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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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MECP2 Disorders

, MSc, M Phil and , MBBS, PhD, FRACP, FFSc, FRCPA, FAHMS.

Author Information and Affiliations

Initial Posting: ; Last Update: September 19, 2019.

Estimated reading time: 37 minutes

Summary

Clinical characteristics.

The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability.

  • Females: 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.
  • Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.

Diagnosis/testing.

The diagnosis of a MECP2 disorder is established by molecular genetic testing in a female proband with suggestive findings and a heterozygous MECP2 pathogenic variant, and in a male proband with suggestive findings and a hemizygous MECP2 pathogenic variant.

Management.

Treatment of manifestations: Treatment is mainly symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach that should also 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 per standard care.

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 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 pathogenic variant or possibly from inheritance of the pathogenic variant from a parent who has germline mosaicism. Rarely, a MECP2 variant may be inherited from a heterozygous mother in whom favorable skewing of X-chromosome inactivation results in minimal to no clinical findings. When the mother is a known heterozygote, the risk to her offspring of inheriting the MECP2 variant is 50%. When the pathogenic MECP2 variant has been identified in the family, heterozygote testing for at-risk female relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible. Because of the possibility of parental germline mosaicism, it is appropriate to offer prenatal diagnosis to couples who have had a child with a MECP2 disorder regardless of whether the MECP2 pathogenic variant has been detected in a parent.

GeneReview Scope

MECP2 Disorders: Included Phenotypes 1, 2
Females
  • MECP2 classic Rett syndrome
  • Variant Rett syndrome
  • Mild learning disabilities
Males
  • MECP2-related severe neonatal encephalopathy
  • Pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome
  • Syndromic/nonsyndromic intellectual disability
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

2.

Note: The allelic disorder MECP2 duplication syndrome is not included in this GeneReview. See Genetically Related Disorders.

Diagnosis

Note: Duplication of MECP2 (ranging from 0.3 to 4 Mb and larger) is associated with the allelic disorder MECP2 duplication syndrome and is not addressed in this GeneReview.

Suggestive Findings in Females

A MECP2 disorder should be suspected/considered in females with the following clinical findings suggestive of MECP2 classic Rett syndrome or variant Rett syndrome (based on clinical diagnostic criteria published by Neul et al [2010] [full text] prior to the widespread availability of molecular genetic testing), or mild learning disabilities.

Clinical findings of MECP2 classic Rett syndrome and variant Rett syndrome

  • Most distinguishing finding: A period of regression (range: ages 1-4 years) followed by recovery or stabilization (range: ages 2-10 years; mean: age 5 years)
  • Main findings
    • 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
  • Supportive findings
    • Breathing disturbances when awake
    • Bruxism when awake
    • Impaired sleep pattern
    • Abnormal muscle tone
    • Peripheral vasomotor disturbances
    • Scoliosis/kyphosis
    • Growth restriction
    • Small, cold hands and feet
    • Inappropriate laughing/screaming spells
    • Diminished response to pain
    • Intense eye communication – "eye pointing"
  • Exclusionary findings
    • 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

Clinical findings of MECP2 mild learning disability. Typically mild and non-progressive. Note: Typically, females with mild learning disability are identified through molecular genetic testing following diagnosis of a first-degree relative (e.g., a more significantly affected brother or sister).

Suggestive Findings in Males

MECP2 disorders should be considered in a male with severe neonatal encephalopathy; pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome; or syndromic/nonsyndromic intellectual disability.

Clinical findings of MECP2 severe neonatal encephalopathy

  • Microcephaly
  • Relentless clinical course that follows a metabolic-degenerative type of pattern
  • Abnormal tone
  • Involuntary movements
  • Severe seizures
  • Breathing abnormalities (including central hypoventilation or respiratory insufficiency)

Clinical findings of MECP2 severe intellectual disability (including PPM-X syndrome)

  • Moderate-to-severe intellectual disability
  • Resting tremor
  • Slowness of movements
  • Ataxia
  • PPM-X syndrome: pyramidal signs, parkinsonism, and macroorchidism
  • No seizures or microcephaly
  • Usually normal brain MRI, EEG, EMG, and nerve conduction velocity studies

Establishing the Diagnosis

Female proband. The diagnosis of a MECP2 disorder is usually established in a female proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in MECP2 identified by molecular genetic testing (see Table 1).

Male proband. The diagnosis of a MECP2 disorder is established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in MECP2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous MECP2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (either single-gene, multigene panel) or comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MECP2 disorders is broad, females with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas females and males with a phenotype indistinguishable from many other inherited disorders with intellectual disability and/or neonatal encephalopathy are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the clinical findings suggest the diagnosis of a MECP2 disorder, molecular genetic testing approaches can include use of single-gene testing or a multigene panel:

  • Single-gene testing. Sequence analysis of MECP2 detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • Various multigene panels such as Rett/Angelman syndrome panels and more comprehensive childhood-onset epilepsy panels that include MECP2 and other genes of interest (see Differential Diagnosis) are most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype overlaps with many other inherited disorders characterized by intellectual disability and/or neonatal encephalopathy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in MECP2 Disorders

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
MECP2 Sequence analysis 390%-95% 4
Gene-targeted deletion/duplication analysis 55%-10% 6, 7
1.

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

2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Hardwick et al [2007]) may not be detected by these methods.

6.

The sizes of many reported disease-associated deletions are at the upper limits of detection by sequence analysis and the lower limits of detection by gene-targeted deletion/duplication analysis; therefore, the proportion of pathogenic variants detected by either method depends on the methods used by a laboratory.

7.

Clinical Characteristics

Clinical Description

In females the spectrum of MECP2-related phenotypes ranges from classic Rett syndrome, to variant Rett syndrome (either milder or more severe than classic Rett syndrome), to mild learning disabilities. In males the spectrum ranges from severe neonatal encephalopathy, to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome, to severe syndromic/nonsyndromic intellectual disability.

