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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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MECP2-Related Disorders

, MBBS, PhD, FRACP, FFSc, FRCPA and , BSc, MSc.

Author Information
, MBBS, PhD, FRACP, FFSc, FRCPA
Professor, Pediatrics and Biochemical, Molecular, and Human Genetics
Director, Western Sydney Genetics Program
Children's Hospital at Westmead
Sydney, New South Wales, Australia
, BSc, MSc
NSW Centre for Rett Syndrome Research
Western Sydney Genetics Program
Children's Hospital at Westmead
Sydney, New South Wales, Australia

Initial Posting: ; Last Update: June 28, 2012.

Summary

Disease characteristics. MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities. A MECP2 mutation in a male is presumed to most often be lethal; phenotypes in rare surviving males are primarily severe neonatal encephalopathy and manic-depressive psychosis, pyramidal signs, Parkinsonian, and macro-orchidism (PPM-X syndrome).

Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly.

Atypical Rett syndrome is observed increasingly as MECP2 mutations are identified in individuals previously diagnosed with: clinically suspected but molecularly unconfirmed Angelman syndrome; intellectual disability with spasticity or tremor; mild learning disability; or (rarely) autism.

Severe neonatal encephalopathy resulting in death before age two years is the most common phenotype observed in affected males.

Diagnosis/testing. The diagnosis of all MECP2-related disorders relies on molecular genetic testing. The diagnosis of classic Rett syndrome rests on clinical diagnostic criteria.

Management. Treatment of manifestations: Treatment is mainly symptomatic and multidisciplinary and should include psychosocial support for family members. Risperidone may help in treating agitation; melatonin can ameliorate sleep disturbances. Treatment of seizures, constipation, gastroesophageal reflux, scoliosis, prolonged QTc, and spasticity is routine.

Surveillance: Periodic evaluation by the multidisciplinary team; regular assessment of QTc for evidence of prolongation; regular assessment for scoliosis.

Agents/circumstances to avoid: Drugs known to prolong the QT interval.

Genetic counseling. MECP2-related disorders are inherited in an X-linked manner. More than 99% are simplex cases (i.e., a single occurrence in a family), resulting from a de novo mutation, or possibly from inheritance of the disease-causing mutation from a parent who has germline mosaicism. Rarely, a MECP2 mutation may be inherited from a carrier mother in whom favorable skewing of X-chromosome inactivation results in minimal to no clinical findings. When the mother is a known carrier, the risk to her offspring of inheriting the MECP2 mutation is 50%. Prenatal testing is possible in pregnancies at increased risk if the MECP2 mutation has been identified in the family. Because of the possibility of germline mosaicism, it is appropriate to offer prenatal diagnosis to couples who have had a child with a MECP2-related disorder regardless of whether the disease-causing mutation has been detected in a parent.

GeneReview Scope

MECP2-Related Disorders: Included Disorders
  • Classic Rett syndrome
  • MECP2-related severe neonatal encephalopathy
  • PPM-X syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

The spectrum of phenotypes in MECP2-related disorders includes the following:

  • Classic Rett syndrome
  • Variant Rett syndrome
  • Mild learning disabilities (females) or neonatal encephalopathy and syndromic or nonsyndromic intellectual disability (males)

Classic Rett syndrome. In 1988, well before the discovery of the genetic basis of Rett syndrome, clinical diagnostic criteria were developed. The following are limitations to clinical diagnosis of Rett syndrome using these criteria:

  • Clinical diagnosis may be considered tentative until the affected individual reaches age two to five years, by which point she has likely gone through several stages of the disease.
  • Atypical forms may be either milder or more severe than classic Rett syndrome:
    • In the more severe variant, no period of grossly normal development occurs; and early manifestations include congenital hypotonia and infantile spasms.
    • In the milder variant, girls have less dramatic regression and milder intellectual disability.
    • Other children experience an even more gradual regression that begins after the third year, lose purposeful hand use, and develop seizures; however, they retain some speech and the ability to walk [Zappella et al 1998].

More recently, Neul et al [2010] have modified the diagnostic criteria to resolve inconsistencies and ambiguities in the categorization of affected individuals into classic Rett syndrome or variant Rett syndrome.

Revised Diagnostic Criteria for Rett Syndrome

[Neul et al 2010]

The diagnosis should be considered when there is postnatal deceleration of head growth observed. However, this is not mandatory.

Required for typical or classic Rett syndrome

  • A period of regression followed by recovery or stabilization
  • All of the main criteria and all of the exclusion criteria

Supportive criteria are not required, although often present in typical Rett syndrome.

Required for atypical or variant Rett syndrome

  • A period of regression followed by recovery or stabilization
  • Two of the four main criteria
  • Five of the 11 supportive criteria

Main criteria

  • Partial or complete loss of acquired purposeful hand skills
  • Partial or complete loss of acquired spoken language or language skill (e.g. babble).
  • Gait abnormalities: impaired (dyspraxic) or absence of ability
  • Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms

Exclusion criteria for typical Rett syndrome

  • Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
  • Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met

Supportive criteria for atypical Rett syndrome (currently or at any time)*

  • Breathing disturbances when awake
  • Bruxism when awake
  • Impaired sleep pattern
  • Abnormal muscle tone
  • Peripheral vasomotor disturbances
  • Scoliosis/kyphosis
  • Growth retardation
  • Small cold hands and feet
  • Inappropriate laughing/screaming spells
  • Diminished response to pain
  • Intense eye communication - “eye pointing”

* Younger individuals may need to be reevaluated, as the development of many of these features is age dependent.

