MECP2 Disorders

Kaur S, Christodoulou J.

Publication Details

Estimated reading time: 37 minutes


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.


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.


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

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MECP2 classic Rett syndrome Variant Rett syndrome


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.

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Table 1.

Molecular Genetic Testing Used in MECP2 Disorders

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

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Table 2.

Features of MECP2 Disorders in Females

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

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Table 3.

Features of MECP2 Disorders in Males

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:


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

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Table 4.

Disorders to Consider in the Differential Diagnosis of MECP2 Disorders


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.

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Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with a MECP2 Disorder

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.

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Table 6.

Treatment of Manifestations in Individuals with a MECP2 Disorder

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.


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.

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Table 7.

Recommended Surveillance for Individuals with a MECP2 Disorder

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

Search 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.


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.

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Table A.

MECP2 Disorders: Genes and Databases

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Table B.

OMIM Entries for MECP2 Disorders (View All in OMIM)

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).

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Table 8.

Notable MECP2 Pathogenic Variants

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


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.

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