Rett syndrome

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Rett syndrome/disorder
ICD-10 F84.2
ICD-9 330.8
OMIM 312750
DiseasesDB 29908
MeSH C10.574.500.775

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Rett syndrome is a X-linked dominant neurodevelopmental disorder occurring commonly in girls who undergo the phase of regression after acquiring all the developmental skills. It demonstrates variety of symptoms such as gait abnormalities, head regression, loss of speech, loss of verbal skills, problems with socialization hand-wringing movements and breathing abnormalities. Nearly 90% of cases are due to inherited mutations in methyl-CpG-binding protein 2(MECP2) gene mutation. The other gene involved in rare cases is cyclin dependent kinase like 5(CDKL5). Being one of the most frequent causes of mental disabilities, affected children may have associated scoliosis and ambulatory problems. Girls with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures.


Rett syndrome (symbolized RTT) is caused by mutations in the gene MECP2, a transcriptional regulator gene, located on the X chromosome. The mutations can arise (1) sporadically or (2) from germline mutations. Two more genes have been identified in the recent studies namely; CDKL5(Cyclin dependent kinase gene 5 and FOXG1(FORKHEAD box G1). Mutations in CDKL5 is associated with seizure variant of Rett syndrome. [1]

Sporadic mutations

Rett syndrome is usually caused (95% or more) by a de novo mutation in the child (so it is inherited from a genotypically normal mother, i.e. one without a MECP2 mutation).

In sporadic cases of Rett syndrome, it is thought that the mutated MECP2 is usually derived from the male copy of the X chromosome.[2]

Germline mutations

It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MECP2.[3] MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of Rett syndrome, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects one in every 12,500 female live births by age 12 years.

Gender and Rett syndrome

It almost exclusively affects girls -- male fetuses with the disorder rarely survive to term. Development is typically normal until 6-18 months, when language and motor milestones regress, purposeful hand use is lost and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypes are typical and breathing irregularities such as hyperventilation, breath holding, or sighing are seen in many. Early on, autistic-like behavior could also be seen.

Most individuals with Rett syndrome are female. Because the disease-causing gene is found on the X chromosome , a female born with a MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of an equivalent gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a traditional gene to supply normal proteins additionally to the abnormal proteins caused by a MECP2 mutation, the XY karyotype male fetus is unable to see the development of the disease, hence the failure of the many male fetuses with a MECP2 mutation to survive to term. Females with a MECP2 mutation, however, have a non-mutant chromosome that gives them enough normal protein to survive a minimum of to birth. Research shows that males with Rett's syndrome almost all have Klinefelter's syndrome as well (in which the male has an XXY karyotype).[4] Thus, a non-mutant MECP2 gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.

There have, however, been several cases of 46,XY Karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age.[5] The incidence of Rett syndrome in males is unknown, partly due to low survival of male fetuses with the Rett syndrome associated MECP2 mutations, and partly to differences between symptoms caused by MECP2 mutations and those caused by Rett's.[6][7] T he severity of Rett syndrome in females can vary counting on the sort and position of the mutation of MECP2 and therefore the pattern of X-chromosome inactivation. It is generally assumed that 50% of a female's cells use the maternal X chromosome while the other 50% uses the paternal X chromosome (see X-inactivation). However, if most cells within the brain activate the X chromosome with the functional MECP2 allele, the individual will have very mild Rett syndrome; likewise, if most neurons activate the X chromosome with the mutated MECP2 allele, the individual will have very severe Rett syndrome even as males with MECP2 mutations do (as they only have one X chromosome).

