015) Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis. Pediatr Neurol 52. https:\/\/doi.org\/10.1016\/j.pediatrneurol.2015.02.007","DOI":"10.1016\/j.pediatrneurol.2015.02.007"},{"key":"6291_CR20","doi-asserted-by":"publisher","unstructured":"Anderson A, Wong K, Jacoby P et al (2014) Twenty years of surveillance in Rett syndrome: what does this tell us? Orphanet J Rare Dis 9. https:\/\/doi.org\/10.1186\/1750-1172-9-87","DOI":"10.1186\/1750-1172-9-87"},{"key":"6291_CR21","doi-asserted-by":"publisher","unstructured":"Coutinho AM, Oliveira G, Katz C et al (2007) MECP2 coding sequence and 3\u2032UTR variation in 172 unrelated autistic patients. Am J Med Genet B Neuropsychiatr Genet 144. https:\/\/doi.org\/10.1002\/ajmg.b.30490","DOI":"10.1002\/ajmg.b.30490"},{"key":"6291_CR22","doi-asserted-by":"publisher","unstructured":"Temudo T, Santos M, Ramos E et al (2011) Rett syndrome with and without detected MECP2 mutations: an attempt to redefine phenotypes. Brain Dev 33. https:\/\/doi.org\/10.1016\/j.braindev.2010.01.004","DOI":"10.1016\/j.braindev.2010.01.004"},{"key":"6291_CR23","doi-asserted-by":"publisher","unstructured":"Temudo T, Ramos E, Dias K et al (2008) Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Movement Disorders 23. https:\/\/doi.org\/10.1002\/mds.22115","DOI":"10.1002\/mds.22115"},{"key":"6291_CR24","doi-asserted-by":"publisher","unstructured":"Bebbington A, Anderson A, Ravine D et al (2008) Investigating genotype-phenotype relationships in Rett syndrome using an international data set. Neurology 70. https:\/\/doi.org\/10.1212\/01.wnl.0000304752.50773.ec","DOI":"10.1212\/01.wnl.0000304752.50773.ec"},{"key":"6291_CR25","doi-asserted-by":"publisher","unstructured":"Neul JL, Fang P, Barrish J et al (2008) Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70. https:\/\/doi.org\/10.1212\/01.wnl.0000291011.54508.aa","DOI":"10.1212\/01.wnl.0000291011.54508.aa"},{"key":"6291_CR26","doi-asserted-by":"publisher","unstructured":"Einspieler C, Kerr AM, Prechtl HFR (2005) Abnormal general movements in girls with Rett disorder: the first four months of life. Brain Dev 27. https:\/\/doi.org\/10.1016\/j.braindev.2005.03.014","DOI":"10.1016\/j.braindev.2005.03.014"},{"key":"6291_CR27","doi-asserted-by":"publisher","unstructured":"Einspieler C, Kerr AM, Prechtl HFR (2005) Is the early development of girls with Rett disorder really normal? Pediatr Res 57. https:\/\/doi.org\/10.1203\/01.PDR.0000155945.94249.0A","DOI":"10.1203\/01.PDR.0000155945.94249.0A"},{"key":"6291_CR28","doi-asserted-by":"publisher","unstructured":"Cabral A, Oliveira G, Saraiva JM (2001) S\u00edndroma de Rett. Um Caso Cl\u00ednico com Confirma\u00e7\u00e3o Molecular. Acta Pediatr Port 32.https:\/\/doi.org\/10.25754\/pjp.2001.5237","DOI":"10.25754\/pjp.2001.5237"},{"key":"6291_CR29","unstructured":"Ricardo H (2012) S\u00edndrome de Rett: revis\u00e3o casu\u00edstica. Universidade de Coimbra (Portugal). Available at: https:\/\/hdl.handle.net\/10316\/48434"},{"key":"6291_CR30","doi-asserted-by":"publisher","unstructured":"Operto FF, Mazza R, Pastorino GMG et al (2019) Epilepsy and genetic in Rett syndrome: a review. Brain Behav 9. https:\/\/doi.org\/10.1002\/brb3.1250","DOI":"10.1002\/brb3.1250"},{"key":"6291_CR31","doi-asserted-by":"publisher","unstructured":"Tarquinio DC, Hou W, Berg A et al (2017) Longitudinal course of epilepsy in Rett syndrome and related disorders. Brain 140. https:\/\/doi.org\/10.1093\/brain\/aww302","DOI":"10.1093\/brain\/aww302"},{"key":"6291_CR32","doi-asserted-by":"publisher","unstructured":"Steffenburg U, Hagberg G, Hagberg B (2001) Epilepsy in a representative series of Rett syndrome. Acta Paediatrica, Int J Paediatr 90. https:\/\/doi.org\/10.1080\/080352501750064842","DOI":"10.1080\/080352501750064842"},{"key":"6291_CR33","doi-asserted-by":"publisher","unstructured":"Pintaudi M, Calevo MG, Vignoli A et al (2010) Epilepsy in Rett syndrome: clinical and genetic features. Epilepsy and Behavior 19. https:\/\/doi.org\/10.1016\/j.yebeh.2010.06.051","DOI":"10.1016\/j.yebeh.2010.06.051"},{"key":"6291_CR34","doi-asserted-by":"publisher","unstructured":"Krajnc N (2015) Management of epilepsy in patients with rett syndrome: perspectives and considerations. Ther Clin Risk Manag 11. https:\/\/doi.org\/10.2147\/TCRM.S55896","DOI":"10.2147\/TCRM.S55896"},{"key":"6291_CR35","doi-asserted-by":"publisher","unstructured":"Fu C, Armstrong D, Marsh E et al (2020) Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open 4. https:\/\/doi.org\/10.1136\/bmjpo-2020-000717","DOI":"10.1136\/bmjpo-2020-000717"},{"key":"6291_CR36","doi-asserted-by":"publisher","unstructured":"Neul JL, Percy AK, Benke TA et al (2023) Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nat Med 29. https:\/\/doi.org\/10.1038\/s41591-023-02398-1","DOI":"10.1038\/s41591-023-02398-1"},{"key":"6291_CR37","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1007\/s40263-024-01106-y","volume":"38","author":"AK Percy","year":"2024","unstructured":"Percy AK, Ananth A, Neul JL (2024) Rett syndrome: the emerging landscape of treatment strategies. CNS Drugs 38:851\u2013867. https:\/\/doi.org\/10.1007\/s40263-024-01106-y","journal-title":"CNS Drugs"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-025-06291-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-025-06291-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-025-06291-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T20:03:13Z","timestamp":1754337793000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-025-06291-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["6291"],"URL":"https:\/\/doi.org\/10.1007\/s00431-025-06291-6","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,3]]},"assertion":[{"value":"10 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Approval was obtained from the Ethics Committee of\n                      Unidade Local de Sa\u00fade de Coimbra\n                      (process number PI 2024-ESI.SF-267). All the methods included in this study are in accordance with the declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from the parents.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors authorize publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"465"}}