- Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD more...
Rett syndrome (RS) is a neurodevelopmental disorder that occurs almost exclusively in females and has a typically degenerative course. It is related to various mutations on the MECP2 gene, which codes for methyl-CpG binding protein-2 (MECP2). Recent studies suggest that MECP2 is expressed in neurons and glial cells and that it will someday be possible to reverse the disorder even after birth when behavioral symptoms occur.
Signs and symptoms
RS progresses through 4 stages, typically reached at the following ages:
- Stage I - Developmental arrest (6-18 months)
- Stage II - Rapid deterioration or regression (1-4 years)
- Stage III - Pseudostationary (2-10 years)
- Stage IV - Late motor deterioration (>10 years)
The history varies according to the clinical stage. Common symptoms reported include the following:
- Stage I - Gross motor development delay, disinterest in play, and loss of eye contact; hypotonia; hand wringing; unusual placidity and calmness; vague and nonspecific early symptoms; breath-holding spells
- Stage II - Deterioration; autisticlike behavior; stereotypic hand movements during wakefulness; breathing irregularities; seizures and vacant spells that resemble seizures; sleep disorders, intermittent strabismus, and irritability
- Stage III - Some improvement in behavior, hand use, and communication skills; good eye contact and attempts to communicate intent; continued mental impairment and hand stereotypies; increasing rigidity, bruxism, and involuntary tongue movements; motor dysfunction and seizures; continued breathing irregularities; poor weight gain despite good appetite; difficult feeding and some degree of oral motor dysfunction
- Stage IV - No additional deterioration of cognitive skills, communication skills, or hand skills; increased motor problems; cessation of walking; possible reduction of seizure frequency
Physical findings also vary according to the clinical stage of the disorder. Common findings on physical examination include the following:
- Stage I - Gross motor development delay; loss of eye contact; deceleration of head, weight, and height growth; hypotonia; hand wringing; abnormal placidity and calmness; no cutaneous findings on Wood lamp examination
- Stage II - Autisticlike behavior; midline hand wringing, clapping, hand washing, or hand-to-mouth movements; episodes of hyperventilation or breath-holding; seizures and vacant spells that resemble seizures; intermittent strabismus and irritability
- Stage III - Hand stereotypies, rigidity, hyperventilation, breath holding, bruxism, involuntary tongue movements, poor weight gain, and scoliosis
- Stage IV - Dystonia, rigidity, muscle wasting, quadriparesis, scoliosis or kyphoscoliosis, loss of ambulation, growth retardation, hyperventilation, and seizures; improved frequency and intensity of hand movements; preserved eye contact
See Presentation for more detail.
The differential diagnosis varies according to the clinical stage of RS. Conditions that should receive particular consideration in each of the 4 stages of the syndrome are as follows:
- Stage I - Benign congenital hypotonia, cerebral palsy, Prader-Willi syndrome, Angelman syndrome, and metabolic disorders (eg, fetal alcohol syndrome and trisomy 13)
- Stage II - Autism spectrum disorder, Angelman syndrome, encephalitis, hearing or visual disturbance, Landau-Kleffner syndrome, psychoses, slow virus panencephalopathy, tuberous sclerosis, metabolic disorders (eg, phenylketonuria and ornithine transcarbamoylase deficiency), and infantile neuronal ceroid lipofuscinosis
- Stage III - Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, Lennox-Gastaut syndrome, and Angelman syndrome (probably not Kabuki makeup syndrome, because patients would have macrocephaly)
- Stage IV - Other degenerative disorders
Laboratory studies that may be warranted include the following:
- Genetic testing (for all patients who meet the clinical diagnostic criteria for RS)
- 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)
Other studies that may be helpful include the following:
- Barium swallow study or overnight pH probe study
- Neuroimaging (eg, MRI)
- Electrocardiography (ECG)
- Electroencephalography (EEG)
- Neurophysiologic testing (auditory brainstem-evoked responses, somatosensory-evoked responses, electromyography [EMG])
- Electroretinography (ERG)
- Polygraphic respiratory recordings
- Psychometric testing
No medications are available specifically for treatment of RS. Agents that may be considered in RS patients include the following:
- Antiepileptic drugs (AEDs) for epilepsy
- Antireflux drugs for GER
Nonpharmacologic therapy may include the following as appropriate:
- Vagal nerve stimulation
