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for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities; phenotypes in 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, mental retardation with spasticity or tremor, mild learning disability or rarely in individuals diagnosed with 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. Sequence analysis and deletion testing for exonic, multiexonic, and whole-gene deletions are available on a clinical basis. 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, 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. Over 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 somatic or 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.
The spectrum of phenotypes in MECP2-related disorders includes classic Rett syndrome, variant Rett syndrome, and mild learning disabilities in females and neonatal encephalopathy and syndromic or nonsyndromic mental retardation syndromes in 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 mental retardation.
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, the diagnostic criteria have been modified to resolve inconsistencies and ambiguities in the categorization of affected individuals into classic Rett syndrome (Table 1) or variant Rett syndrome (Table 2) [Hagberg et al 2002].
| Criteria | |
|---|---|
| Necessary | Normal prenatal and perinatal history Normal psychomotor development for the first six months Normal head circumference at birth Postnatal deceleration of head growth in most individuals Loss of purposeful hand skills between age six months and 2.5 years Hand stereotypies Evolving social withdrawal, communication dysfunction, loss of acquired speech, and cognitive impairment Impairment or deterioration of locomotion |
| Supportive | Breathing disturbances during waking hours Bruxism Impairment of sleeping pattern from early infancy Abnormal muscle tone associated with muscle wasting and dystonia Peripheral vasomotor disturbances Progressive kyphosis or scoliosis Growth retardation Hypotrophic, small, and cold feet and/or hands |
| Exclusion | Evidence of a storage disorder including organomegaly Cataract, retinopathy, or optic atrophy History of perinatal or postnatal brain damage Confirmed inborn error of metabolism or neurodegenerative disorder Acquired neurologic disorder caused by severe head trauma or infection |
| Criteria | |
|---|---|
| Inclusion | At least three of the six main criteria At least five of the 11 supportive criteria |
| Main | Reduction or absence of hand skills Loss or reduction of speech (including babble) Hand stereotypies Loss or reduction of communication skills Deceleration of head growth from early childhood Regression followed by recovery of interaction |
| Supportive | Breathing irregularities Abdominal bloating or air swallowing Bruxism Abnormal locomotion Kyphosis or scoliosis Lower limb amyotrophy Cold, discolored, and usually hypotrophic feet Night-time screaming and other sleep disturbances Inexplicable episodes of screaming or laughing Apparently diminished sensitivity to pain Intense eye contact and/or eye pointing |
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. MECP2 is the only gene known to be associated with MECP2-related disorders.
Clinical testing
Sequence analysis/mutation scanning. Bidirectional sequencing and/or mutation scanning (e.g., DHPLC) 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].
Deletion/duplication analysis. Such testing identifies exonic, multiexonic, and whole-gene deletions in 30% of individuals with classic Rett syndrome who do not have a mutation identified by sequence analysis [Archer et al 2006, Pan et al 2006, Zahorakova et al 2007] and 7% of individuals with atypical Rett syndrome who do not have a mutation identified by sequence analysis [Laccone et al 2004, Archer et al 2006]).
Overall, large deletions account for approximately 8% of classic Rett syndrome and 3% of atypical Rett syndrome.
Table 3 summarizes molecular genetic testing for this disorder.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Rate by Test Method and Phenotype | Test Availability | ||
|---|---|---|---|---|---|---|
| Classic Rett Syndrome | Atypical Rett Syndrome | Other | ||||
| MECP2 | Sequence analysis/ mutation scanning 1 | Sequence variants 2 | 80% | 40% | See footnote 4 | Clinical
 |
| Deletion/ duplication analysis 3 | Partial- and whole-gene deletions | 8% | 3% | See footnote 5 | ||
1. The sensitivity of complete bidirectional sequencing of all exons and the intron-exon boundaries of MECP2 is expected to be at least as great as that using mutation scanning.
2. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in females. However, lack of amplification by PCR prior to sequence analysis can suggest a putative exonic and whole-gene deletion on the X chromosome in males; confirmation requires deletion analysis.
3. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array CGH may be used.
4. Other phenotypes associated with MECP2 sequence variants:
Nonspecific mental retardation: 0.5% [Donzel-Javouhey et al 2006, Moog et al 2006, Campos et al 2007, Lesca et al 2007]
Autism: ~ 0.3% [Coutinho et al 2007, Wong & Li 2007, Xi et al 2007]
Severe encephalopathy in males: unknown
5. Phenotypes associated with MECP2 duplications:
Severe mental retardation in males: ~2.5% [Van Esch et al 2005, Lugtenberg et al 2006, Lugtenberg et al 2009]
X-linked mental retardation: ~1% [ Lugtenberg et al 2009]
Severe encephalopathy in females: rare [Lugtenberg et al 2009]
Interpretation of test results
For issues to consider in interpretation of sequence analysis results, click here.
If the pathogenic significance of a sequence variation is uncertain, testing of both parents for the identified sequence variation may help resolve this uncertainty.
Establishing the diagnosis in a proband. Testing for MECP2 mutations begins with sequencing or mutation scanning methods for exons 3 and 4, followed by deletion analysis. If no mutation is identified, sequencing of exon 1 should be performed.
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.