MECP2 Disorders in Females

Table 2.

Features of MECP2 Disorders in Females

PhenotypeFeature% of Persons w/Feature
MECP2 classic Rett syndrome Regression followed by recovery or stabilization99%
Deceleration of head growth80%
Gait abnormalities99%
Seizures60%-80%
Hand stereotypies & loss of purposeful hand skills100% 1
Absence of speech; high-pitched crying99%
Cold extremities99%
Irregular breathing99%
Variant Rett syndrome Regression followed by recovery or stabilization99%
Gait abnormalities80%-99%
Sleep disturbences80%-99%
Seizures6%-80%
Hand stereotypies & loss of purposeful hand skills97.3%
Breathing irregularities80%-99%
Agitation80%-99%
1.

Stallworth et al [2019]; 44% showed different patterns including hand wringing, washing, clapping, and tapping.

MECP2 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 variants resulting in somatic mosaicism have been described [Clayton-Smith et al 2000, Topçu et al 2002].

Although early development is reportedly normal in children with classic Rett syndrome, parents – in retrospect – often identify subtle differences compared to unaffected sibs. Most (but not all) affected children have acquired microcephaly; stereotypic hand movements and breathing irregularities are seen in the majority.

Variant Rett syndrome. Females with variant Rett syndrome exhibit a broader spectrum of clinical features than those observed in classic Rett syndrome. At the more severe end of the spectrum, development is delayed from very early infancy; congenital hypotonia and infantile spasms are also seen. At the milder end of the spectrum, regression is less dramatic and intellectual disability is much less severe; some speech may be preserved.

Mild learning disabilities. In rare instances, females with a pathogenic MECP2 variant may only exhibit mild learning disabilities or some autistic features, presumably as a consequence of favorable skewing of X-chromosome inactivation. When there is no regression phase and no characteristic hand stereotypes, the clinical course differs from that of classic and variant Rett syndrome.

MECP2 Disorders in Males

Table 3.

Features of MECP2 Disorders in Males

PhenotypeFeature% of Persons w/Feature
PresentAbsentNot
reported
MECP2-related
severe neonatal
encephalopathy 1		Normal birth parameters71%29%
Head growth deceleration / microcephaly94%5.8%
Hypotonia &/or feeding difficulties in infancy82.4%17.6%
Hypertonia of extremities52.9%11.8%35.3%
Movement disorder, e.g., myoclonus, tremors, & dystonia58.8%17.7%23.5%
Mild cerebral atrophy18%35%47%
Polymicrogyria5.9%23.5%70.6%
Poor head control35%12%53%
Seizures58.8%17.7%23.5%
Severe development delay82.4%17.6%
Irregular breathing / sleep apnea47.1%29.4%23.5%
Gastroesophageal reflux35.3%64.7%
EEG abnormality88.2%5.9%5.9%
Pyramidal signs,
parkinsonism, &
macroorchidism
(PPM-X syndrome) 2		Psychosis67.6%10.8%21.6%
Pyramidal signs46%2.7%51.3%
Macroorchidism19%81%
Intellectual disability50%50%
Parkinsonism2.7%97.3%
Progressive spasticity67.6%32.4%
Delayed development54%46%
Speech difficulties50%50%
Seizures2.7%
Bilateral juvenile cataract2.7%
Scoliosis or kyphosis10.8%
Large ears8.1%
Movement disorders32.4%
Apraxia2.7%36%
Seizures8.1%91.9%
Dysmorphic features5.4%94.6%
Syndromic/
nonsyndromic
intellectual
disability 3		Severe intellectual disability90%10%
Gait abnormalities57%7%36%
Facial dysmorphism10%3%87%
Behavioral problems40%3%57%
Autistic-like behavior3%53%44%
Seizures20%30%50%
Poor/absent language skills47%17%36%
Hypotonia23%77%
Microcephaly13%23%64%
History of regression17%27%56%
Spasticity33%17%50%
Sleep disturbances13%10%77%

Severe neonatal-onset encephalopathy is characterized by 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 a severe neonatal encephalopathy 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 ID and PPM-X syndrome. PPM-X syndrome, caused by the p.(Ala140Val) MECP2 variant in males, is characterized by moderate-to-severe intellectual disability. Most have spasticity that may be progressive; some may have extrapyramidal movements. Episodic psychosis is seen in many but not all. Most affected males also have macroorchidism. Microcephaly is variable. See also Genotype-Phenotype Correlations.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are inconsistent, due in part to the pattern of X-chromosome inactivation (XCI); females who have a MECP2 pathogenic variant and favorably skewed XCI may have mild or no manifestations [Wan et al 1999, Amir et al 2000, Cheadle et al 2000, Huppke et al 2000, Weaving et al 2003, Chae et al 2004, Schanen et al 2004,Charman et al 2005].

MECP2 pathogenic variants with some residual function that are associated with milder phenotypes include the following:

Prevalence

The worldwide prevalence is 1:10,000-1:23,000 female births [Ellaway et al 1999, Armstrong et al 2010]. Reports of incidence are limited; available estimates range from 0.43-0.71:10,000 for females in France [Bienvenu et al 2006] to 0.586:10,000 for females in Serbia [Sarajlija et al 2015] and 1.09:10,000 for females in Australia [Laurvick et al 2006].

Differential Diagnosis

Table 4.

