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Rett Syndrome Workup

  • Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD  more...
Updated: Jul 15, 2015

Laboratory Studies

Females who meet the clinical diagnostic criteria for Rett syndrome (RS) should undergo genetic testing. Several laboratories provide diagnostic sequencing of the MECP2 gene; details on how to order this testing are available from the International Rett Syndrome Foundation (IRSF). Patients with positive MECP2 mutational gene analysis need no further diagnostic testing.

Mutations in the MECP2 gene have been identified in a wide spectrum of clinical phenotypes, including girls with classic RS, girls with atypical or variant forms of RS, girls with autism spectrum disorder, healthy females (carriers), males with severe infantile encephalopathies, males with classic RS, and males with X-linked neurologic problems (eg, motor deficits or communication deficits).[31, 32]

Patients in whom no MECP2 mutation is found should undergo other diagnostic tests aimed at identifying other possible causes of their signs and symptoms. Such tests may include the following:

  • Serum lactate, ammonia, pyruvate, and amino acids
  • Urinary organic acids
  • Chromosomal studies, including specific tests for Angelman syndrome (chromosome 15)
  • Urinary tests for uroporphobilinogen to rule out intermittent porphyria (rarely helpful)

Barium Swallow or Overnight pH Probe Study

A barium swallow study or an overnight pH probe study may be performed to document gastroesophageal reflux (GER), which is present in approximately 15% of patients with RS. GER may cause weight loss, discomfort with meals, vomiting after eating, obstructive apnea, or recurrent respiratory congestion and problems. Swallowing studies frequently document poor oral motor skills and risk of aspiration.



Neuroimaging may be useful. Magnetic resonance imaging (MRI) may help include or exclude other causes of a patient’s signs and symptoms. Although RS is associated with a significant decrease in cerebral cortex size, cerebellar atrophy, and a brain weight that is approximately 70-90% of normal, these findings are not specific for the diagnosis of RS. Changes may also be observed in the corticospinal tracts, with reduced myelin and some gliosis.



Findings on electrocardiography (ECG) may include an inverted T wave and a prolonged QT interval.[33] Studies have demonstrated that the incidence of sudden death in persons with RS is greater than that in the general population. Patients with RS may also have significantly lower heart rate variability. These cardiac abnormalities may increase through the successive stages of the syndrome.



Abnormal results on electroencephalography (EEG) are common.[34] Seizures are reported in 60-90% of patients with RS. Differentiation from Landau-Kleffner syndrome (acquired epileptic aphasia) should be made clinically and secondary to response to therapy. Patients also frequently have epileptiform abnormalities that appear to be age-related and to occur most frequently during clinical stage III, as well as with abnormalities that can be noted earlier during nonrapid eye movement (NREM) sleep.

Video-EEG polygraphic monitoring may be required to determine whether antiepileptic therapy is indicated. Many reported seizure episodes are nonepileptic behavioral events, whereas actual seizures may be underrecognized because they occur during sleep.


Neurophysiologic Testing

Auditory brainstem-evoked response testing generally demonstrates normal hearing with a delayed conduction time. Somatosensory-evoked responses demonstrate spinal cord and brainstem conduction abnormalities. Electromyographic (EMG) studies are typically normal and need not be completed, except for the purpose of excluding other conditions.



Electroretinography (ERG), in conjunction with EEG and the continued decline observed children with infantile neuronal ceroid lipofuscinosis, can help differentiate RS from infantile neuronal ceroid lipofuscinosis. Both disorders cause rapid regression of psychomotor development and the development of hand and finger stereotypes in children aged 1-2 years.


Polygraphic Respiratory Recordings

Polygraphic respiratory recordings may demonstrate a pattern of disorganized breathing characterized by periods of apnea or hyperventilation and significant oxygen desaturation and clinical cyanosis.

Normal breathing occurs during sleep in persons with RS. Total sleep time may be decreased. Patients may demonstrate prolonged periods (≥18 h) of wakefulness or sleep. Nighttime awakenings with frequent laughing are reported. Screaming episodes may also occur at night; however, the possibility of other medical problems (eg, GER) must also be considered.


Psychometric Testing

Generally, the results of psychometric testing in patients with RS are indicative of profound intellectual disability. However, standard instruments that depend on the use of hands and oral language may be inadequate for full assessment of these individuals. Specialized tests, such as the Gilliam Autism Rating Scale or the Children’s Autism Rating Scale, can be helpful for detailing autisticlike symptomatology.


Histologic Findings

Morphologic features in individuals with RS include reduced brain weight (including reduced volume of the frontal cortex and caudate), reduced neuronal size, and dendritic arborizations in certain areas (frontal correlates, motor correlates, and limbic correlates), with preservation in the visual cortex and decreased organ weights proportional to height and weight.