MECP2 duplication syndrome, characterized by infantile hypotonia, severe mental retardation, absence of speech, progressive spasticity, recurrent respiratory infections, and seizures, results from duplications of the MECP2 gene ranging in size from 0.3 to 2.3 Mb [Van Esch et al 2005, Friez et al 2006].
MECP2-related disorders include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities in females, and neonatal encephalopathy and mental retardation in males. Males with a 46,XY karyotype can have mutations in MECP2 [Orrico et al 2000, Villard et al 2000, Masuyama et al 2005].
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 post-zygotic 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 mental retardation, 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 the 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, the 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 is 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].
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 more like 1.5% [Hitchins et al 2004, Kleefstra et al 2004, Ylisaukko-Oja et al 2005].
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].
Although MECP2 mutations in males are rare, the most common clinical presentation is as 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 their second year [Schanen et al 1998, Wan et al 1999].
The severe encephalopathy phenotype appears to be rare in females [Lugtenberg et al 2009].
MECP2 mutations may also be found in families exhibiting X-linked mental retardation, which may range from mild, non-progressive mental retardation in females to severe mental retardation 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 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, such as p.Ala140Val, do not totally inactivate the protein, they cause mental retardation 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.
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.
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.
The prevalence of Rett syndrome in females is estimated to be 1:8,500 by age 15 years [Laurvick et al 2006].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Angelman syndrome (AS) is characterized by mental retardation, 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. Virtually all individuals with CDKL5 mutations reported to date have 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 seems that mutations in this gene account for only a small subset of individuals with a Rett syndrome-like phenotype. In addition, CDKL5 mutations are found in a significant proportion of 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].
Cerebral palsy is often suspected in older individuals with Rett syndrome or males with spasticity, severe wasting, and mental retardation. A detailed history of early childhood development in the light of the revised diagnostic criteria [Hagberg et al 2002] 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 mental retardation.
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
Assessment of brain stem autonomic dysfunction to identify appropriate therapies [Julu et al 2001, Julu & Witt Engerström 2005]
Examination for scoliosis
The treatment program needs to be individualized following an assessment of the patient’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 blockage. 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.
Some patients known to have prolonged QTc may benefit from the use of β-blockers or cardiac pacing, in consultation with a specialist pediatric cardiologist.
Osteopenia may be avoided with careful attention to nutrition, particularly calcium intake.
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
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)
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
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 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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
MECP2-related disorders are inherited in an X-linked manner.
Parents of a female proband
Approximately 99.5% of cases are single occurrences in a family, resulting either from a de novo mutation in the child with a MECP2-related disorder or from inheritance of the disease-causing mutation from one parent who has germline mosaicism. If the disease-causing MECP2 mutation has been identified in the proband, it is appropriate to offer molecular genetic testing to the mother, and to both parents if the significance of the identified MECP2 variation is unclear.
A mother who has a MECP2 mutation may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected.
Parents of a male proband
The father of an affected male will not have a MECP2-related disorder nor will he be a carrier of the MECP2 mutation.
If the disease-causing MECP2 mutation has been identified in the proband, it is appropriate to offer molecular genetic testing to the mother.
A mother who has a MECP2 mutation may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected.
Sibs of a proband
The risk to sibs depends on the genetic status of the parents.
When the mother of an affected individual is found to have the MECP2 mutation identified in 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 mental retardation 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 found to be affected or to have a MECP2 mutation, her family members may be at risk.
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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Pregnancies of women with a known MECP2 mutation. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
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 mental retardation. 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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| MECP2 | Xq28 | Methyl-CpG-binding protein 2 |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 300005 | METHYL-CpG-BINDING PROTEIN 2; MECP2 |
| 300673 | ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATIONS |
| 312750 | RETT SYNDROME; RTT |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| MECP2 | MECP2 | 4204 (MIM No. 300005) | MECP2 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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 [Nan et al 1998, Tate et al 1996]. 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 mutations 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 the human MECP2 gene, 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.
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 the mouse Mecp2 gene 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.
Studies in mouse models and in humans [Horike et al 2005, Kaufmann et al 2005, Makedonski et al 2005] show 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].
Normal allelic variants. The MECP2 gene 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 more recently 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].
Pathologic allelic variants. To date, more than 270 individual pathogenic mutations have been described [Christodoulou et al 2003]; the eight most commonly occurring missense and nonsense mutations account for almost 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 5' of the transcriptional repression domain (TRD), mostly in the methyl binding domain (MBD); another clustering of nonsense and frameshift mutations appears beyond the MBD. 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].
On the other hand, pathogenic mutations 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].
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.397C>T | p.Arg133Cys | NM_004992.3NP_004983.1 |
| c.419C>T | p.Ala140Val |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
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.
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].
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].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
International Rett Syndrome Foundation
4600 Devitt Drive
Cincinnati OH 45246
Phone: 800-818-7388; 513-874-3020
Fax: 513-874-2520
www.rettsyndrome.org
National Library of Medicine Genetics Home Reference
Rett syndrome
NCBI Genes and Disease
Rett syndrome
Angelman, Rett & Prader-Willi Syndromes Consortium Registry
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza Room T619
Houston TX 77030
Phone: 713-798-4795
Fax: 713-798-7773
Email: sweaver@bcm.tmc.edu
Angelman, Rett & Prader-Willi Syndromes Consortium Registry
InterRett: International Rett Syndrome database
The Australian Rett Syndrome Study
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
InterRett
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
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)
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