Disorders to Consider in the Differential Diagnosis of MECP2 Disorders

DiffDx
Disorder		Gene(s) / Genetic MechanismMOIClinical Features of DiffDx Disorder
Overlapping w/MECP2 DisordersDistinguishing from MECP2 Disorders
Angelman syndrome Deficient expression or function of maternally inherited UBE3A alleleSee footnote 1.ID, severe speech impairment, gait ataxia &/or tremulousness of the limbs; microcephaly & seizures common; DD 1st noted at age ~6 mosIn classic Rett syndrome DD is not overtly evident in the 1st 6 mos.
Early infantile epileptic encephalopathy (See CDKL5 Deficiency Disorder.) CDKL5 XLIn females: early-onset severe seizures w/poor cognitive development; facial gestalt, cortical visual impairment;
In males: severe-profound ID & early-onset intractable seizures 2		Very early-onset seizures, facial dysmorphism, & cortical visual impairment are not generally seen in classic Rett syndrome.
Rett syndrome, congenital variant (See FOXG1 Syndrome.) FOXG1 ADShort normal period of development before onset of regression leading to severe ID, DD, postnatal microcephaly, agenesis of the corpus callosum, seizures, dyskinesia, & hypotonia 3Except for microcephaly, structural abnormalities are not usually seen on brain MRI.

AD = autosomal dominant; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or uniparental disomy (UPD), and as high as 50% for probands with an imprinting defect or a pathogenic variant of UBE3A.

2.
3.

Overlapping features and a similar facial appearance between individuals with FOXG1 pathogenic variants has led to the suggestion that these individuals should be regarded as having FOXG1 syndrome rather than a variant of Rett syndrome [Kortüm et al 2011].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a MECP2 disorder, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with a MECP2 Disorder

System/ConcernEvaluationComment
Constitutional Measurement of height, weight, & head circumference
Neurologic Neurologic evalTo incl brain MRI; consider EEG / video monitoring if seizures are a concern.
Development Developmental assessment
  • Motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Psychiatric/
Behavioral 		Neuropsychiatric evalIn persons age >12 mos: screening for problems incl sleep disturbances, ADHD, anxiety, &/or findings suggestive of ASD
Musculoskeletal Orthopedics, physical medicine & rehab, PT/OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Scoliosis
  • Mobility & activities of daily living & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team evalTo incl:
  • Eval of aspiration risk & nutritional status
  • History of constipation & GERD
Consider need for gastric tube placement.
Respiratory Overnight sleep studies
  • Analysis for abnormalities of breathing regularity
  • Noninvasive assessment of pulmonary gas exchange
Sleep disorder Breathing monitoring using portable polygraphic screening devicesTo assess occurrence of apnea & hypopnea
Cardiovascular Cardiac evalTo assess for prolonged QTc
Osteopenia Bone densitometryTo assess for osteopenia
Eyes Ophthalmologic evalTo assess for ↓ vision, abnormal ocular movement, strabismus
Hearing Audiology evalAssess for hearing loss
ENT/Mouth
Genitourinary
Integument History & exam↓ perfusion of hands & feet (possible autonomic abnormalities)
Miscellaneous/
Other 		Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling
Family supports/
resources		Assess need for:

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy

Treatment of Manifestations

Treatment needs to be individualized following an assessment of the affected individual's clinical problems and needs.

Management is symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach with input from a pediatric or adult specialist physician, dietician, occupational therapist, speech therapist, music therapist, dentist, and other medical subspecialists as needed.

Table 6.

Treatment of Manifestations in Individuals with a MECP2 Disorder

Manifestation/
Concern		TreatmentConsiderations/Other

DD/ID

See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy Standardized treatment w/ASM by an experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Psychiatric/
Behavioral 		Risperidone (low dose) or selective serotonin uptake inhibitors have been somewhat successful in treating agitation.
Musculoskeletal ScoliosisPer guidelines 2
Poor weight gain /
Failure to thrive 		Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia; nutritional guidelines are available. 3
Spasticity Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices, disability parking placard.
Sleep disorder Melatonin can ameliorate sleep disturbances.Chloral hydrate, hydroxyzine, or diphenhydramine may be used w/melatonin.
Abnormal vision &/or strabismus Standard treatment(s) as recommended by ophthalmologistCommunity vision services through early intervention or school district
Central visual impairment No specific treatment; early intervention to help stimulate visual development
Hearing Hearing aids may be helpful; per otolaryngologistCommunity hearing services through early intervention or school district
Gastrointestinal
  • Constipation: stool softeners, prokinetics, osmotic agents, or laxatives as needed
  • GERD: anti-reflux agents, smaller & thickened feedings, & positioning
Cardiovascular Treatment for prolonged QTcUnder care of pediatric cardiologist
Osteopenia Baseline densitometry; optimization of physical activity & calcium & vitamin D levelsGuidelines for management of bone health are available. 4
Family/
Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
  • Ongoing assessment for need of palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; DD = developmental delay; GERD = gastroesophageal reflux disease; ID = intellectual disability; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

2.
3.
4.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine if any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically by an occupational or speech therapist) is recommended to improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Many of the clinical features in females with atypical Rett syndrome (Table 2) evolve with age and hence should be reassessed every six to 12 months.

Table 7.

Recommended Surveillance for Individuals with a MECP2 Disorder

System/ConcernEvaluationFrequency
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each multidisciplinary
clinic visit;
at least annually
Gastrointestinal Monitor for constipation.
Respiratory Monitor for evidence of aspiration, respiratory insufficiency.
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.
Development Monitor developmental progress & educational needs.
Speech & language Monitor communication skills.
Psychiatric/
Behavioral 		Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
Musculoskeletal
  • Physical medicine, OT/PT assessment of mobility, self-help skills
  • Monitor scoliosis.
Cardiovascular Monitor for prolonged QTc.
Respiratory Apnea/hyperventilation
Miscellaneous/
Other 		Assess family need for social work support (e.g., palliative/respite care, home nursing; other local resources) & care coordination.

OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

Because individuals with MECP2 disorders are at increased risk for 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 CredibleMeds® (free registration required) for a more extensive list of drugs to avoid.

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 under way, including observational studies, studies focused on improvement of language and communication skills, and drug trials.