- Snoezelen multisensory approach, with or without hydrotherapy
- Placement of a gastrostomy tube
- Fundoplication, if GER is refractory to medical treatment
- Surgical treatment of scoliosis, if the condition does not respond to orthotics
Dietary measures may include the following:
- High-calorie diet, with approximately 70% of calories from fats and 15% each from carbohydrates and proteins
- Vitamin D, calcium supplements, and bisphosphonate for osteoporosis
- Ketogenic diet
Optimal management of RS involves early multidisciplinary evaluation and treatment, including the following:
- Communication assessment
- Oral motor assessment
- Other assessments and therapies, such as music, hydrotherapy, hippotherapy (ie, horseback riding), massage, psychosocial support for families, educational planning with schools, and help with accessing community resources for home care
Issues that may have to be addressed in long-term management of RS include the following:
- Agitation and screaming
- Sleep disturbances
- Osteopenia with possible fractures
- Birth control
Rett syndrome (RS) is a neurodevelopmental disorder first reported in 1966 by Andreas Rett, an Austrian pediatric neurologist. It occurs almost exclusively in females and has a typically degenerative course. Before the discovery of RS, incidents were mistaken for many other neurologic disorders. The specific mutation on the gene related to RS (methyl-CpG binding protein-2 [MECP2]) was identified late in 1999.[2, 3, 4, 5, 6, 7, 8, 9, 10, 11]
Initially, RS patients have seemingly healthy development. In retrospect, however, it can be seen that girls were frequently reported to have been placid as infants, with low tone and subtle slowing of development. An early clinical feature is deceleration of head growth that begins when the individual is aged 2-4 months. A period of developmental stagnation is followed by a period of regression.
Males with RS also manifest a spectrum of symptoms, ranging from severe congenital encephalopathy, dystonia, apraxia, and retardation to psychiatric illness with mild intellectual disability. Individuals who are less severely affected may tolerate or even prefer interpersonal contact, show affection to others, and suffer from learning disabilities and speech fragmentation related to breathing irregularity.
RS can be differentiated into 2 types, classic and variant (atypical). At least 200 different mutations have been found to be associated with the disease, including missense and truncating mutations. The common BDNF polymorphism may modify disease severity in RS, and the severity of the phenotype varies depending on the MECP2 mutation type and locations. The BDNF functional polymorphism (p.Val66Met; valine substitution with methionine at codon 66) may protect against early seizures.
The regression phase in individuals with RS may occur acutely over a period of days or, more insidiously, months. Regression is characterized by loss of purposeful hand skills and oral language and the development of hand stereotypies and gait dyspraxia.
Other problems include breath-holding and apnea during wakefulness with normal breathing during sleep, epilepsy, oral-motor dysfunction with gut motility problems (eg, constipation or gastroesophageal reflux [GER]), scoliosis, autonomic dysfunction (cold, blue extremities), and somatic growth failure. During the regression period, individuals with RS demonstrate screaming episodes, sleep disturbances, and poor social interactions.
After the regression period, people with RS demonstrate no further cognitive decline, become more interactive with their environment and other persons, and may demonstrate some improvements in hand and communication skills. They progress through puberty and survive to adulthood; however, they never regain significant purposeful hand use or oral language skills.
Currently, the diagnosis of RS is made if the patient meets defined clinical criteria; it is not made through molecular genetic testing, though MECP2 mutations are frequently identified in individuals meeting the clinical criteria for RS. As many as 20% of females who meet the full clinical criteria for RS may have no identified mutation, and some individuals have MECP2 mutations but do not have RS.
Because no cure is available, treatment is palliative and supportive. A multidisciplinary approach to care is recommended.
Although RS is no longer listed as a DSM diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), it is listed as a differential diagnosis for autism spectrum disorder. During the regressive phase of the syndrome, some young girls with RS may have a presentation that meets diagnostic criteria for autism spectrum disorder; however, after this period, autistic features generally cease to be a major area of concern.
