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REVIEW PAPER
Rett syndrome: from diagnosis to treatment – current state of knowledge
1
Student Scientific Society, Department of Paediatric Neurology, Medical University, Lublin, Poland
2
Department of Paediatric Neurology, Medical University, Lublin, Poland
Corresponding author
Wiktoria Tochman
Student Scientific Society at the Department of Paediatric Neurology, Medical University, Lublin, Poland
Student Scientific Society at the Department of Paediatric Neurology, Medical University, Lublin, Poland
KEYWORDS
TOPICS
ABSTRACT
Introduction and objective:
Rett syndrome (RTT) is a rare, genetically determined neurodevelopmental disorder that represents one of the most frequent monogenic causes of severe intellectual disability in females. The aim of the study is to present the current state of knowledge on Rett syndrome, with particular emphasis on pathophysiology, clinical presentation, diagnostic criteria, and contemporary and emerging therapeutic strategies.
Review methods:
A comprehensive literature search was performed in the PubMed, Google Scholar and Scopus dabatases from 2001 – 2025 using mainly the key words: ‘‘Rett syndrome’’, ‘‘MECP2’’, ‘‘Rett syndrome treatment’’. Over 60% of the selected articles were published within the last five years.
Brief description of the state of knowledge:
Rett syndrome is mostly caused by mutations in the MECP2 gene, leading to impaired regulation of gene expression, synaptic dysfunction, and abnormalities in the functioning of multiple systems. The clinical presentation comprises developmental regression, severe neurological disorders and numerous somatic complications. The introduction of trofinetide is an important step in the treatment of RTT, although treatment remains mainly symptomatic.
Summary:
Further research into mechanisms of the disease and innovative therapeutic strategies is essential, not only for the development of more effective, disease-modifying treatments, but also to enable earlier diagnosis, better prognostic assessment, and most importantly, to improve long-term outcomes and quality of life of patients with Rett syndrome.
Rett syndrome (RTT) is a rare, genetically determined neurodevelopmental disorder that represents one of the most frequent monogenic causes of severe intellectual disability in females. The aim of the study is to present the current state of knowledge on Rett syndrome, with particular emphasis on pathophysiology, clinical presentation, diagnostic criteria, and contemporary and emerging therapeutic strategies.
Review methods:
A comprehensive literature search was performed in the PubMed, Google Scholar and Scopus dabatases from 2001 – 2025 using mainly the key words: ‘‘Rett syndrome’’, ‘‘MECP2’’, ‘‘Rett syndrome treatment’’. Over 60% of the selected articles were published within the last five years.
Brief description of the state of knowledge:
Rett syndrome is mostly caused by mutations in the MECP2 gene, leading to impaired regulation of gene expression, synaptic dysfunction, and abnormalities in the functioning of multiple systems. The clinical presentation comprises developmental regression, severe neurological disorders and numerous somatic complications. The introduction of trofinetide is an important step in the treatment of RTT, although treatment remains mainly symptomatic.
Summary:
Further research into mechanisms of the disease and innovative therapeutic strategies is essential, not only for the development of more effective, disease-modifying treatments, but also to enable earlier diagnosis, better prognostic assessment, and most importantly, to improve long-term outcomes and quality of life of patients with Rett syndrome.
REFERENCES (47)
1.
Neul JL, Benke TA, Marsh ED et al. The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. Am J Med Genet B Neuropsychiatr Genet. 2019 Jan;180(1):55–67. https://doi.org/10.1002/ajmg.b....
2.
Petriti U, Dudman DC, Scosyrev E et al. Global prevalence of Rett syndrome: systematic review and meta-analysis. Syst Rev. 2023 Jan 16;12(1):5. https://doi.org/10.1186/s13643....
3.
Neul JL, Percy AK, Benke TA, et al. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nat Med. 2023 Jun;29(6):1468–1475. https://doi.org/10.1038/s41591....
4.
Haase F, Singh R, Gloss B, et al. Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome. Int J Mol Sci. 2022 Sep 22;23(19):11125. https://doi.org/10.3390/ijms23....
5.
Abbas A, Fayoud AM, El Din Moawad MH, et al. Safety and efficacy of trofinetide in Rett syndrome: a systematic review and meta-analysis of randomized controlled trials. BMC Pediatr. 2024 Mar 23;24(1):206. https://doi.org/10.1186/s12887....
6.
Percy AK, Ananth A, Neul JL. Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs. 2024 Nov;38(11):851–867. https://doi.org/10.1007/s40263....