Molecular Genetic Testing

Gene. MECP2 is the only gene in which mutations are known to cause MECP2-related disorders.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in MECP2-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method and Phenotype 3
Classic Rett SyndromeAtypical Rett SyndromeOther
MECP2Sequence analysis 4, 5, 6, 7Sequence variants80% 840% 8See footnote 9
Deletion/duplication analysis 10Partial- and whole-gene deletions8% 113% 11See footnote 12

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Bidirectional sequencing of the entire MECP2 coding region detects disease-causing mutations in approximately 80% of individuals with classic Rett syndrome [Fukuda et al 2005, Li et al 2007, Zahorakova et al 2007] and 40% of individuals with atypical Rett syndrome [Kammoun et al 2004, Fukuda et al 2005, Li et al 2007].

5. Laboratories serving specific populations may offer targeted sequence analysis for specific mutations.

6. Some laboratories may offer tiered testing of select exons, beginning with those in which most mutations have been identified.

7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

9. Other phenotypes associated with MECP2 sequence variants include: (a) nonspecific intellectual disability: 0.5% [Donzel-Javouhey et al 2006, Moog et al 2006, Campos et al 2007, Lesca et al 2007]; (b) autism: ~0.3% [Coutinho et al 2007, Wong & Li 2007, Xi et al 2007]; (c) Angelman syndrome:~1.5% [Hitchins et al 2004, Kleefstra et al 2004, Ylisaukko-Oja et al 2005]; (b) severe encephalopathy in males (percentage unknown).

10. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

11. Overall, large deletions account for approximately 8% of classic Rett syndrome and 3% of atypical Rett syndrome. Among individuals who do not have a mutation identified by sequence analysis, 30% with classic Rett syndrome had large deletions [Archer et al 2006, Pan et al 2006, Zahorakova et al 2007], while 7% with atypical Rett syndrome had large deletions [Laccone et al 2004, Archer et al 2006].

12. Phenotypes associated with MECP2 duplications include: (a) severe intellectual disability in males: ~2.5% [Van Esch et al 2005, Lugtenberg et al 2006, Lugtenberg et al 2009]; (b) X-linked intellectual disability: ~1% [ Lugtenberg et al 2009]; (c) severe encephalopathy in females: rare [Lugtenberg et al 2009].

Interpretation of test results

If the pathogenic significance of a sequence variation is uncertain, testing of both parents for the identified sequence variation may help resolve this uncertainty.

Testing Strategy

To confirm/establish the diagnosis in a proband. Testing for MECP2 mutations begins with sequencing for all exons 1-4, followed by deletion/duplication analysis if sequencing is normal. Some laboratories offer tiered testing of exons 2-4, followed by exon 1 (see Molecular Genetics, Pathogenic allelic variants)

Carrier testing for at-risk relatives. Once a pathogenic mutation has been identified in a proband, it is appropriate to offer testing to all first-degree female relatives regardless of their clinical status, and first-degree male relatives who have neurologic or neurodevelopmental abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities. MECP2 mutations are typically lethal in males with a 46,XY karyotype; rare surviving males with neonatal encephalopathy and intellectual disability have been reported [Orrico et al 2000, Villard et al 2000, Masuyama et al 2005].

Classic Rett Syndrome

Most individuals with classic Rett syndrome are female; however, males meeting the clinical criteria for classic Rett syndrome who have a 47,XXY karyotype [Hoffbuhr et al 2001, Leonard et al 2001, Schwartzman et al 2001] and postzygotic MECP2 mutations resulting in somatic mosaicism have been described [Clayton-Smith et al 2000, Topcu et al 2002].

Neurologic findings. Affected girls usually have a normal birth and neonatal course followed by apparently normal psychomotor development during the first six to 18 months of life, although analysis of retrospective data shows that the majority of these children have subtle behavioral differences in early infancy. They are described as very placid, with poor suck or a weak cry [Burford 2005, Einspieler et al 2005].

Head growth may begin decelerating as early as age three months, and brain size may eventually be smaller than normal by 30% or more. However, microcephaly is not an invariant feature of Rett syndrome: Oexle et al [2005] reported an adult woman with a MECP2 mutation and intellectual disability, seizures, and macrocephaly.

Affected girls then enter a short period of developmental stagnation followed by rapid regression in language and motor skills. The hallmark of classic Rett syndrome is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements. Most parents describe screaming fits and inconsolable crying by age 18-24 months. Additional characteristics include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, seizures, gait ataxia and apraxia, and tremors. After this period of rapid deterioration, the neurologic manifestations become relatively stable, although girls will likely develop dystonia and foot and hand deformities as they grow older.

Seizures are reported in up to 90% of females with Rett syndrome; generalized tonic-clonic seizures and partial complex seizures are the most common [Steffenburg et al 2001]. Additional manifestations of seizure activity include focal clonic activity, head or eye deviation, and/or apnea [Glaze et al 1998]. Seizure frequency is greatest when the disease stabilizes and then often decreases during the late motor deterioration stage. Activity described as seizures may not be associated with epileptiform activity on EEG, and clinical events accompanying EEG epileptiform activities are not always recognized as seizures by the parents [Glaze 2005].

Certain EEG findings common to Rett syndrome are not unique to Rett syndrome and thus are not diagnostic. Nonetheless, it may be helpful to know that EEG shows slowing of the occipital dominant rhythm and background activity with spike or sharp wave discharges during sleep early in the disease course. During the regression stage, EEG shows loss of occipital dominant rhythm, further slowing of background activity, and loss of non-rapid eye movement sleep characteristics. Theta and delta activity is markedly slowed, with multifocal spike and wave discharges. Video/EEG monitoring reveals frequent episodes of apnea and hyperventilation, laughing, screaming, and vacant staring spells. Focal electrographic seizures are usually associated with focal clonic activity, head or eye deviation, and sometimes apnea. Generalized electrographic seizures are frequently accompanied by absence episodes or flexor spasms.

