Satya Sai Sri Narava, Sowmya Kucherlapati, Vinod Kumar Mugada, Srinivasa Rao Yarguntla
Satya Sai Sri Narava1*, Sowmya Kucherlapati1, Vinod Kumar Mugada1, Srinivasa Rao Yarguntla2
1Department of Pharmacy Practice, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.
2Department of Pharmaceutics, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.
Volume - 15,
Issue - 4,
Year - 2023
Rett syndrome is a neurodevelopmental disorder primarily affecting females, characterised by slowed growth, developmental regression, loss of fine motor skills, communication difficulties, and stereotypical hand movements. It is strongly associated with mutations in the MECP2 gene, while other variations have been linked to FOXG1 and CDKL5 mutations. This review provides an in-depth understanding of Rett syndrome, including its causes, symptoms, and available treatments. The epidemiology of Rett syndrome indicates a varying prevalence across different regions. Males with Rett syndrome, though rare, have been reported. The aetiology of Rett syndrome involves MECP2 mutations that lead to functional loss, affecting synapse development and maintenance. Mitochondrial dysfunction and oxidative stress have also been implicated in the disorder. Neuropathological findings reveal specific abnormalities in various brain regions. The symptoms of Rett syndrome include slowed head growth, abnormal gait, loss of intentional hand movements, breathing difficulties, and loss of speech. Complications such as metabolic issues, epilepsy, scoliosis, and gastrointestinal dysfunction are common. The diagnosis relies on clinical criteria and genetic testing for MECP2 mutations. Treatment for Rett syndrome is symptomatic and includes individualised rehabilitation therapies such as physical therapy, applied behaviour analysis, environmental enrichment, hydrotherapy, and music therapy. The review emphasises the importance of early intervention and family involvement in rehabilitation programmes.
Cite this article:
Satya Sai Sri Narava, Sowmya Kucherlapati, Vinod Kumar Mugada, Srinivasa Rao Yarguntla. A Review on Rett Syndrome: A Debilitating Neurodevelopmental Disorder. Research Journal of Pharmacology and Pharmacodynamics.2023;15(4):159-4. doi: 10.52711/2321-5836.2023.00029
Satya Sai Sri Narava, Sowmya Kucherlapati, Vinod Kumar Mugada, Srinivasa Rao Yarguntla. A Review on Rett Syndrome: A Debilitating Neurodevelopmental Disorder. Research Journal of Pharmacology and Pharmacodynamics.2023;15(4):159-4. doi: 10.52711/2321-5836.2023.00029 Available on: https://rjppd.org/AbstractView.aspx?PID=2023-15-4-3
1. Kaufmann WE, Stallworth JL, Everman DB, Skinner SA. Neurobiologically-based treatments in Rett syndrome: opportunities and challenges. Expert Opinion on Orphan Drugs. 2016;4(10):1043–55.
2. Díaz de León-Guerrero S, Pedraza-Alva G, Pérez-Martínez L. In sickness and in health: the role of methyl-CpG binding protein 2 in the central nervous system. European Journal of Neuroscience. 2011;33(9):1563–74.
3. Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, et al. Rett syndrome: Revised diagnostic criteria and nomenclature. Annals of Neurology. 2010 Dec;68(6):944–50
4. Masuyama T, Matsuo M, Jing JJ, Tabara Y, Kitsuki K, Yamagata H, et al. Classic Rett syndrome in a boy with R133C mutation of MECP2. Brain and Development. 2005;27(6):439–42.
5. Whitney R, Moharir M, Allen A, Cortez MA. Paroxysmal Alpha Activity in Rett Syndrome: A Case Report. Pediatric Neurology. 2014;51(3):421–5.
6. Dolce A, Ben-Zeev B, Naidu S, Kossoff EH. Rett Syndrome and Epilepsy: An Update for Child Neurologists. Pediatric Neurology. 2013;48(5):337–45.
7. Sarajlija A, Kisic-Tepavcevic D, Nikolic Z, Pavićević DS, Obradovic S, Djuric M, et al. Epidemiology of Rett Syndrome in Serbia: Prevalence, Incidence and Survival. Neuroepidemiology [Internet]. 2015;44(1):1–5.
8. Kozinetz CA, Skender ML, MacNaughton N, Almes MJ, Schultz RJ, Percy AK, et al. Epidemiology of Rett Syndrome: A Population-Based Registry. Pediatrics. 1993 Feb 1;91(2):445–50.
9. Chahil G. Rett Syndrome [Internet]. StatPearls - NCBI Bookshelf.Chahil G. Rett Syndrome [Internet]. StatPearls - NCBI Bookshelf.