For details see www.rettsyndrome.org.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MECP2 disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • Approximately 99.5% of affected individuals represent simplex cases (i.e., a single occurrence in the family).
  • Female proband. MECP2 molecular genetic testing is recommended for both parents.
  • Male proband. MECP2 molecular genetic testing is recommended for the mother. (Note: The father of an affected male will not have a MECP2 disorder nor will he be hemizygous for the MECP2 pathogenic variant; therefore, he does not require further evaluation/testing.)
  • The mother of a proband who is found to be heterozygous for a MECP2 variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected.
  • If the MECP2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Maternal and paternal germline mosaicism have been reported [Amir et al 1999, Zeev et al 2002, Mari et al 2005].

Sibs of a proband. The risk to sibs depends on the genetic status of the parents:

  • If the mother of the proband has a MECP2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
    • Females who inherit the pathogenic variant are at high risk of developing a MECP2 disorder, although skewed X-chromosome inactivation may result in a variable phenotype.
    • Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the MECP2 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism [Amir et al 1999, Zeev et al 2002, Mari et al 2005, Venâncio et al 2007, Zhang et al 2019].

Offspring of a proband

  • Each child of a female proband with a MECP2 disorder has a 50% chance of inheriting the MECP2 pathogenic variant. Females with more severe MECP2 disorders do not reproduce; mildly affected females have reproduced.
  • Males with a MECP2 disorder are not known to reproduce.

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

Related Genetic Counseling Issues

First-degree female relatives. Once the pathogenic MECP2 variant has been identified in a proband, it is appropriate to offer testing to all first-degree female relatives regardless of their clinical status. Apparently unaffected sisters of a female proband with a MECP2 disorder may be heterozygous for the MECP2 variant present in their sister but have few to no manifestations because of skewed X-chromosome inactivation. Genetic counseling should address this possibility as clinically unaffected sisters may be at risk of transmitting the pathogenic MECP2 variant to their children.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 pathogenic MECP2 variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the MECP2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Males with a MECP2 variant who survive infancy will most likely have severe intellectual disability. The phenotype in a female with a MECP2 variant is difficult to predict and can range from apparently normal to severely affected.

Note: Because parental germline mosaicism for a MECP2 pathogenic variant has been reported in multiple families, it is appropriate to offer prenatal testing to the parents of a child with a MECP2 disorder whether or not the MECP2 pathogenic variant has been identified in the leukocyte DNA of either parent.

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.

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 Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
MECP2 Xq28 Methyl-CpG-binding protein 2 MECP2 @ LOVD
CCHMC - Human Genetics Mutation Database (MECP2)
RettBASE 		MECP2 MECP2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MECP2 Disorders (View All in OMIM)

300005METHYL-CpG-BINDING PROTEIN 2; MECP2
300055INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13; MRXS13
300496AUTISM, SUSCEPTIBILITY TO, X-LINKED 3; AUTSX3
300673ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATIONS
312750RETT SYNDROME; RTT

Molecular Pathogenesis

Loss of the protein MeCP2 leads to epigenetic aberrations of chromatin, suggesting that MeCP2 deficiency could lead to loss of imprinting, thereby contributing to the pathogenesis of Rett syndrome [Horike et al 2005, Kaufmann et al 2005, Makedonski et al 2005].

The nuclear MeCP2 protein functional domains include:

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 may be a transcriptional activator [Chahrour et al 2008].

Mechanism of disease causation. Most pathogenic MECP2 variants occur de novo. It has been suggested that pathogenic variants result in loss of protein function; some functional studies show that pathogenic MECP2 variants affect the MBD or TRD domains of the abnormal protein, depending on the location of the variant [Kudo et al 2001, Kudo et al 2002, Kudo et al 2003].

MECP2-specific laboratory technical considerations. Two transcripts have been described:

  • NM_001110792.1: encodes MECP2_e1, includes exons 1, 3, and 4 but not exon 2 (498 amino acids)
  • NM_004992.3: encodes MECP2_e2, includes exons 2, 3, and 4 but not exon 1 (486 amino acids)

Although the isoforms are nearly identical, use of two alternative start codons creates alternative N-termini. The e1 transcript is much more highly expressed in brain than the e2 transcript [Kriaucionis & Bird 2004, Mnatzakanian et al 2004].Of note:

The majority of pathogenic variants occur 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 variants 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 variants delete the C-terminal end of the protein (3' end of exon 4).

Table 8.

Notable MECP2 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_004492​.3
NP_004983​.1 		c.473C>Tp.Thr158MetCommon, recurrent pathogenic variants [Miltenberger-Miltenyi & Laccone 2003, Archer et al 2006, Philippe et al 2006]
c.502C>Tp.Arg168Ter
c.763C>Tp.Arg255Ter
c.808C>Tp.Arg270Ter
c.916C>Tp.Arg306Cys
c.397C>Tp.Arg133CysMilder phenotype in females is consistent w/in vitro functional studies showing that DNA binding is not impaired [Leonard et al 2003, Sheikh et al 2016].
c.419C>Tp.Ala140ValNonclassic, variant Rett syndrome, observed in familial cases w/affected males [Dotti et al 2002, Klauck et al 2002, Gomot et al 2003, Venkateswaran et al 2014, Lambert et al 2016, Sheikh et al 2016]; heterozygous females may have mild ID & impaired speech acquistion [Klauck et al 2002, Lambert et al 2016].
c.925C>Tp.Arg309TrpObserved in females & males w/ID & some features of a MECP2 disorder, but not classic or variant Rett syndrome [Campos et al 2007, Schönewolf-Greulich et al 2016]

ID = intellectual disability

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

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

Chapter Notes

Author History

Vicky L Brandt; Baylor College of Medicine (2000-2004)
John Christodoulou, MBBS, PhD, FRACP, FRCPA, FHGSA (2006-present)
Gladys Ho, MSc; Children's Hospital at Westmead, Sydney (2009-2019)
Simranpreet Kaur, MSci, MPhil (2019-present)
Huda Y Zoghbi, MD; Baylor College of Medicine (2004-2006)

Revision History

  • 19 September 2019 (bp) Comprehensive update posted live
  • 28 June 2012 (me) Comprehensive update posted live
  • 2 April 2009 (me) Comprehensive update posted live
  • 15 August 2006 (me) Comprehensive update posted live
  • 11 February 2004 (me) Comprehensive update posted live
  • 3 October 2001 (me) Review posted live
  • September 2000 (vb) Original submission

References

Published Guidelines / Consensus Statements

  • Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine. 2009;34:E607-17.