Pathophysiology and Etiology
RS is a genetic disorder of neurodevelopmental arrest rather than a progressive process. The gene is located on the X chromosome. Females with a single mutated MECP2 gene are more likely to survive because 1 X chromosome is activated randomly in each cell.
The symptoms and severity of RS may depend on both the percentage of activated defective genes and the type of mutation. Multiple mutation types have been found in the 3 coding regions of the MECP2 gene, with most of them causing truncations and missense proteins. Mutations have been found in as many as 80% of analyzed cases of classic RS. The MECP2 protein may act as a transcriptional repressor or activator, depending on the target gene with which it associates.[1, 18]
The mutations that cause RS are almost all sporadic. In families with a girl who has RS, the increased risk of having a second girl with the syndrome is reportedly less than 0.4%. However, recurrence in families can occur through mechanisms such as germline mosaicism.
About 70% of RS cases are due to 4 missense mutations (ie, R106W, R133C, T158M, R306C) and 4 nonsense protein-truncating mutations (ie, R168X, R255X, R270X, R294X), which are large deletions that cause significant gene destruction, resulting in greater severity. Another cluster of mutations near the end of the gene abrogate only the very end of the protein (C-terminal truncations). Physical therapy and speech therapy may result in intragroup differences, causing different outcomes.
RS is the first human disease determined to be caused by defects in a protein that regulates gene expression through interaction with methylated DNA. Accordingly, it involves abnormal chromatin structure, with broad-ranging effects on expression of genes that are otherwise not mutated. The normal MECP2 gene encodes the MECP2 protein, which binds to methylated DNA in conjunction with a corepressor. This causes activation of histone deacetylase.
Mutations in the MECP2 gene produce loss of function of this protein and unregulated expression of the genes that it normally affects, some of which appear to be crucial in nervous system development beyond the initial stages. Although the nervous system is the primary site, the specific target genes are not known. Astrocyte function is abnormal in RS, presumably owing to dysfunction of the MECP2 gene.
A study of 974 RS patients was conducted using data from databases that employed multiplex ligation-dependent probe amplification (MLPA) to detect large deletions on MECP2. Those with large deletions were less likely to have learned to walk, were not walking, and were more likely to have the most severe gross motor dysfunction and epilepsy; they also appeared to develop epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. These findings may help predict age of onset and symptom severity in RS.
Areas of research have included the study of insulinlike growth factor 1 (IGF-1), which may extend the life span and increase brain weight in mice with RS. In addition, IGF-1 may correct the deficit in brain synaptic maturation and reverse the reduction of PSD-95 in the motor cortex.
United States and international statistics
The incidence of RS has been reported to be approximately 1 per 23,000 live female births.
Wide variations in incidence have been reported in various countries; rates as high as 1 per 10,000 live female births have been reported. One study in Japan found an incidence of 1 per 45,000 girls aged 6-14 years. Variations in incidence may be partly accounted for by the inclusion of atypical or variant forms of RS. These atypical forms include congenital RS, milder forms with later onset of regression, and preserved speech variants.
Age-, sex-, and race-related demographics
RS generally becomes clinically evident by age 2-4 years; however, the underlying neurodevelopmental arrest probably starts in children aged 6-18 months or younger.
Most patients identified are female because the disease is X-linked. Many males with RS are believed to die in utero. However, a few reports have detailed males with mutations in MECP2 and RS-like symptoms.[3, 6, 8] Excess male fetal loss has not been demonstrated in families with a history of RS; thus, an alternative explanation for female predominance may be noted.
No racial variations have been reported. In a study by Kozinetz et al, which included Latin Americans, Caucasians, and African Americans in Texas, no variations in the incidence or prevalence of RS were found.
Developmental potential for patients with RS is difficult to predict. Some individuals with this syndrome achieve and maintain some functional skills. As many as 60% of RS patients may retain their abilities to ambulate; the remainder lose ambulation or never walk because of atrophy, dystonia, and scoliosis.
Survival rates decline in individuals older than 10 years; the 35-year survival rate is 70%. Death may be sudden and often is secondary to pneumonia. Risk factors include seizures, loss of mobility, and difficulties with swallowing. The life expectancy is more favorable in patients with RS than in other individuals with profound intellectual disability, which is associated with a 35-year survival rate of only 27%.