10. Leonard H, Silberstein J, Falk R, Houwink-Manville I, Ellaway C, Raffaele LS, et al. Occurrence of Rett Syndrome in Boys. Journal of Child Neurology. 2001;16(5):333–8.
11. Vorsanova SG, Demidova IA, UlasVYu, Soloviev IV, Kazantzeva LZ, Yurov YB. Cytogenetic and molecular-cytogenetic investigation of Rett syndrome. NeuroReport. 1996;8(1):187–9.
12. Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001;56(11):1486–95.
13. Salomão Schwartzman J, Zatz M, dos Reis Vasquez L, Ribeiro Gomes R, Koiffmann CP, Fridman C, et al. Rett Syndrome in a Boy with a 47,XXY Karyotype. The American Journal of Human Genetics. 1999;64(6):1781–4.
14. Castro J, Mellios N, Sur M. Mechanisms and therapeutic challenges in autism spectrum disorders. Current Opinion in Neurology. 2013;26(2):154–9.
15. Topçu M, Akyerli C, Sayı A, Törüner GA, Koçoğlu SR, Cimbiş M, et al. Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. European Journal of Human Genetics. 2002;10(1):77–81.
16. Ohki I, Shimotake N, Fujita N, Jee J-G, Ikegami T, Nakao M, et al. Solution Structure of the Methyl-CpG Binding Domain of Human MBD1 in Complex with Methylated DNA. Cell. 2001;105(4):487–97.
17. Sharma K, Singh J, Pillai PP, Frost EE. Involvement of MeCP2 in Regulation of Myelin-Related Gene Expression in Cultured Rat Oligodendrocytes. Journal of Molecular Neuroscience [Internet]. 2015;57(2):176–84.
18. Weaving LS, Williamson SL, Bennetts B, Davis M, Ellaway CJ, Leonard H, et al. Effects of MECP2 Mutation Type, Location and X-inactivation in Modulating Rett Syndrome Phenotype. Am J Med Genet A [Internet]. 2003 [cited 2023 Jan 25];118A(2):103–14.
19. Villard L. MECP2 mutations in males. Journal of Medical Genetics. 2007;44(7):417–23.
20. Bülow P, Wenner PA, Faundez V, Bassell GJ. Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment Are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome. Front Cell Dev Biol. 2021;9.
21. Crivellari I, Pecorelli A, Cordone V, Marchi S, Pinton P, Hayek J, et al. Impaired mitochondrial quality control in Rett Syndrome. Arch BiochemBiophys [Internet]. 2021;700:108790.
22. Gibson JH, Slobedman B, H KN, Williamson SL, Minchenko D, El-Osta A, et al. Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain. BMC Neurosci. 2010;11(1).
23. Sierra C, VilasecaMA, Brandi N, Artuch R, Mira A, Nieto M, et al. Oxidative stress in Rett syndrome. Brain and Development. 2001;23:S236–9.
24. De Felice C, Ciccoli L, Leoncini S, Signorini C, Rossi M, Vannuccini L, et al. Systemic oxidative stress in classic Rett syndrome. Free Radical Biology and Medicine [Internet]. 2009;47(4):440–8.
25. Jellinger K, Seitelberger F, Opitz JM, Reynolds JF. Neuropathology of rett syndrome. American Journal of Medical Genetics. 1986;25(S1):259–88.
26. Reiss AL, Faruque F, Naidu S, Abrams M, Beaty T, Bryan RN, et al. Neuroanatomy of Rett syndrome: a volumetric imaging study. Annals of Neurology [Internet]. 1993 Aug 1 [cited 2020 Mar 23];34(2):227–34
27. Karaikovic EE, Daubs MD, Madsen RW, Gaines RWJ. Morphologic Characteristics of Human Cervical Pedicles. Spine [Internet]. 1997 Mar 1 [cited 2023 Jan 25];22(5):493.
28. Silke Grabherr, Egger C, Vilarino R, Campana L, Jotterand M, Fabrice Dedouit. Modern post-mortem imaging: an update on recent developments. 2017 Jun 7 [cited 2023 Jun 6];2(2):52–64.
29. Duncan Armstrong D. Neuropathology of Rett Syndrome. Journal of Child Neurology. 2005; 20(9):747–53.
30. Smeets EEJ, Pelc K, Dan B. Rett Syndrome. Molecular Syndromology [Internet]. 2011 [cited 2019 Oct 8];2(3-5):113–27.
31. Hagberg B. Clinical manifestations and stages of rett syndrome. Mental Retardation and Developmental Disabilities Research Reviews. 2002; 8(2):61–5.
32. Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J, et al. Cholesterol Metabolism Is Altered in Rett Syndrome: A Study on Plasma and Primary Cultured Fibroblasts Derived from Patients. Landsberger N, editor. PLoS ONE. 2014;9(8):e104834.