Development and symptoms

The infant with Rett syndrome is not detected until 6-18 months due to a relatively normal appearance and normal development. The manifestations appear progressively over 4 stages: stagnation(6-18 months, rapid regression(1-4 years), pseudo-stationary(2-potential life) and late motor deterioration(10 years to life). Characteristic features include loss of speech and acquired motor skills, repetitive hand movements, breathing difficulties and seizures. Few children may have gastrointestinal problems, bruxism, screaming spells and early onset osteoporosis. During regression some features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism. [4]


Symptoms of Rett syndrome that are similar to autism:

  • screaming fits
  • panic attack
  • inconsolable crying
  • avoidance of eye contact
  • lack of social/emotional reciprocity
  • general lack of interest
  • markedly impaired use of nonverbal behaviors to regulate social interaction
  • loss of speech
  • Balance and coordination problems, including losing the ability to walk in many cases

Symptoms of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion should rarely be made):

Symptoms may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Anti-social behavior may change to highly social behavior. Motor functions may slow as rigidity and dystonia appear. Seizures may be problematic, with a wide range of severity. Scoliosis occurs in most and requires corrective surgery in about 10%. Those who remain ambulatory tend to have less progression of scoliosis.

Differential diagnosis

Rett syndrome must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
Rett syndrome + - - +
  • Occurs almost exclusively in females
  • Normal development during first six months followed by regression and loss of milestones
  • Loss of speech capability
  • Stereotypic hand movements
  • Seizures
  • Autistic features
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa

Treatment and prognosis

Currently there is no cure for Rett syndrome, although there have been some promising results with gene therapy in mice.[5]

Treatment of Rett syndrome includes:

The challenge of developing therapies for MECP2 disorders[6]

The recent studies demonstrating that neurological deficits resulting from loss of MeCP2 can be reversed upon restoration of gene function are quite exciting because they show that neurons that have suffered the consequences of loss of MeCP2 function are poised to regain functionality once MeCP2 is provided gradually and in the correct spatial distribution. This provides hope for restoring neuronal function in patients with RTT. However, the strategy in humans will require providing the critical factors that function downstream of MeCP2 because of the challenges in delivering the correct MeCP2 dosage only to neurons that lack it, given that the slightest perturbation in MeCP2 level is deleterious. Thus, therapeutic strategies necessitate the identification of the molecular mechanisms underlying individual RTT phenotypes and picking out the candidates that can be therapeutically targeted. The next phase of research needs to assess how complete the recovery is. Clearly, lethality, level of activity, and hippocampal plasticity are rescued, but are the animals free of any other RTT symptoms such as social behavior deficits, anxiety, and cognitive impairments? Since postnatal rescue results in viability, it will be important to evaluate if even the subtler phenotypes of RTT and MECP2 disorders are rescued when protein function is restored postnatally. This is particularly important given emerging data about early neonatal experiences and their long-term effects on behavior in adults.


Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic mosaicism.

Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:

A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:

  • spontaneous brainstem dysfunction
  • cardiac arrest
  • seizures
  • cardiac conduction abnormalities - abnormally prolonged QT interval on ECG
  • gastric perforation


  1. "StatPearls". 2021. PMID 29489169.
  2. Trappe R, Laccone F, Cobilanschi J; et al. (2001). "MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin". American journal of human genetics. 68 (5): 1093–101. doi:10.1086/320109. PMC 1226090. PMID 11309679. Unknown parameter |month= ignored (help)
  3. "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2" Amir, R. et al.
  4. Kyle SM, Vashi N, Justice MJ (2018). "Rett syndrome: a neurological disorder with metabolic components". Open Biol. 8 (2). doi:10.1098/rsob.170216. PMC 5830535. PMID 29445033.
  5. "Autism-like disorder 'reversible'", BBC News, 8 February 2007.
  6. "The Story of Rett Syndrome: From Clinic to Neurobiology." Chahrour et al. Neuron, Vol 56, 422-437, 08 November 2007


Further reading

  • Ben Zeev Ghidoni B (2007). "Rett syndrome". Child Adolesc Psychiatr Clin N Am. 16 (3): 723–43. doi:10.1016/j.chc.2007.03.004. PMID 17562589.
  • Bittner JG; et al. (2008). "Rett Syndrome and gastric perforation". Am Surg. 74 (4): 315–317.

Rett Disorder and the Developing Brain. edited by Alison Kerr & Ingegerd Witt Engerstrom Oxford University Press ISBN 0-19-856815-0, 2005

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