Rett Syndrome

Rett syndrome is a rare debilitating neurological disorder occurring mostly in females after 6-18 months of apparently normal development.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, which occurs worldwide in approximately one of every 10,000 to 15,000 female births (6,000 to 9,000 patients in the US).1,2 While the majority of patients are females, males who meet the criteria for RTT have also been reported.3

In ~95% of patients diagnosed with classic RTT, the disease is caused by mutations in the X-linked MECP2 gene.4 MECP2 encodes methyl-CpG binding protein 2 (MeCP2) which modulates gene expression by binding to methylated CpG dinucleotides, primarily by activating but also by repressing transcription.5-8 The activity of the MeCP2 protein is diminished in both neurons and astrocytes in individuals with RTT.9

RTT is diagnosed based on clinical evaluation, typically by 3 years of age, with confirmatory genetic testing used to determine the presence and type of underlying mutations.10,11 The diagnostic criteria for RTT reflect the current understanding of the clinical features of RTT, which include disturbances in ambulation, hand use, language, growth and muscle tone abnormalities, breathing and sleep disturbances, and other manifestations.10 Although underlying mutations in genes such as MEPC2 are neither necessary nor sufficient for diagnosis, mutational analysis can help predict severity in order to better prepare for the needs of individuals with RTT.10,12 

Individuals with RTT undergo seemingly normal development until approximately 6 months of age, then the manifestations of RTT begin to appear progressively over several stages: developmental stagnation (age 6-18 months), sudden developmental regression (age 1-4 years), pseudostationary/plateau (age 2 years-potentially life), and motor deterioration (age 10 years-life).13,14 They experience profound functional impairment related to the central nervous system, such as a loss of speech/communication skills (including eye contact), loss of purposeful hand use (fine motor skills), development of hand stereotypies, absent or impaired mobility (gross motor skills), respiratory dysfunction, and seizures.13,14 Neurobehavioral impairments are prevalent in RTT, including disruptive and anxiety-like behaviors as well as mood dysregulation and sleep disturbances.15  

RTT is a complex, multisystem disorder and individuals may experience a range of symptoms associated with the syndrome, including gastrointestinal complications, skeletal abnormalities, cardiac conduction problems, and neuroendocrine abnormalities.16,17 Individuals with RTT may require assistance for most activities of daily living.18 

References

1. National Institute of Neurological Disorders and Stroke. Rett Syndrome Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Rett-Syndrome-Fact-Sheet. Accessed Mar 15, 2022.

2. Acadia Pharmaceuticals Inc. Data on file. RTT US Prevalence. March 2022.

3. 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;180(1):55-67.

4. Percy AK, Neul JL, Glaze DG, et al. Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann Neurol. 2010;68(6):951-955.

5. Ip JPK, Mellios N, Sur M. Rett syndrome: insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018;19(6):368-382.

6. Neul JL, Fang P, Barrish J, et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008;70(16):1313-1321.

7. Kriaucionis S, Bird A. DNA methylation and Rett syndrome. Hum Mol Genet. 2003;12 Spec No 2:R221-227.

8. Hite KC, Adams VH, Hansen JC. Recent advances in MeCP2 structure and function. Biochem Cell Biol. 2009;87(1):219-227.

9. Yasui DH, Xu H, Dunaway KW, Lasalle JM, Jin LW, Maezawa I. MeCP2 modulates gene expression pathways in astrocytes. Mol Autism. 2013;4(1):3.

10. Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-950.

11. Tarquinio DC, Hou W, Neul JL, et al. Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis. Pediatr Neurol. 2015;52(6):585-591.

12. Cuddapah VA, Pillai RB, Shekar KV, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014;51(3):152-158.

13. Hagberg B. Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev. 2002;8(2):61-65.

14. Hagberg B and Witt-Engerström I. Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet Suppl. 1986;24:47-59.

15. Buchanan CB, Stallworth JL, Scott AE, et al. Behavioral profiles in Rett syndrome: data from the Natural History Study. Brain Dev. 2019;41(2):123-134.

16. Motil KJ, Ellis KJ, Barrish JO, et al. Bone mineral content and bone mineral density are lower in older than in younger females with Rett syndrome. Pediatr Res. 2008;64:435-439. .

17. Motil KJ, Caeg E, Barrish JO, et al. Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome. J Pediatr Gastroenterol Nutr. 2012;55(3):292-298.

18. Hunter K. The Rett syndrome handbook. Clinton, MD: IRSA Publishing; 2007:40.