Literature Cited

  • Amir RE, Fang P, Yu Z, Glaze DG, Percy AK, Zoghbi HY, Roa BB, Van den Veyver IB. Mutations in exon 1 of MECP2 are a rare cause of Rett syndrome. J Med Genet. 2005;42:e15. [PMC free article: PMC1735975] [PubMed: 15689438]
  • Amir RE, Van den Veyver IB, Schultz R, Malicki DM, Tran CQ, Dahle EJ, Philippi A, Timar L, Percy AK, Motil KJ, Lichtarge O, Smith EO, Glaze DG, Zoghbi HY. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol. 2000;47:670–9. [PubMed: 10805343]
  • Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. 1999;23:185–8. [PubMed: 10508514]
  • Archer HL, Whatley SD, Evans JC, Ravine D, Huppke P, Kerr A, Bunyan D, Kerr B, Sweeney E, Davies SJ, Reardon W, Horn J, MacDermot KD, Smith RA, Magee A, Donaldson A, Crow Y, Hermon G, Miedzybrodzka Z, Cooper DN, Lazarou L, Butler R, Sampson J, Pilz DT, Laccone F, Clarke AJ. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. J Med Genet. 2006;43:451–6. [PMC free article: PMC2564520] [PubMed: 16183801]
  • Armstrong AH, Hangauer J, Agazzi H, Nunez A, Gieron-Korthals M. Individuals with intellectual and developmental disabilities. In: David AS, ed. Handbook of Pediatric Neuropsychology. New York: Springer. 2010;537-50.
  • Baker SA, Chen L, Wilkins AD, Yu P, Lichtarge O, Zoghbi HY. An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell. 2013;152:984–96. [PMC free article: PMC3641682] [PubMed: 23452848]
  • Bienvenu T, Philippe C, de Roux N, Raynaud M, Bonnefond JP, Pasquier L, Lesca G, Mancini J, Jonveaux P, Moncla A, Feingold J, Chelly J, Villard L. The incidence of Rett syndrome in France. Pediatr Neurol. 2006;34:372–5. [PubMed: 16647997]
  • Buschdorf JP, Stratling WH. A WW domain binding region in methyl-CpG-binding protein MeCP2: impact on Rett syndrome. J Mol Med. 2004;82:135–43. [PubMed: 14618241]
  • Campos M Jr, Abdalla CB, Santos-Rebouças CB, dos Santos AV, Pestana CP, Domingues ML, dos Santos JM, Pimentel MM. Low significance of MECP2 mutations as a cause of mental retardation in Brazilian males. Brain Dev. 2007;29:293–7. [PubMed: 17084570]
  • Casas-Delucchi CS, Becker A, Bolius JJ, Cristina Cardoso M. Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization. Nucl Acids Res. 2012;40:e176. [PMC free article: PMC3526307] [PubMed: 22923521]
  • Chae JH, Hwang H, Hwang YS, Cheong HJ, Kim KJ. Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype. J Child Neurol. 2004;19:503–8. [PubMed: 15526954]
  • Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320:1224–9. [PMC free article: PMC2443785] [PubMed: 18511691]
  • Charman T, Neilson TC, Mash V, Archer H, Gardiner MT, Knudsen GP, McDonnell A, Perry J, Whatley SD, Bunyan DJ, Ravn K, Mount RH, Hastings RP, Hulten M, Orstavik KH, Reilly S, Cass H, Clarke A, Kerr AM, Bailey ME. Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome. Eur J Hum Genet. 2005;13:1121–30. [PubMed: 16077736]
  • Cheadle JP, Gill H, Fleming N, Maynard J, Kerr A, Leonard H, Krawczak M, Cooper DN, Lynch S, Thomas N, Hughes H, Hulten M, Ravine D, Sampson JR, Clarke A. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000;9:1119–29. [PubMed: 10767337]
  • Claes S, Devriendt K, D'Adamo P, Meireleire J, Raeymaekers P, Toniolo D, Cassiman JJ, Fryns JP. X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies. Clin Genet. 1997;52:155–61. [PubMed: 9377804]
  • Clayton-Smith J, Watson P, Ramsden S, Black GC. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet. 2000;356:830–2. [PubMed: 11022934]
  • Dotti MT, Orrico A, De Stefano N, Battisti C, Sicurelli F, Severi S, Lam CW, Galli L, Sorrentino V, Federico A. A Rett syndrome MECP2 mutation that causes mental retardation in men. Neurology. 2002;58:226–30. [PubMed: 11805248]
  • Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine. 2009;34:E607–17. [PubMed: 19644320]
  • Einspieler C, Marschik PB. Regression in Rett syndrome: developmental pathways to its onset. Neurosci Biobehav Rev. 2019;98:320–32. [PubMed: 30832924]
  • Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology. 2008;71:997–9. [PubMed: 18809835]
  • Ellaway C, Williams K, Leonard H, Higgins G, Wilcken B, Christodoulou J. Rett syndrome: randomized controlled trial of L-carnitine. J Child Neurol. 1999;14:162–7. [PubMed: 10190267]
  • Evans JC, Archer HL, Whatley SD, Kerr A, Clarke A, Butler R. Variation in exon 1 coding region and promoter of MECP2 in Rett syndrome and controls. Eur J Hum Genet. 2005;13:124–6. [PubMed: 15367913]
  • Gauthier J, de Amorim G, Mnatzakanian GN, Saunders C, Vincent JB, Toupin S, Kauffman D, St-Onge J, Laurent S, Macleod PM, Minassian BA, Rouleau GA. Clinical stringency greatly improves mutation detection in Rett syndrome. Can J Neurol Sci. 2005;32:321–6. [PubMed: 16225173]
  • Gendrot C, Ronce N, Raynaud M, Ayrault AD, Dourlens J, Castelnau P, Muh JP, Chelly J, Moraine C. X-linked nonspecific mental retardation (MRX16) mapping to distal Xq2 8: linkage study and neuropsychological data in a large family. Am J Med Genet. 1999;83:411–8. [PubMed: 10232754]