33. Justice MJ, Buchovecky CM, Kyle SM, Djukic A. A role for metabolism in Rett syndrome pathogenesis. Rare Dis. 2013;1(1):e27265.
34. Blardi P, de Lalla A, D’Ambrogio T, Vonella G, Ceccatelli L, Auteri A, et al. Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clinical Endocrinology. 2009 May;70(5):706–9.
35. Acampa M, Guideri F, Hayek J, Blardi P, Lalla AD, Zappella M, et al. Sympathetic overactivity and plasma leptin levels in Rett syndrome. Neuroscience Letters [Internet]. 2008 [cited 2023 Jan 25];432(1):69.
36. Hanefeld F, Christen H-J ., Holzbach U, Kruse B, Frahm J, Hänicke W. Cerebral Proton Magnetic Resonance Spectroscopy in Rett Syndrome. Neuropediatrics. 1995;26(02):126–7.
37. Matsuishi T, Urabe F, Percy AK, Komori H, Yamashita Y, Schultz RS, et al. Abnormal Carbohydrate Metabolism in Cerebrospinal Fluid in Rett Syndrome. Journal of Child Neurology. 1994;9(1):26–30.
38. Horska A, Naidu S, Herskovits EH, Wang PY, Kaufmann WE, Barker PB. Quantitative 1H MR spectroscopic imaging in early Rett syndrome. Neurology. 2000;54(3):715–5.
39. Pintaudi M, Calevo MG, Vignoli A, Parodi E, Aiello F, Baglietto MG, et al. Epilepsy in Rett syndrome: Clinical and genetic features. Epilepsy and Behavior. 2010;19(3):296–300.
40. Nissenkorn A, Levy-Drummer RS, Bondi O, Renieri A, Villard L, Mari F, et al. Epilepsy in Rett syndrome-Lessons from the Rett networked database. Epilepsia. 2015;56(4):569–76.
41. Jian L, Nagarajan L, de Klerk N, Ravine D, Christodoulou J, Leonard H. Seizures in Rett syndrome: An overview from a one-year calendar study. European Journal of Paediatric Neurology [Internet]. 2007 Sep [cited 2019 Dec 13];11(5):310–7.
42. Bao X, Downs J, Wong K, Williams S, Leonard H. Using a large international sample to investigate epilepsy in Rett syndrome. Developmental Medicine and Child Neurology. 2013 Feb 19;55(6):553–8.
43. Krajnc, N. Management of epilepsy in patients with Rett syndrome: perspectives and considerations. Therapeutics and Clinical Risk Management.2015; 11: 925–932.
44. Ramirez JM, MarlusaKarlen-Amarante, Jia-Der Ju Wang, Huff A, Burgraff NJ. Breathing disturbances in Rett Syndrome. 2022 [cited 2023 Jun 6];139–51.
45. Huang TJ, Lubicky JP, Hammerberg KW. Scoliosis in Rett syndrome. Orthopaedic Review [Internet]. 1994 [cited 2023 Jan 25];23(12):931–7.
46. Percy AK. Rett syndrome. Neurologic Clinics. 2002; 20(4):1125–41.
47. Dr. Om Prakash Singh. Indian Journal of Psychiatry [Internet]. journals.lww.com. 2023.
48. Renieri A. Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant) [Internet]. 2009.
49. Smith-Hicks CL, Gupta S, Ewen JB, Hong M, Kratz L, Kelley R, et al. Randomized open-label trial of dextromethorphan in Rett syndrome. Neurology. 2017; 89(16):1684–90.
50. Fonzo M, Sirico F, Corrado B. Evidence-Based Physical Therapy for Individuals with Rett Syndrome: A Systematic Review. Brain Sciences. 2020; 10(7):410.
51. Jones RSP, McCaughey RE. Gentle Teaching and Applied Behavior Analysis: A Critical Review. Journal of Applied Behavior Analysis. 1992; 25(4):853–67.
52. Downs J, Rodger J, Li C, Tan X, Hu N, Wong K, et al. Environmental enrichment intervention for Rett syndrome: an individually randomised stepped wedge trial. Orphanet Journal of Rare Diseases. 2018; 13(1).
53. Bumin G, Uyanik M, Yilmaz I, Kayihan H, Topçu M, Topc¸u M, et al. Hydrotherapy for Rett Syndrome. Journal of Rehabilitation Medicine. 2003; 35(1):44–5.
54. Wesecky A, Opitz JM, Reynolds JF. Music therapy for children with rett syndrome. American Journal of Medical Genetics. 1986; 25(S1):253–7.
55. Luljeta. The Rett syndrome—Clinical presentation of the first 9 Albanian cases. vdocuments.site [Internet]. 2022.