Other findings in classic Rett syndrome

  • Growth failure and wasting that worsen with age are observed in 85%-90% of girls with classic Rett syndrome [Motil et al 1998], perhaps in part caused by oropharyngeal and gastroesophageal incoordination that result in poor food intake [Motil et al 1999].
  • Bowel dysmotility, constipation, and functional megacolon are common; in extreme cases, fecal impaction, volvulus, and intussusception occur.
  • Gallbladder dysfunction, including gallstones seem to be more frequent in children with Rett syndrome than in the age-related general population [Percy & Lane 2005, International Rett Syndrome Association].
  • Intermittent esotropia is common.
  • Vasomotor changes are often noted, especially in the lower limbs.
  • Some degree of scoliosis is observed in more than 80% of individuals by age 25 years [Kerr et al 2003].
  • Osteopenia occurs in up to 74% in females with Rett syndrome under age 20 years, including very young girls [Leonard et al 1999]. The associated decreased bone mineral density increases the risk of fractures [Budden & Gunness 2001]. Ambulatory individuals have better bone mineral density than non-ambulatory individuals [Cepollaro et al 2001].

Life expectancy in classic Rett syndrome. Females with Rett syndrome typically survive into adulthood; but the incidence of sudden, unexplained death is significantly higher than in controls of similar age [Kerr & Julu 1999]. This sudden death may in part be caused by the higher incidence of longer corrected QT intervals, T-wave abnormalities, and reduced heart rate variability in Rett syndrome [Guideri et al 1999].

Variant Rett Syndrome

Hagberg & Gillberg [1993] described five possible Rett syndrome variants, or atypical forms:

  • A form seen in females with apparently classic Rett syndrome in whom the presentation is dominated by seizures and onset is before age six months. Note: Individuals with this phenotype who are MECP2 mutation negative may have mutations in CDKL5 [Tao et al 2004, Weaving et al 2004, [Evans et al 2005a, Scala et al 2005].
  • Congenital or precocious Rett syndrome, in which regression is never clearly identified but the clinical picture is otherwise classic. Individuals with this phenotype who are MECP2 mutation negative may have mutations in FOXG1 [Ariani et al 2008].
  • A form in which regression develops later and more gradually than in classic Rett syndrome
  • 'Forme fruste' Rett syndrome, with a milder, incomplete, and protracted clinical course. Regression occurs later (age 1-3 years) and is not as severe as that in classic Rett syndrome, as hand use may be preserved and stereotypic hand movements may be minimal or atypical.
  • 'Preserved speech' variant. The MECP2 mutation p.Arg133Cys is particularly common in this group.

MECP2 mutations may be found in clinically suspected but molecularly unconfirmed Angelman syndrome. In these individuals neurodevelopmental regression (not usually a feature of Angelman syndrome) is seen. Although early studies suggested that up to 10% of individuals with apparent Angelman syndrome but without other recognized chromosome 15q11.2-13 molecular abnormalities could have a MECP2 mutation, more recent studies indicate that this proportion is closer to 1.5% [Hitchins et al 2004, Kleefstra et al 2004, Ylisaukko-Oja et al 2005].

Other Phenotypes Observed Primarily in Females

Rarely, MECP2 mutations have been found in females with mild learning disability [Orrico et al 2000].

MECP2 mutations have even been identified in a few women with no apparent symptoms who demonstrate highly skewed X-chromosome inactivation [Wan et al 1999, Amir et al 2000].

Neonatal Encephalopathy

MECP2 mutations are nearly always male lethal. In the rare surviving males, the most common clinical presentation is the so-called severe neonatal-onset encephalopathy with microcephaly, a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities (including central hypoventilation or respiratory insufficiency) [Wan et al 1999, Villard et al 2000, Zeev et al 2002, Kankirawatana et al 2006]. Often, males with MECP2 mutations have such a severe neonatal encephalopathy that they die before age two years [Schanen et al 1998, Wan et al 1999].

The severe encephalopathy phenotype appears to be rare in females [Lugtenberg et al 2009].

X-Linked Intellectual Disability (including PPM-X Syndrome)

MECP2 mutations may also be found in families exhibiting X-linked intellectual disability, which may range from mild, non-progressive intellectual disability in females to severe intellectual disability in males associated with manic-depressive psychosis, pyramidal signs, parkinsonian features, and macro-orchidism (the so-called PPM-X syndrome) [Dotti et al 2002, Klauck et al 2002, Gomot et al 2003]. Affected males usually have severe intellectual disability, a resting tremor, and slowness of movements and ataxia, but no seizures or microcephaly. MRI of the brain, EEG, EMG, and nerve conduction velocity studies are usually normal.

Genotype-Phenotype Correlations

Genotype-phenotype correlation studies have so far yielded inconsistent results.

Cheadle et al [2000] and Huppke et al [2000] both reported several individuals with the same mutation but different phenotypes, findings suggesting that factors other than mutation type influence disease severity. One such factor is the pattern of X-chromosome inactivation (XCI); females who have a mutation but have favorably skewed XCI may have mild or no symptoms [Wan et al 1999, Amir et al 2000].

Weaving et al [2003] showed that clinical severity can in part be predicted based on the type of mutation (missense versus truncation), its location (particularly when positioned within a functional domain), and the presence of skewed X-chromosome inactivation (XCI) [Weaving et al 2003]; similar conclusions were reached by Chae et al [2004], Schanen et al [2004], and Charman et al [2005].