In a case study by Hagberg et al, the median age at death was 24 years; in most cases, death was sudden and unexpected. However, subsequent experiences based on longer follow-up care indicated that with attention to nutritional needs and comprehensive programs of physical and occupational therapies, RS patients can be expected to survive long into adulthood. Most survive into the fifth or sixth decade of life, often with severe disabilities. Reports of women with RS in their sixth or even eighth decade of life are now available.
Although no cure for RS is available, accurate diagnosis has many advantages. For example, girls with RS may be able to retain some communicative skills with proper assistance. Dietary adjustments can be implemented to prevent malnutrition, for which RS patients are at substantial risk. The increased risk of sudden death (possibly from long-QT sequelae) can be taken into account. Finally, diagnosis can bring relief to parents and help to identify the scope of clinical problems that can be anticipated.
Early identification of RS can facilitate educational efforts that may alleviate some parental concerns and help maximize the girl’s potential, which is influenced by an active lifestyle, good nutrition, and the amount of effective physical therapy received. In view of the expected survival into adulthood, it is important to discuss provisions for guardianship and long-term care with parents and caregivers of individuals with RS.
The International Rett Syndrome Foundation (IRSF; 800-818-7388), supports international research and meetings of parents and professionals to improve knowledge of Rett syndrome. The Web site provides overviews of RS and highlights individuals living with RS. It also provides a discussion group for parents, doctors, and researchers; updated research findings; research contacts; an online library; specifics of how to obtain diagnostic sequencing of the MECP2 gene; and links to other RS-related sites.
The Blue Bird Circle Rett Center of Baylor College of Medicine (713-798-RETT  or 888-430-RETT) operates one of the largest RS clinics in the world. The Center is part of a Rett Consortium with the University of Alabama at Birmingham and the University of California at Los Angeles.
The Rett Syndrome Research Program of the Center for Genetic Disorders of Cognition and Behavior at the Kennedy-Krieger Institute, Johns Hopkins University School of Medicine (800-873-3377), can provide additional information.
Kubota T, Miyake K, Hirasawa T. Role of epigenetics in Rett syndrome. Epigenomics. 2013 Oct. 5(5):583-92. [Medline].
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].
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].
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].
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].
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].
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].
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].
Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev. 2006 Jun. 16(3):276-81. [Medline].
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].
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].
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].
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].
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].
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].
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 5th. Arlington, VA: American Psychiatric Association; 2013. 57.
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].
Zhang Y, Minassian BA. Will my Rett syndrome patient walk, talk, and use her hands?. Neurology. 2008 Apr 15. 70(16):1302-3. [Medline].
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].
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].
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].
Glaze DG, Schultz RJ. Rett Syndrome: Meeting the Challenge of This Gender-Specific Neurodevelopmental Disorder. Medscape Womens Health. 1997 Jan. 2(1):3. [Medline].
Sampieri K, Meloni I, Scala E, et al. Italian Rett database and biobank. Hum Mutat. 2007 Apr. 28(4):329-35. [Medline].
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].
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].
Kozinetz CA, Skender ML, MacNaughton N, et al. Epidemiology of Rett Syndrome: a population-based registry. Pediatrics. 1993. 91(2):445-50. [Medline].
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].
Kerr AM, Julu PO. Recent insights into hyperventilation from the study of Rett syndrome. Arch Dis Child. 1999 Apr. 80(4):384-7. [Medline].
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].
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].
Ham AL, Kumar A, Deeter R. Does genotype predict phenotype in Rett syndrome?. J Child Neurol. 2005 Sep. 20(9):768-78. [Medline].
Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT interval in Rett syndrome. Arch Dis Child. 1999 May. 80(5):470-2. [Medline].
Glaze DG, Schultz RJ, Frost JD. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol. 1998 Jan. 106(1):79-83. [Medline].
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].
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].
Chung JC, Lai CK, Chung PM, French HP. Snoezelen for dementia. Cochrane Database Syst Rev. 2002. CD003152. [Medline].
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].
Lotan M. Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories. ScientificWorldJournal. 2006. 6:791-807. [Medline].
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].
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].
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].
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].
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.
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.
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.
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].