7.
Panayotis N, Ehinger Y, Felix MS, et al. State-of-the-art therapies for Rett syndrome. Dev Med Child Neurol. 2023 Feb;65(2):162–170. https://doi.org/10.1111/dmcn.1....
8.
Percy AK, Benke TA, Marsh ED et al. Rett syndrome: The Natural History Study Journey. Ann Child Neurol Soc. 2024;2(3):189–205. https://doi.org/10.1002/cns3.2....
9.
Percy AK, Lane JB, Childers J et al. Rett syndrome: North American database. J Child Neurol. 2007 Dec;22(12):1338–41. https://doi.org/10.1177/088307....
10.
Guy J, Hendrich B, Holmes M, et al. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001 Mar;27(3):322–6. https://doi.org/10.1038/85899.
11.
Chen RZ, Akbarian S, Tudor M, et al. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001 Mar;27(3):327–31. https://doi.org/10.1038/85906.
12.
Neul JL, Fang P, Barrish J, et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome Neurology. 2008 Apr 15;70(16):1313–21. https://doi.org/10.1212/01.wnl....
13.
Kishi N, MacDonald JL, Ye J, et al. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nat Commun. 2016 Jan 29;7:10520. https://doi.org/10.1038/ncomms....
14.
Ohashi M, Korsakova E, Allen D, et al. Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence. Stem Cell Reports. 2018 May 8;10(5):1453–1463. https://doi.org/10.1016/j.stem....
15.
Chao HT, Chen H, Samaco RC, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010 Nov 11;468(7321):263–9. https://doi.org/10.1038/nature....
16.
Ure K, Lu H, Wang W, et al. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife. 2016 Jun 21;5:e14198. https://doi.org/10.7554/eLife.....
17.
Musokhranova U, Grau C, Vergara C, et al. Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome. J Transl Med. 2023 Oct 26;21(1):756. https://doi.org/10.1186/s12967....
18.
Justice MJ, Buchovecky CM, Kyle SM, et al. A role for metabolism in Rett syndrome pathogenesis: New clinical findings and potential treatment targets. Rare Dis. 2013 Dec 18;1:e27265. https://doi.org/10.4161/rdis.2....
19.
Gold WA, Percy AK, Neul JL, et al. Rett syndrome. Nat Rev Dis Primers. 2024 Nov 7;10(1):84. https://doi.org/10.1038/s41572....
20.
Vilvarajan S, McDonald M, Douglas L, et al. Multidisciplinary Management of Rett Syndrome: Twenty Years’ Experience. Genes (Basel). 2023 Aug 11;14(8):1607. https://doi.org/10.3390/genes1....
21.
Pascual-Alonso A, Martínez-Monseny AF, Xiol C, et al. MECP2-Related Disorders in Males. Int J Mol Sci. 2021 Sep 4;22(17):9610. https://doi.org/10.3390/ijms22....
22.
McGraw SA, Smith-Hicks C, Nutter J, et al. Meaningful Improvements in Rett Syndrome: A Qualitative Study of Caregivers. J Child Neurol. 2023 Apr;38(5):270–282. https://doi.org/10.1177/088307....
23.
Pepe G, Coco R, Corica D, et al. Endocrine disorders in Rett syndrome: a systematic review of the literature. Front Endocrinol (Lausanne). 2024 Oct 31;15:1477227. https://doi.org/10.3389/fendo.....
24.
Downs J, Wong K, Leonard H. Associations between genotype, phenotype and behaviours measured by the Rett syndrome behaviour questionnaire in Rett syndrome. J Neurodev Disord. 2024 Oct 25;16(1):59. https://doi.org/10.1186/s11689....
25.
Rodocanachi Roidi ML, Cozzi F, Isaias IU, et al. Clinical and genetic correlations of scoliosis in Rett syndrome. Eur Spine J. 2022 Nov;31(11):2987–2993. https://doi.org/10.1007/s00586....
26.
Menachem S, Hershkovich O, Ackshota N et al. Scoliosis in RETT Syndrome: A National Referral Centre Experience. Clin Spine Surg. 2023 Mar 1;36(2):E75-E79. https://doi.org/10.1097/BSD.00....
27.
Weeda JE, van Kuijk SMJ, van den Berg MP, et al. Identification of Predictors for Progression of Scoliosis in Rett Syndrome. Dev Neurorehabil. 2024 Apr-May;27(3–4):126–133. https://doi.org/10.1080/175184....