Neurochemical findings include the following:

  • Reduced levels of catecholamines in the substantia nigra
  • Reduced dopamine D2 receptors and dopamine reuptake in the caudate nucleus
  • Reduced choline acetyltransferase in the hippocampus, caudate, and thalamus
  • Reduced acetylcholine vesicles or transporters in the putamen and thalamus
  • Reduced benzodiazepine receptor binding in the frontal and temporal cortex
  • Reduced beta-endorphins in the thalamus and cerebellum but increased beta-endorphins in the cerebrospinal fluid (CSF)
  • Increased glutamate in the CSF
  • Reduced melanin in the substantia nigra
  • Decreased substance P levels in the CSF
Contributor Information and Disclosures

Bettina E Bernstein, DO Distinguished Fellow, American Academy of Child and Adolescent Psychiatry; Distinguished Fellow, American Psychiatric Association; Clinical Assistant Professor of Neurosciences and Psychiatry, Philadelphia College of Osteopathic Medicine; Clinical Affiliate Medical Staff, Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia; Consultant to theVillage, Private Practice; Consultant PMHCC/CBH at Family Court, Philadelphia

Bettina E Bernstein, DO is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, American Psychiatric Association

Disclosure: Nothing to disclose.


Daniel G Glaze, MD Medical Director, Blue Bird Circle Rett Center; Professor, Departments of Pediatrics and Neurology, Baylor College of Medicine

Daniel G Glaze, MD is a member of the following medical societies: American Clinical Neurophysiology Society, American Neurological Association, Child Neurology Society

Disclosure: Nothing to disclose.

Chief Editor

Caroly Pataki, MD Health Sciences Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine

Caroly Pataki, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, New York Academy of Sciences, Physicians for Social Responsibility

Disclosure: Nothing to disclose.


Joseph H Schneider, MD Assistant Professor of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School

Joseph H Schneider, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Texas Medical Association, and Texas Pediatric Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

  1. Kubota T, Miyake K, Hirasawa T. Role of epigenetics in Rett syndrome. Epigenomics. 2013 Oct. 5(5):583-92. [Medline].

  2. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. 1999 Oct. 23(2):185-8. [Medline].

  3. Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. 2007 Jan. 29(1):47-50. [Medline].

  4. Hoffbuhr K, Devaney JM, LaFleur B. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001 Jun 12. 56(11):1486-95. [Medline].

  5. Huppke P, Laccone F, Kramer N, et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. 2000 May 22. 9(9):1369-75. [Medline].

  6. Kankirawatana P, Leonard H, Ellaway C, et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 2006 Jul 11. 67(1):164-6. [Medline].

  7. Kerr AM, Archer HL, Evans JC, et al. People with MECP2 mutation-positive Rett disorder who converse. J Intellect Disabil Res. 2006 May. 50(Pt 5):386-94. [Medline].

  8. Moog U, Smeets EE, van Roozendaal KE, et al. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003. 7(1):5-12. [Medline].

  9. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev. 2006 Jun. 16(3):276-81. [Medline].

  10. Philippe C, Villard L, De Roux N, et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb. 49(1):9-18. [Medline].

  11. Wan M, Lee SS, Zhang X, et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec. 65(6):1520-9. [Medline].

  12. Zeev BB, Bebbington A, Ho G, Leonard H, de Klerk N, Gak E, et al. The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology. 2009 Apr 7. 72(14):1242-7. [Medline].

  13. Temudo T, Ramos E, Dias K, Barbot C, Vieira JP, Moreira A, et al. Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Mov Disord. 2008 Jul 30. 23(10):1384-90. [Medline].

  14. Nectoux J, Bahi-Buisson N, Guellec I, Coste J, De Roux N, Rosas H, et al. The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome. Neurology. 2008 May 27. 70(22 Pt 2):2145-51. [Medline].

  15. Percy AK, Neul JL, Glaze DG, et al. Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann Neurol. 2010 Dec. 68(6):951-5. [Medline]. [Full Text].

  16. Suter B, Treadwell-Deering D, Zoghbi HY, Glaze DG, Neul JL. Brief Report: MECP2 Mutations in People Without Rett Syndrome. J Autism Dev Disord. 2013 Aug 7. [Medline].

  17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 5th. Arlington, VA: American Psychiatric Association; 2013. 57.

  18. Monteggia LM, Kavalali ET. Rett syndrome and the impact of MeCP2 associated transcriptional mechanisms on neurotransmission. Biol Psychiatry. 2009 Feb 1. 65(3):204-10. [Medline].

  19. Zhang Y, Minassian BA. Will my Rett syndrome patient walk, talk, and use her hands?. Neurology. 2008 Apr 15. 70(16):1302-3. [Medline].

  20. Maezawa I, Swanberg S, Harvey D, LaSalle JM, Jin LW. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J Neurosci. 2009 Apr 22. 29(16):5051-61. [Medline].