Because some of the missense mutations (e.g., p.Ala140Val) do not totally inactivate the protein, they cause intellectual disability in males but only very mild cognitive impairment in females [Dotti et al 2002, Klauck et al 2002, Gomot et al 2003].

Leonard et al [2003] determined that the phenotype of individuals with the p.Arg133Cys mutation is less severe than the usual phenotype, which is consistent with in vitro functional studies demonstrating that p.Arg133Cys does not impair binding to DNA.

Amir et al [2000] found a positive correlation between truncating mutations and breathing abnormalities, whereas scoliosis was more common in individuals with missense mutations. Neither the overall severity score nor other parameters (age of onset, mortality, seizures, and somatic growth failure) correlated with the type of mutation.

Cheadle et al [2000] found significantly milder disease in individuals with missense mutations than in those with truncating mutations; they also found that truncating mutations towards the 3’ end of the coding sequence produced milder phenotypes than truncating mutations located towards the more 5’ end of the coding sequence.

Penetrance

Occasionally, females who are obligate heterozygous for a pathogenic MECP2 mutation may have no clinical evidence of an abnormal neurologic phenotype—the result of protective, highly skewed X-chromosome inactivation.

Nomenclature

Females who fulfill all of the diagnostic criteria for Rett syndrome are classified as having typical or classic Rett syndrome. With increasing experience, it has become clear that females with MECP2 mutations present with a much broader phenotype than originally described, including variant Rett syndrome which may be milder or more severe than classic Rett syndrome.

Prevalence

The prevalence of Rett syndrome in females is estimated to be 1:8,500 by age 15 years [Laurvick et al 2006].

Differential Diagnosis

Rett syndrome and variant Rett syndrome multi-gene panels may include testing for a number of the genes associated with the disorders discussed in this section. Note: The genes involved and methods used vary by laboratory.

Angelman syndrome (AS) is characterized by intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor. Microcephaly and seizures are common. Developmental delay is first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. Developmental regression should help distinguish variant Rett syndrome from Angelman syndrome clinically, and seizures tend to be much more difficult to manage in Angelman syndrome than in variant Rett syndrome, except for the congenital onset and early seizure variants.

Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, uniparental disomy, or an imprinting defect; UBE3A sequence analysis detects mutations in an additional approximately 11% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have a presently unidentified genetic mechanism. Watson et al [2001] found MECP2 mutations in four of 25 females and one of 22 males who had a clinical diagnosis of AS but no molecular abnormality involving 15q11.2-13. Three of the five individuals subsequently demonstrated progressive clinical features more typical of variant Rett syndrome than AS.

Mutations in CDKL5, a gene also located on the X chromosome and encoding cyclin dependent-like kinase 5, have been identified in individuals with a Rett syndrome-like phenotype. Initially, reported individuals with CDKL5 mutations had an early-onset seizure variant of Rett syndrome, the so-called Hanefield variant [Tao et al 2004, Weaving et al 2004, Evans et al 2005a, Scala et al 2005, Bahi-Buisson et al 2008]; however, it appears that mutations in CDKL5 account for only a small subset of individuals with a Rett syndrome-like phenotype. It is now recognized that CDKL5 mutations are more likely to be found in females with early-onset severe seizures who have poor cognitive development but little in the way of Rett syndrome-like features [Archer et al 2006, Bahi-Buisson et al 2008], and may be found in males with severe-profound intellectual disability and early-onset intractable seizures [Elia et al 2008]. Moreover, the distinct clinical profile, including somewhat consistent soft dysmorphic facial features, has led to the proposal that individuals with CDKL5 mutations should be considered as having a disorder distinct from Rett syndrome [Fehr et al 2013].

Mutations in FOXG1 are associated with the congenital form of Rett syndrome [Ariani et al 2008, Bahi-Buisson et al 2010, Mencarelli et al 2010]. The gene was first implicated in Rett syndrome by identification of microdeletions at its genetic locus on 14q12 [Papa et al 2008, Jacob et al 2009]. FoxG1 is a winged-helix transcription factor, involved in telencephalic development [Martynoga et al 2005], and promotes neurogenesis and antagonizes neuronal differentiation [Dou et al 1999, Brancaccio et al 2010]. In addition to the nine reported cases of microdeletion, 20 point mutations have also been identified, predominantly in individuals with a short normal period of development before onset of regression, leading to severe intellectual impairment, developmental delay, postnatal microcephaly, seizures, dyskinesia and hypotonia [Kortüm et al 2011]. These features and a similar facial appearance between individuals with FOXG1 mutations has led to the suggestion that these individuals should be regarded as having the FOXG1 syndrome rather than a variant of Rett syndrome [Kortüm et al 2011].

In contrast to MECP2 and CDKL5, FOXG1 is an autosomal gene and mutations are equally likely to affect males as females. A frameshift mutation has been reported in a boy with features of the congenital variant of Rett syndrome [Le Guen et al 2011].

Duplications of FOXG1 are also found in individuals with epilepsy and intellectual impairment [Yeung et al 2009, Brunetti-Pierri et al 2011, Striano et al 2011, Tohyama et al 2011], highlighting the importance of gene dosage at this locus.

Table 2. Summary of Sequence Variations in Genes Associated with a Rett or Rett-Like Clinical Phenotype

Gene Pathogenic MutationsSilent Mutations or PolymorphismsUnknown Pathogenic Significance
MECP2396 (2847)64 (228) & 98 (515)191 (377)
CDKL578 (103)5 (11) & 22 (146) 27 (34)
FOXG118 (23)1 (2)1 (1)

Table is derived from the data contained within RettBASE (mecp2​.chw.edu.au; accessed 7-9-14). Numbers represent unique variations; numbers in parentheses represent the total number of entries in each category.