  • Giudice-Nairn P, Downs J, Wong K, Wilson D, Ta D, Gattas M, Amor D, Thompson E, Kirrali-Borri C, Ellaway C, Leonard H. The incidence, prevalence and clinical features of MECP2 duplication syndrome in Australian children. J Paediatr Child Health. 2019;55:1315–22. [PubMed: 30756435]
  • Gold WA, Krishnaraj R, Ellaway C, Christodoulou J. Rett syndrome: a genetic update and clinical review focusing on comorbidities. ACS Chem Neurosci. 2018;9:167–76. [PubMed: 29185709]
  • Gomot M, Gendrot C, Verloes A, Raynaud M, David A, Yntema HG, Dessay S, Kalscheuer V, Frints S, Couvert P, Briault S, Blesson S, Toutain A, Chelly J, Desportes V, Moraine C. MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. Am J Med Genet A. 2003;123A:129–39. [PubMed: 14598336]
  • Hansen JC, Ghosh RP, Woodcock CL. Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin. IUBMB Life. 2010;62:732–8. [PMC free article: PMC3096928] [PubMed: 21031501]
  • Hardwick SA, Reuter K, Williamson SL, Vasudevan V, Donald J, Slater K, Bennetts B, Bebbington A, Leonard H, Williams SR, Smith RL, Cloosterman D, Christodoulou J. Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. Eur J Hum Genet. 2007;15:1218–29. [PubMed: 17712354]
  • Heckman LD, Chahrour MH, Zoghbi HY. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. eLife. 2014;3:e02676. [PMC free article: PMC4102243] [PubMed: 24970834]
  • Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, Schuette J, Innis J, Marino M, Philippart M, Narayanan V, Umansky R, Kronn D, Hoffman EP, Naidu S. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001;56:1486–95. [PubMed: 11402105]
  • Horike S, Cai S, Miyano M, Cheng JF, Kohwi-Shigematsu T. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet. 2005;37:31–40. [PubMed: 15608638]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • Huppke P, Laccone F, Kramer N, Engel W, Hanefeld F. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. 2000;9:1369–75. [PubMed: 10814718]
  • Jefferson A, Leonard H, Siafarikas A, Woodhead H, Fyfe S, Ward LM, Munns C, Motil K, Tarquinio D, Shapiro JR, Brismar T, Ben-Zeev B, Bisgaard AM, Coppola G, Ellaway C, Freilinger M, Geerts S, Humphreys P, Jones M, Lane J, Larsson G, Lotan M, Percy A, Pineda M, Skinner S, Syhler B, Thompson S, Weiss B, Witt Engerström I, Downs J. Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence. PLoS One. 2016;11:e0146824. [PMC free article: PMC4743907] [PubMed: 26849438]
  • Kankirawatana P, Leonard H, Ellaway C, Scurlock J, Mansour A, Makris CM, Dure LS 4th, Friez M, Lane J, Kiraly-Borri C, Fabian V, Davis M, Jackson J, Christodoulou J, Kaufmann WE, Ravine D, Percy AK. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 2006;67:164–6. [PubMed: 16832102]
  • Kaufmann WE, Jarrar MH, Wang JS, Lee YJ, Reddy S, Bibat G, Naidu S. Histone modifications in Rett syndrome lymphocytes: a preliminary evaluation. Brain Dev. 2005;27:331–9. [PubMed: 16023547]
  • Klauck SM, Lindsay S, Beyer KS, Splitt M, Burn J, Poustka A. A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. Am J Hum Genet. 2002;70:1034–7. [PMC free article: PMC379098] [PubMed: 11885030]
  • Kortüm F, Das S, Flindt M, Morris-Rosendahl DJ, Stefanova I, Goldstein A, Horn D, Klopocki E, Kluger G, Martin P, Rauch A, Roumer A, Saitta S, Walsh LE, Wieczorek D, Uyanik G, Kutsche K, Dobyns WB. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet. 2011;48:396–406. [PMC free article: PMC5522617] [PubMed: 21441262]
  • Kriaucionis S, Bird A. The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res. 2004;32:1818–23. [PMC free article: PMC390342] [PubMed: 15034150]
  • Kudo S, Nomura Y, Segawa M, Fujita N, Nakao M, Dragich J, Schanen C, Tamura M. Functional analyses of MeCP2 mutations associated with Rett syndrome using transient expression systems. Brain Dev. 2001;23:S165–73. [PubMed: 11738866]
  • Kudo S, Nomura Y, Segawa M, Fujita N, Nakao M, Hammer S, Schanen C, Terai I, Tamura M. Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation. J Med Genet. 2002;39:132–6. [PMC free article: PMC1735040] [PubMed: 11836365]
  • Kudo S, Nomura Y, Segawa M, Fujita N, Nakao M, Schanen C, Tamura M. Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain. J Med Genet. 2003;40:487–93. [PMC free article: PMC1735522] [PubMed: 12843318]
  • Lambert S, Maystadt I, Boulanger S, Vrielynck P, Destrée A, Lederer D, Moortgat S. Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity. Eur J Med Genet. 2016;59:522–5. [PubMed: 27465203]
  • Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, Williamson S, Leonard H. Rett syndrome in Australia: a review of the epidemiology. J Pediatr. 2006;148:347–52. [PubMed: 16615965]