  21. Bebbington A, Downs J, Percy A, Pineda M, Zeev BB, Bahi-Buisson N, et al. The phenotype associated with a large deletion on MECP2. Eur J Hum Genet. 2012 Apr 4. [Medline].

  22. Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009 Feb 10. 106(6):2029-34. [Medline].

  23. Glaze DG, Schultz RJ. Rett Syndrome: Meeting the Challenge of This Gender-Specific Neurodevelopmental Disorder. Medscape Womens Health. 1997 Jan. 2(1):3. [Medline].

  24. Sampieri K, Meloni I, Scala E, et al. Italian Rett database and biobank. Hum Mutat. 2007 Apr. 28(4):329-35. [Medline].

  25. Terai K, Munesue T, Hiratani M, Jiang ZY, Jibiki I, Yamaguchi N. The prevalence of Rett syndrome in Fukui prefecture. Brain Dev. 1995 Mar-Apr. 17(2):153-4. [Medline].

  26. Huppke P, Maier EM, Warnke A, et al. Very mild cases of Rett syndrome with skewed X inactivation. J Med Genet. 2006 May 11. [Medline].

  27. Kozinetz CA, Skender ML, MacNaughton N, et al. Epidemiology of Rett Syndrome: a population-based registry. Pediatrics. 1993. 91(2):445-50. [Medline].

  28. Hagberg B, Berg M, Steffenburg U. Rett Syndrome - an odd handicap afffecting girls. A current 25-year follow-up in western Sweden. Lakartidningen. 1999. 96(49):5488-90. [Medline].

  29. Kerr AM, Julu PO. Recent insights into hyperventilation from the study of Rett syndrome. Arch Dis Child. 1999 Apr. 80(4):384-7. [Medline].

  30. Vignoli A, La Briola F, Canevini MP. Evolution of stereotypies in adolescents and women with Rett syndrome. Mov Disord. 2009 Jul 15. 24(9):1379-83. [Medline].

  31. Amir RE, Sutton VR, Van den Veyver IB. Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy. J Child Neurol. 2005 Sep. 20(9):779-83. [Medline].

  32. Ham AL, Kumar A, Deeter R. Does genotype predict phenotype in Rett syndrome?. J Child Neurol. 2005 Sep. 20(9):768-78. [Medline].

  33. Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT interval in Rett syndrome. Arch Dis Child. 1999 May. 80(5):470-2. [Medline].

  34. Glaze DG, Schultz RJ, Frost JD. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol. 1998 Jan. 106(1):79-83. [Medline].

  35. Glaze DG, Percy AK, Motil KJ, Lane JB, Isaacs JS, Schultz RJ, et al. A study of the treatment of Rett syndrome with folate and betaine. J Child Neurol. 2009 May. 24(5):551-6. [Medline].

  36. Wilfong AA, Schultz RJ. Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol. 2006 Aug. 48(8):683-6. [Medline].

  37. Chung JC, Lai CK, Chung PM, French HP. Snoezelen for dementia. Cochrane Database Syst Rev. 2002. CD003152. [Medline].

  38. Lavie E, Shapiro M, Julius M. Hydrotherapy combined with Snoezelen multi-sensory therapy. Int J Adolesc Med Health. 2005 Jan-Mar. 17(1):83-7. [Medline].

  39. Lotan M. Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories. ScientificWorldJournal. 2006. 6:791-807. [Medline].

  40. Downs J, Young D, de Klerk N, Bebbington A, Baikie G, Leonard H. Impact of scoliosis surgery on activities of daily living in females with Rett syndrome. J Pediatr Orthop. 2009 Jun. 29(4):369-74. [Medline].

  41. Hartman AL. Does the effectiveness of the ketogenic diet in different epilepsies yield insights into its mechanisms?. Epilepsia. 2008 Nov. 49 Suppl 8:53-6. [Medline].

  42. Motil KJ, Schultz RJ, Browning K, et al. Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome. J Pediatr Gastroenterol Nutr. 1999 Jul. 29(1):31-7. [Medline].

  43. Leonard H, Thomson MR, Glasson EJ, et al. A population-based approach to the investigation of osteopenia in Rett syndrome. Dev Med Child Neurol. 1999 May. 41(5):323-8. [Medline].

  44. PapiniAM, Nuti F, Real-Fernandez F, Rossi G, Tiberi C, Sabatino G, et al. Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N (Glc) IgM Antibody Fraction. J of Immunology Research. 2014. 1-6.

  45. Gadalla KKE, Ross PD, Riddell JS, Bailey MES, Cobb SR. Knockout Mouse Model of Rett Syndrome Reveals Early-Onset and Progressive Motor Deficits. PLoS One. 2014. 9(11):1-5.

  46. Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures. J of Neuroscience. Feb 2014. Feb 12:2754-2763.

  47. Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome. Am J Respir Cell Mol Biol. 2014 Jun. 50 (6):1031-9. [Medline].

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