Cerebral palsy is often suspected in older individuals with Rett syndrome or males with spasticity, severe wasting, and intellectual disability. A detailed history of early childhood development in light of the revised diagnostic criteria [Neul et al 2010] and molecular genetic testing of MECP2 should reveal the proper diagnosis.

Autism. Individuals with Rett syndrome — especially those who do not have microcephaly, seizures, or kyphoscoliosis — may be diagnosed with autism; however, MECP2 mutations are not a significant cause of autism [Lobo-Menendez et al 2003, Coutinho et al 2007, Wong & Li 2007, Xi et al 2007]. See Autism Overview.

MECP2-related disorders should be considered in male infants with neonatal encephalopathy or severe hypotonia, or in families with a history of X-linked intellectual disability.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a MECP2-related disorder, the following evaluations should be considered:

  • Formal developmental assessment
  • Assessment of feeding/eating, digestive problems (including constipation and gastroesophageal reflux), and nutrition using history, growth measurements and, if needed, gastrointestinal investigations
  • History of sleep and/or breathing problems
  • Video/EEG monitoring to obtain definitive information about the occurrence of seizures and the need for antiepileptic drugs
  • Screening for prolonged QTc by ECG and Holter monitoring
  • Consider assessment of brain stem autonomic dysfunction to identify appropriate therapies, although this remains controversial [Julu et al 2001, Julu & Witt Engerström 2005]
  • Examination for scoliosis
  • Medical genetic consultation

Treatment of Manifestations

The treatment program needs to be individualized following an assessment of the affected individual’s clinical problems and needs.

Management is mainly symptomatic and focuses on optimizing the individual's abilities using a dynamic multidisciplinary approach, with specialist input from dietitians, physiotherapists, and occupational, speech, and music therapists [Lotan et al 2004, Weaving et al 2005].

Psychosocial support for families is an integral part of management.

Therapeutic horseback riding, swimming, and music therapy have been reported to be of benefit.

Effective communication strategies, including the use of augmentative communication techniques, need to be explored for these severely disabled individuals [Ryan et al 2004].

Treatment for seizures needs to be individualized with input from a pediatric neurologist. Topiramate may improve seizure control and/or respiratory abnormalities [Goyal et al 2004].

Risperidone (low dose) or selective serotonin uptake inhibitors have been somewhat successful in treating agitation.

Melatonin can ameliorate sleep disturbances [McArthur & Budden 1998]. Chloral hydrate, hydroxyzine, or diphenhydramine may be used along with melatonin.

Ample fluid intake and a high-fiber diet can help prevent acute intestinal obstruction. When diet is ineffective, Miralax® (polyethylene glycol) and other stool softeners may be used to control constipation; they are tolerated better than milk of magnesia.

Anti-reflux agents, smaller and thickened feedings, and positioning can decrease gastroesophageal reflux.

Scoliosis [Kerr et al 2003] and spasticity need to be treated to maintain mobility. Recently, guidelines were developed for the management of scoliosis in Rett syndrome [Downs et al 2009; click Image guidelines.jpg for full text (registration or institutional access required)].

Some individuals known to have prolonged QTc may benefit from the use of β-blockers or cardiac pacing, in consultation with a specialist pediatric cardiologist.

Prevention of Secondary Complications

Osteopenia may be avoided with careful attention to nutrition, particularly calcium intake.

Surveillance

The following are appropriate:

  • Examination at regular intervals by a multidisciplinary team with particular attention to growth, nutritional intake, dentition, gastrointestinal function, mobility and communication skills, hand function, and orthopedic and neurologic complications
  • Periodic ECG to screen for prolonged QTc
  • Examination at regular intervals for the progression of scoliosis

Agents/Circumstances to Avoid

Because individuals with Rett syndrome have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, avoidance of drugs known to prolong the QT interval, including the following, is recommended:

  • Prokinetic agents (e.g., cisapride)
  • Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine)
  • Antiarrhythmics (e.g., quinidine, sotolol, amiodarone)
  • Anesthetic agents (e.g., thiopental, succinylcholine)
  • Antibiotics (e.g., erythromycin, ketoconazole)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A number of clinical trials are currently being conducted, including both observational and interventional studies. Phase I and II trials of parenteral administration of the tri-peptide form of insulin-like growth factor, rhIGF-1 (mecasermin [rDNA]), are currently underway. The tricyclic antidepressant desipramine (DMI) is currently in phase II studies, specifically focusing on the respiratory abnormalities associated with Rett syndrome. The NMDA receptor antagonist dextromethorphan (DM) is currently in trials targeting glutamate and NMDA receptor associated neuronal toxicity, and is focused on respiratory, seizure, and motor outcomes.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

The ketogenic diet has been tried in Rett syndrome with some improvement in seizure control and other modest subjective improvements [Haas et al 1986].

L-carnitine was tested in a double-blind trial. Although parents and caregivers reported improvements in the general well-being of individuals with Rett syndrome [Ellaway et al 1999], significant functional improvements were not observed.

Carbidopa/levodopa may be tried for treatment of rigidity seen in Rett syndrome, but its benefit is unsubstantiated.

Following the report of reduced CSF folate concentration in four females with Rett syndrome [Ramaekers et al 2003], Neul and colleagues analyzed CSF from an additional 76 individuals with Rett syndrome, but could not reproduce earlier findings, and found that supplementation with folinic acid did not lead to any noticeable clinical improvements [Neul et al 2005]. It therefore remains to be established whether cerebral folate deficiency contributes to the pathophysiology of Rett syndrome.