28.
Fabio RA, Chiarini L, Canegallo V. Pain in Rett syndrome: a pilot study and a single case study on the assessment of pain and the construction of a suitable measuring scale. Orphanet J Rare Dis. 2022 Sep 14;17(1):356. https://doi.org/10.1186/s13023....
29.
Singh J, Lanzarini E, Nardocci N, et al. Movement disorders in patients with Rett syndrome: A systematic review of evidence and associated clinical considerations. Psychiatry Clin Neurosci. 2021 Dec;75(12):369–393. https://doi.org/10.1111/pcn.13....
30.
Layne CS, Young DR, Lee BC, et al. Kinematics associated with treadmill walking in Rett syndrome. Disabil Rehabil. 2021 Jun;43(11):1585–1593. https://doi.org/10.1080/096382....
31.
Zhang X, Smits M, Curfs L, et al. Sleep and the Social Profiles of Individuals With Rett Syndrome. Pediatr Neurol. 2024 Mar;152:153–161.https://doi.org/10.1016/j.pedi....
32.
Zhang XY, Spruyt K. Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome. Int J Environ Res Public Health. 2022 Mar 14;19(6):3422. https://doi.org/10.3390/ijerph....
33.
Ihekweazu FD, Motil KJ. Gastrointestinal manifestations of Rett syndrome: An updated analysis using the Gastrointestinal Health. Questionnaire. J Pediatr Gastroenterol Nutr. 2025 Jan;80(1):46–56. https://doi.org/10.1002/jpn3.1....
34.
Peron A, Canevini MP, Ghelma F, et al. Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition. J Med Genet. 2022 Jan;59(1):39–45. https://doi.org/10.1136/jmedge....
35.
Mendoza J, Downs J, Wong K, et al. Determinants of quality of life in Rett syndrome: new findings on associations with genotype. J Med Genet. 2021 Sep;58(9):637–644. https://doi.org/10.1136/jmedge....
36.
May DM, Neul J, Piña-Garza JE, et al. Gastrointestinal manifestations in pediatric and adult patients with Rett syndrome: an analysis of US claims and physician survey data. J Comp Eff Res. 2024 Jan;13(1):e230054. https://doi.org/10.57264/cer-2....
37.
Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010 Dec;68(6):944–50. https://doi.org/10.1002/ana.22....
38.
Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020 Sep 13;4(1):e000717. https://doi.org/10.1136/bmjpo-....
39.
Bricker K, Vaughn BV. Rett syndrome: a review of clinical manifestations and therapeutic approaches. Front Sleep. 2024 May 21;3:1373489. https://doi.org/10.3389/frsle.....
40.
Einspieler C, Marschik PB. Regression in Rett syndrome: Developmental pathways to its onset. Neurosci Biobehav Rev. 2019 Mar;98:320–332. https://doi.org/10.1016/j.neub....
41.
Lee JY, Leonard H, Piek JP, et al. Early development and regression in Rett syndrome. Clin Genet. 2013 Dec;84(6):572–6. https://doi.org/10.1111/cge.12....
42.
Fehr S, Wilson M, Downs J, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013 Mar;21(3):266–73. https://doi.org/10.1038/ejhg.2....
43.
Gold WA, Krishnarajy R, Ellaway C, et al. Rett Syndrome: A Genetic Update and Clinical Review Focusing on Comorbidities. ACS. Chem Neurosci. 2018 Feb 21;9(2):167–176. https://doi.org/10.1021/acsche....
44.
FDA Prescribing Information – DAYBUE (trofinetide). www.accessdata.fda.gov/drugsatfda_docs/label/2023/217026s000lbl.pdf (access: 2026.01.08).
45.
Percy AK, Neul JL, Benke TA, et al. Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study. Med. 2024 Sep 13;5(9):1178–1189.e3. https://doi.org/10.1016/j.medj....
46.
Campbell K, Neul JL, Lieberman DN, et al. A randomized, placebocontrolled, cross-over trial of ketamine in Rett syndrome. J Neurodev Disord. 2025 Jan 24;17(1):4. https://doi.org/10.1186/s11689....
47.
Rashid N, Darer JD, Ruetsch C, et al. Aspiration, respiratory complications, and associated healthcare resource utilization among individuals with Rett syndrome. Orphanet J Rare Dis. 2025 May 15;20(1):232. https://doi.org/10.1186/s13023....
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| ISSN: | 1898-2395 |
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