  • Leonard H, Colvin L, Christodoulou J, Schiavello T, Williamson S, Davis M, Ravine D, Fyfe S, de Klerk N, Matsuishi T, Kondo I, Clarke A, Hackwell S, Yamashita Y. Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations? J Med Genet. 2003;40:e52. [PMC free article: PMC1735457] [PubMed: 12746406]
  • Leonard H, Ravikumara M, Baikie G, Naseem N, Ellaway C, Percy A, Abraham S, Geerts S, Lane J, Jones M, Bathgate K, Downs J, et al. Assessment and management of nutrition and growth in Rett syndrome. J Pediatr Gastroenterol Nutr. 2013;57:451–60. [PMC free article: PMC3906202] [PubMed: 24084372]
  • Leonard H, Silberstein J, Falk R, Houwink-Manville I, Ellaway C, Raffaele LS, Engerstrom IW, Schanen C. Occurrence of Rett syndrome in boys. J Child Neurol. 2001;16:333–8. [PubMed: 11392517]
  • Lindsay S, Splitt M, Edney S, Berney TP, Knight SJ, Davies KE, O'Brien O, Gale M, Burn J. PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28. Am J Hum Genet. 1996;58:1120–6. [PMC free article: PMC1915053] [PubMed: 8651288]
  • Lubs H, Abidi F, Bier JA, Abuelo D, Ouzts L, Voeller K, Fennell E, Stevenson RE, Schwartz CE, Arena F. XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28. Am J Med Genet. 1999;85:243–8. [PubMed: 10398236]
  • Lugtenberg D, Kleefstra T, Oudakker AR, Nillesen WM, Yntema HG, Tzschach A, Raynaud M, Rating D, Journel H, Chelly J, Goizet C, Lacombe D, Pedespan JM, Echenne B, Tariverdian G, O'Rourke D, King MD, Green A, van Kogelenberg M, Van Esch H, Gecz J, Hamel BC, van Bokhoven H, de Brouwer AP. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy. Eur J Hum Genet. 2009;17:444–53. [PMC free article: PMC2986218] [PubMed: 18985075]
  • Makedonski K, Abuhatzira L, Kaufman Y, Razin A, Shemer R. MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. Hum Mol Genet. 2005;14:1049–58. [PubMed: 15757975]
  • Mari F, Caselli R, Russo S, Cogliati F, Ariani F, Longo I, Bruttini M, Meloni I, Pescucci C, Schurfeld K, Toti P, Tassini M, Larizza L, Hayek G, Zappella M, Renieri A. Germline mosaicism in Rett syndrome identified by prenatal diagnosis. Clin Genet. 2005;67:258–60. [PubMed: 15691364]
  • Meins M, Lehmann J, Gerresheim F, Herchenbach J, Hagedorn M, Hameister K, Epplen JT. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J Med Genet. 2005;42:e12. [PMC free article: PMC1735993] [PubMed: 15689435]
  • Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F, D'Adamo P, Denvriendt K, Fryns JP, Toniolo D, Renieri A. A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet. 2000;67:982–5. [PMC free article: PMC1287900] [PubMed: 10986043]
  • Miltenberger-Miltenyi G, Laccone F. Mutations and polymorphisms in the human methyl CpG-binding protein MECP2. Hum Mutat. 2003;22:107–15. [PubMed: 12872250]
  • Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ, Jones JR, Scherer SW, Schanen NC, Friez MJ, Vincent JB, Minassian BA. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet. 2004;36:339–41. [PubMed: 15034579]
  • Moog U, Smeets EE, van Roozendaal KE, Schoenmakers S, Herbergs J, Schoonbrood-Lenssen AM, Schrander-Stumpel CT. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003;7:5–12. [PubMed: 12615169]
  • Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68:944–50. [PMC free article: PMC3058521] [PubMed: 21154482]
  • Orrico A, Lam C, Galli L, Dotti MT, Hayek G, Tong SF, Poon PM, Zappella M, Federico A, Sorrentino V. MECP2 mutation in male patients with non-specific X-linked mental retardation. FEBS Lett. 2000;481:285–8. [PubMed: 11007980]
  • Pan H, Li MR, Nelson P, Bao XH, Wu XR, Yu S. Large deletions of the MECP2 gene in Chinese patients with classical Rett syndrome. Clin Genet. 2006;70:418–9. [PubMed: 17026625]
  • Philippe C, Villard L, De Roux N, Raynaud M, Bonnefond JP, Pasquier L, Lesca G, Mancini J, Jonveaux P, Moncla A, Chelly J, Bienvenu T. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006;49:9–18. [PubMed: 16473305]
  • Poirier K, Francis F, Hamel B, Moraine C, Fryns JP, Ropers HH, Chelly J, Bienvenu T. Mutations in exon 1 of MECP2B are not a common cause of X-linked mental retardation in males. Eur J Hum Genet. 2005;13:523–4. [PubMed: 15770224]
  • Psoni S, Sofocleous C, Traeger-Synodinos J, Kitsiou-Tzeli S, Kanavakis E, Fryssira-Kanioura H. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res. 2010;67:551–6. [PubMed: 20098342]
  • Ramocki MB, Peters SU, Tavyev YJ, Zhang F, Carvalho CM, Schaaf CP, Richman R, Fang P, Glaze DG, Lupski JR, Zoghbi HY. Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann Neurol. 2009;66:771–82. [PMC free article: PMC2801873] [PubMed: 20035514]
  • Ravn K, Nielsen JB, Skjeldal OH, Kerr A, Hulten M, Schwartz M. Large genomic rearrangements in MECP2. Hum Mutat. 2005;25:324. [PubMed: 15712379]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Sarajlija A, Kisic-Tepavcevic D, Nikolic Z, Savic Pavicevic D, Obradovic S, Djuric M, Pekmezovic T. Epidemiology of Rett syndrome in Serbia: prevalence, incidence and survival. Neuroepidemiology. 2015;44:1–5. [PubMed: 25571926]