Because elevated opioids had been observed in the CSF of individuals with Rett syndrome, the oral opiate antagonist, naltrexone, was investigated. Although it decreased breathing dysrhythmias and had some sedating properties, the efficacy of naltrexone is controversial [Percy et al 1994].

Based on the hypothesis that altering DNA methylation could improve global DNA methylation and thereby improve residual MeCP2 function, a trial of oral creatine has been undertaken. A statistical increase in global DNA methylation was seen. Improvement in the total and subscores of the Rett Syndrome Motor and Behavioral Assessment was observed, although it did not reach statistical significance [Freilinger et al 2011].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MECP2-related disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of a female proband

Parents of a male proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • When the mother of an affected individual has the same MECP2 mutation as her affected child, the risk to sibs at conception of inheriting the mutant MECP2 allele is 50%.
  • If a mutation is not detected in a parent, the risk to sibs is low. However, germline mosaicism in either parent cannot be excluded even if the disease-causing MECP2 mutation present in the proband has not been found in DNA extracted from the leukocytes of either parent. Germline mosaicism has been reported [Amir et al 1999, Zeev et al 2002, Mari et al 2005].

Offspring of a female proband

  • Each child of an individual with a MECP2-related disorder has a 50% chance of inheriting the mutation. Although individuals with classic Rett syndrome do not reproduce, mildly affected females have reproduced.
  • Females who inherit the mutation are at high risk of developing Rett syndrome, although skewed X-chromosome inactivation may result in a variable phenotype.
  • Males who inherit the mutation may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.

Offspring of a male proband. No male with a MECP2 mutation has been known to reproduce.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's mother. If the mother is affected or has a MECP2 mutation, her family members may be at risk.

Related Genetic Counseling Issues

As with many other genetic conditions, the diagnosis of a MECP2-related disorder in a family member may result in evaluation and diagnosis of the mother and other family members who were previously unaware of the presence of a genetic disorder in the family. This discovery can be difficult for the family because of its implications for their own health and because of a sense of "responsibility" for illness in their children. Efforts should be made to anticipate these issues.

Apparently unaffected sisters of a girl with classic Rett syndrome could have the MECP2 mutation that is present in their sister but have few to no symptoms because of skewed X-chromosome inactivation. Genetic counseling needs to address this possibility, as the unaffected sisters may be at risk of transmitting the disease-causing MECP2 mutation to their children.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected or are at risk of having a MECP2 mutation.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Pregnancies of women with a known MECP2 mutation. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Male fetuses with a MECP2 mutation who survive infancy will most likely have severe intellectual disability. The phenotype in a female with a MECP2 mutation is difficult to predict; it can range from apparently normal to severely affected.

Pregnancies of a couple who have a child with a MECP2-related disorder. Germline mosaicism cannot be excluded in either parent even when the disease-causing MECP2 mutation present in the proband is not detected in DNA extracted from parental leukocytes; thus, it is appropriate to offer prenatal diagnosis to such couples whether or not the disease-causing mutation has been identified in a parent [Armstrong et al 2002]. One of nine pregnancies of women who did not have evidence of the MECP2 mutation identified in their daughters with classic Rett syndrome resulted in the birth of a daughter with the same MECP2 mutation as the proband [Mari et al 2005].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Rett Syndrome Foundation (IRSF)
    4600 Devitt Drive
    Cincinnati OH 45246
    Phone: 800-818-7388 (toll-free); 513-874-3020
    Fax: 513-874-2520
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Rett Syndrome Research Trust
    67 Under Cliff Road
    Trumbull CT 06611
    Phone: 203-445-0041
    Fax: 203-445-9234
    Email: monica@rsrt.org
  • Rett UK
    Langham House West
    Mill Street
    Luton LU1 2NA
    United Kingdom
    Phone: 01582 798 910
    Email: info@rettuk.org
  • Angelman, Rett & Prader-Willi Syndromes Rare Disease Consortium Registry
  • Australian Rett Syndrome Study / InterRett Registry
    Telethon Institute for Child Health Research
    PO Box 855
    West Perth 6872
    Australia
    Phone: +61 8 9489 7790; +61 419 956 946
    Fax: +61 8 9489 7700
    Email: rett@ichr.uwa.edu.au

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. MECP2-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for MECP2-Related Disorders (View All in OMIM)

300005METHYL-CpG-BINDING PROTEIN 2; MECP2
300673ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATIONS
312750RETT SYNDROME; RTT

Molecular Genetic Pathogenesis

The principal characteristics of Rett syndrome and their developmental pattern indicate that abnormal development of the cortex in late infancy may result from dysregulation of subcortical regulator systems, brain stem, basal forebrain nuclei, and basal ganglia. Brain stem involvement is apparent based on many of the functional disturbances in Rett syndrome: breathing, cardiac rate, swallowing, peripheral vasomotor disturbances, sleep, bowel motility, salivation, and pain discrimination. These findings suggest dysregulation of autonomic tone with failure to regulate vagal (parasympathetic) tone and respiratory rhythm, suggesting immaturity of the respiratory regulator. The neuropathology of affected individuals demonstrates that the brains are small and closely packed with neurons. Decreased dendritic spines and arbors have been noted in brain neuropathology [Armstrong 2005].

The abundantly expressed nuclear protein MeCP2 is thought to mediate transcriptional silencing and epigenetic regulation of methylated DNA through its association with 5-methylcytosine (5-mC)-rich heterochromatin [Tate et al 1996, Nan et al 1998]. The methyl CpG-binding domain (MBD) of MeCP2 binds to symmetrically methylated CpG dinucleotides; the transcriptional repression domain (TRD) interacts with the co-repressor Sin3A, and together they recruit histone deacetylases [Jones et al 1998, Nan et al 1998, Ng & Bird 1999]. When lysine residues of the core histones H3 and H4 become deacetylated, the chromatin structure changes and renders the DNA inaccessible to the transcriptional machinery. DNA methylation-dependent repression is important for X-chromosome inactivation (XCI) and genomic imprinting. MeCP2 is expressed in all tissues and was hypothesized to act as a global transcriptional repressor [Nan et al 1998, Coy et al 1999].

Most MECP2 mutations are de novo. The leading hypothesis holds that MeCP2 dysfunction resulting from mutation in the TRD or MBD disrupts the delicate precision of gene expression during development. Some mutations affect residues that are important for DNA binding, whereas others may disrupt the native structure of the protein and/or its interactions with other proteins. The documented nonsense, frameshift, and splicing mutations, most of which are distal to the MBD, likely result in premature termination of the protein. Truncated proteins may still bind methylated DNA but be unable to interact with the corepressor Sin3A; it is also possible that mutations in the carboxy terminus of the protein disable DNA binding [Chandler et al 1999]. In either case, the silencing complex would not be properly assembled and the target genes could not be properly silenced.

It is puzzling that a ubiquitously expressed gene should give rise to a predominantly neurologic phenotype. Brain tissues may be more vulnerable to compromises in MeCP2 function, or tissue-specific differences in MeCP2 expression levels may occur. (There are, in fact, alternate transcripts that are differentially expressed in the brain during development [Kriaucionis & Bird 2004, Mnatzakanian et al 2004].) Alternatively, the post-mitotic nature of neurons may make them more susceptible to the ill effects of MeCP2 dysfunction. To understand the pathogenesis of Rett syndrome, it will first be necessary to identify the genes normally targeted by MeCP2 activity. MeCP2 has been known to silence specific genes, such as brain-derived neurotrophic factor [Chen et al 2003, Martinowich et al 2003], Hairy2a [Stancheva et al 2003], Dlx5 [Horike et al 2005], and sgk [Nuber et al 2005]. More recently, studies of a mouse model with a Mecp2 knockout and a trangenic mouse model with overexpression of human MECP2, led to the discovery that MeCP2 may not only be a transcriptional repressor but also a transcriptional activator [Chahrour et al 2008]. The constellation and consistency of features among individuals with classic Rett syndrome suggest that the disorder may be attributable to the dysfunction of a select group of genes. Functional studies of the various mutations and analysis of animal models for Rett syndrome may illuminate the pathogenesis of the disorder and establish how DNA methylation-dependent processes are disrupted.

It has also been shown that MeCP2 plays a role in gene splicing [Young et al 2005] and in long-range chromatin remodeling [Horike et al 2005], and it is possible that abnormalities of these functions may be contributing to the pathophysiology associated with MeCP2 deficiency.

Different mouse models of Rett syndrome that lack functional MeCP2 have been made [Chen et al 2001, Guy et al 2001, Shahbazian et al 2002, Pelka et al 2006]. Male mice that are null are born alive and develop tremors, hypoactivity, and small brains. They typically die between age eight and 12 weeks [Chen et al 2001, Guy et al 2001]. Deletion of mouse Mecp2 in neurons produces a phenotype very similar to that seen with deletion of Mecp2 in all cells [Chen et al 2001], indicating that despite its purported role as a global transcriptional repressor, MeCP2 function — or one of its functions — may be most critical in neurons. Other mouse models, including one caused by a C-terminal deletion [Shahbazian et al 2002], and knock-ins of a common human mutation, p.Arg168Ter [Brendel et al 2011], and a less common one, p.Thr158Ala [Goffin et al 2011], recapitulate many features of the human disorder.

Studies in mouse models and in humans [Horike et al 2005, Kaufmann et al 2005, Makedonski et al 2005] demonstrated that Mecp2 deficiency leads to epigenetic aberrations of chromatin suggesting that Mecp2 deficiency could lead to loss of imprinting, thereby contributing to the pathogenesis of Rett syndrome. Similarly, mouse models and human studies show overexpression of MeCP2 protein, which could have detrimental effects on brain development and function [Collins et al 2004, Shi et al 2005, Van Esch et al 2005].

Gene structure. The longest transcript, NM_001110792.1, encodes a polypeptide of 498 amino acids, and includes exons 1, 3, and 4 but not exon 2. This is the MECP2_e1 transcript. The shorter transcript, NM_004992.3, encodes a polypeptide of 486 amino acids, and includes exons 2, 3, and 4 but not exon 1. This is the MECP2_e2 transcript. The e1 transcript is much more highly expressed in brain than the e2 transcript.

MECP2 contains four exons, transcribed from telomere to centromere. Exons 2, 3, and 4 were thought to contain the coding sequence; the first exon was identified through sequence homology between species and was thought to contain a non-coding 5' untranslated region (UTR) [Reichwald et al 2000]. However, it has been shown that a transcript containing exon 1 is the predominant isoform in the brain [Kriaucionis & Bird 2004, Mnatzakanian et al 2004]. Most of exon 4 encodes the unusually long (8.5-kb) 3' UTR; alternate polyadenylation sites here result in differentially expressed transcripts of various sizes, all encoding for the same size protein.