  • Saunders CJ, Minassian BE, Chow EW, Zhao W, Vincent JB. Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome. Am J Med Genet A. 2009;149A:1019–23. [PubMed: 19365833]
  • Saxena A, de Lagarde D, Leonard H, Williamson SL, Vasudevan V, Christodoulou J, Thompson E, MacLeod P, Ravine D. Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2. J Med Genet. 2006;43:470–7. [PMC free article: PMC2593027] [PubMed: 16155192]
  • Schanen C, Houwink EJ, Dorrani N, Lane J, Everett R, Feng A, Cantor RM, Percy A. Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am J Med Genet A. 2004;126A:129–40. [PubMed: 15057977]
  • Schanen NC, Kurczynski TW, Brunelle D, Woodcock MM, Dure LS 4th, Percy AK. Neonatal encephalopathy in two boys in families with recurrent Rett syndrome. J Child Neurol. 1998;13:229–31. [PubMed: 9620015]
  • Schönewolf-Greulich B, Tejada MI, Stephens K, Hadzsiev K, Gauthier J, Brøndum-Nielsen K, Pfundt R, Ravn K, Maortua H, Gener B, Martínez-Bouzas C, Piton A, Rouleau G, Clayton-Smith J, Kleefstra T, Bisgaard AM, Tümer Z. The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome. Clin Genet. 2016;89:733–8. [PubMed: 26936630]
  • Schüle B, Armstrong DD, Vogel H, Oviedo A, Francke U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet. 2008;74:116–26. [PubMed: 18477000]
  • Schwartzman JS, Bernardino A, Nishimura A, Gomes RR, Zatz M. Rett syndrome in a boy with a 47,XXY karyotype confirmed by a rare mutation in the MECP2 gene. Neuropediatrics. 2001;32:162–4. [PubMed: 11521215]
  • Sheikh TI, Ausió J, Faghfoury H, Silver J, Lane JB, Eubanks JH, MacLeod P, Percy AK, Vincent JB. From function to phenotype: impaired DNA binding and clustering correlates with clinical severity in males with missense mutations in MECP2. Sci Rep. 2016;6:38590. [PMC free article: PMC5144150] [PubMed: 27929079]
  • Sheikh TI, de Paz AM, Akhtar S, Ausió J, Vincent JB. MeCP2_E1 N-terminal modifications affect its degradation rate and are disrupted by the Ala2Val Rett mutation. Hum Mol Genet. 2017;26:4132–41. [PMC free article: PMC5886153] [PubMed: 28973632]
  • Stallworth JL, Dy ME, Buchanan CB, Chen CF, Scott AE, Glaze DG, Lane JB, Lieberman DN, Oberman LM, Skinner SA, Tierney AE, Cutter GR, Percy AK, Neul JL, Kaufmann WE. Hand stereotypies: lessons from the Rett Syndrome Natural History Study. Neurology. 2019;92:e2594–603. [PMC free article: PMC6556084] [PubMed: 31053667]
  • Topçu M, Akyerli C, Sayi A, Toruner GA, Kocoglu SR, Cimbis M, Ozcelik T. Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. Eur J Hum Genet. 2002;10:77–81. [PubMed: 11896459]
  • Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P, Fryns JP, Froyen G. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet. 2005;77:442–53. [PMC free article: PMC1226209] [PubMed: 16080119]
  • Venâncio M, Santos M, Pereira SA, Maciel P, Saraiva JM. An explanation for another familial case of Rett syndrome: maternal germline mosaicism. Eur J Hum Genet. 2007;15:902–4. [PubMed: 17440498]
  • Venkateswaran S, McMillan HJ, Doja A, Humphreys P. Adolescent onset cognitive regression and neuropsychiatric symptoms associated with the A140V MECP2 mutation. Dev Med Child Neurol. 2014;56:91–4. [PubMed: 24328834]
  • Villard L, Kpebe A, Cardoso C, Chelly PJ, Tardieu PM, Fontes M. Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology. 2000;55:1188–93. [PubMed: 11071498]
  • Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, Budden S, Naidu S, Pereira JL, Lo IF, Zoghbi HY, Schanen NC, Francke U. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999;65:1520–9. [PMC free article: PMC1288362] [PubMed: 10577905]
  • Weaving LS, Williamson SL, Bennetts B, Davis M, Ellaway CJ, Leonard H, Thong MK, Delatycki M, Thompson EM, Laing N, Christodoulou J. Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype. Am J Med Genet A. 2003;118A:103–14. [PubMed: 12655490]
  • Winnepenninckx B, Errijgers V, Hayez-Delatte F, Reyniers E, Frank Kooy R. Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening? Hum Mutat. 2002;20:249–52. [PubMed: 12325019]
  • Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci USA. 2005;102:17551–8. [PMC free article: PMC1266160] [PubMed: 16251272]
  • Zahorakova D, Rosipal R, Hadac J, Zumrova A, Bzduch V, Misovicova N, Baxova A, Zeman J, Martasek P. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007;52:342–8. [PubMed: 17387578]
  • Zeev BB, Yaron Y, Schanen NC, Wolf H, Brandt N, Ginot N, Shomrat R, Orr-Urtreger A. Rett syndrome: clinical manifestations in males with MECP2 mutations. J Child Neurol. 2002;17:20–4. [PubMed: 11913564]
  • Zhang Q, Yang X, Wang J, Li J, Wu Q, Wen Y, Zhao Y, Zhang X, Yao H, Wu X, Yu S, Wei L, Bao X. Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort. Genet Med. 2019;21:1330–8. [PMC free article: PMC6752670] [PubMed: 30405208]
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