The significance of the mRNA features with regard to stability, regulation, and function is currently not well understood [Coy et al 1999, Reichwald et al 2000] but may point to a potential, tissue-specific function of the 3' UTR in the regulation of MeCP2 protein synthesis in response to the age-specific requirement of MeCP2 function, at least in the mouse [Pelka et al 2005]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, more than 390 individual pathogenic variants have been described [Christodoulou et al 2003, RettBASE]; the eight most commonly occurring missense and nonsense mutations account for more than 50% of all mutations. Small deletions associated with a deletion hotspot in the C-terminal region of the MeCP2 protein account for an additional 7% of pathogenic mutations [RettBASE]. Although these deletions tend to affect the same region, completely identical deletions are rare.

Mutations are dispersed throughout the gene; however, a clustering of missense mutations occurs in the region encoding the methyl binding domain (MBD, exons 3 and 4; amino acids 90-174 of the MeCP2 e2 isoform), affecting the ability of the MeCP2 protein to bind to target DNA. A number of highly recurrent nonsense mutations are found in the transcriptional repression domain (TRD, exon 4; amino acids 219-322 of the MeCP2 e2 isoform) and beyond the TRD, a large number of frameshift mutations delete the C-terminal end of the protein (3' end of exon 4). More recently, large deletions (kilobases in size) that delete whole exons have been identified in a proportion of affected individuals who were previously considered to be mutation negative. These exonic deletions are more commonly found in females with classic Rett syndrome (36%; 46/128) than atypical Rett syndrome (3%; 7/229) [Ariani et al 2004, Laccone et al 2004, Amir et al 2005, Huppke et al 2005, Ravn et al 2005, Shi et al 2005, Archer et al 2006].

In contrast, pathogenic variants involving exon 1 appear to be only rarely associated with Rett syndrome [Amir et al 2005, Evans et al 2005b, Poirier et al 2005, Ravn et al 2005, Saxena et al 2006]. In almost all cases, the mutations are de novo; and some evidence suggests that, in the majority of cases, the mutation has arisen on the paternal X chromosome [Girard et al 2001, Trappe et al 2001]. To date, no pathogenic mutations have been identified in exon 2.

Table 3. Selected MECP2 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.397C>Tp.Arg133Cys 1, 2NM_004992​.3
NP_004983​.1
c.419C>Tp.Ala140Val 2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. See Variant Rett Syndrome

2. See Genotype-Phenotype Correlations

Normal gene product. The proteins resulting from the two MECP2 isoforms, created by alternative splicing of exon 2 and use of two alternative start codons, are almost identical but have alternative N-termini. Transcript variant NM_001110792.1 encodes a polypeptide of 498 amino acids (NP_001104262.1), while the NM_004992.3 variant encodes a polypeptide of 486 amino acids (NP_004983.1).

The MeCP2 protein has two major functional domains: the methyl binding domain (MBD), which binds specifically to DNA at methylated CpGs, and a transcription repression domain (TRD) that is responsible for recruiting other proteins that mediate transcription repression [Jones et al 1998, Nan et al 1998, Kokura et al 2001, Stancheva et al 2003, Harikrishnan et al 2005]. In addition, the MeCP2 protein has a WW domain at its C-terminus [Buschdorf & Stratling 2004]. The C-terminal domain shares homology with neuronal-specific transcription factors containing forkhead domains, suggesting that the protein may have additional, more complex, possibly neuronal-specific functions [Vacca et al 2001]. This region also contains evolutionarily conserved polyhistidine and polyproline regions that may play a role in the interaction of MECP2 with the nucleosome core [Chandler et al 1999]. Other evidence suggests that MeCP2 may play a role in mediating splicing [Young et al 2005]. See Weaving et al [2005] for MeCP2 domains.

Abnormal gene product. Functional studies have shown that MECP2 mutations affect the methyl binding or transcription repression properties of the mutant protein, depending on the location of the mutation [Kudo et al 2001, Kudo et al 2002, Kudo et al 2003]. MeCP2 binds specifically to certain DNA sequences [Klose et al 2005]. Several studies have identified specific MeCP2 targets, suggesting that downstream alterations in the expression of specific MeCP2 targets may contribute to the neurodevelopmental abnormalities seen in Rett syndrome and other MECP2-related disorders [Chen et al 2003, Martinowich et al 2003, Stancheva et al 2003, Horike et al 2005, Nuber et al 2005].

References

Published Guidelines/Consensus Statements

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Suggested Reading

  1. Caballero IM, Hendrich B. MeCP2 in neurons: closing in on the causes of Rett syndrome. Hum Mol Genet. 2005;14:19–26. [PubMed: 15809268]
  2. Segawa M, Nomura Y. Rett syndrome. Curr Opin Neurol. 2005;18:97–104. [PubMed: 15791137]
  3. Williamson SL, Christodoulou J. Rett syndrome: new clinical and molecular insights. Eur J Hum Genet. 2006;14:896–903. [PubMed: 16865103]
  4. Zoghbi HY, Francke U. Rett syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 255. 2014. Available online. Accessed 7-8-14.

Chapter Notes

Author History

Vicky L Brandt; Baylor College of Medicine (2000-2004)
John Christodoulou, MBBS, PhD, FRACP, FRCPA, FHGSA (2006-present)
Gladys Ho, BSc, MSc (2009-present)
Huda Y Zoghbi, MD; Baylor College of Medicine (2004-2006)

Revision History

  • 28 June 2012 (me) Comprehensive update posted live
  • 2 April 2009 (me) Comprehensive update posted live
  • 25 January 2008 (cd) Revision: MECP2 duplication syndrome added to Genetically Related Disorders
  • 15 August 2006 (me) Comprehensive update posted to live Web site
  • 11 February 2004 (me) Comprehensive update posted to live Web site
  • 3 October 2001 (me) Review posted to live Web site
  • September 2000 (vb) Original submission
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