GeneReviews^® [Internet].

Clinical characteristics.

The spectrum ofMECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinicalphenotype (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 severesyndromic/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 commonphenotype 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 aMECP2 disorder is established bymolecular genetic testing in a femaleproband with suggestive findings and aheterozygousMECP2pathogenic variant, and in a male proband with suggestive findings and ahemizygousMECP2 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 anX-linked manner. More than 99% aresimplex cases (i.e., a single occurrence in a family), resulting from ade novopathogenic variant or possibly from inheritance of the pathogenic variant from a parent who hasgermline mosaicism. Rarely, aMECP2 variant may be inherited from aheterozygous mother in whom favorable skewing ofX-chromosome inactivation results in minimal to no clinical findings. When the mother is a knownheterozygote, the risk to her offspring of inheriting theMECP2 variant is 50%. When the pathogenicMECP2 variant has been identified in the family, heterozygote testing for at-risk female relatives,prenatal testing for pregnancies at increased risk, andpreimplantation genetic testing are possible. Because of the possibility of parental germline mosaicism, it is appropriate to offerprenatal diagnosis to couples who have had a child with aMECP2 disorder regardless of whether theMECP2 pathogenic variant has been detected in a parent.

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Suggestive Findings in Females

AMECP2 disordershould be suspected/considered in females with the following clinical findings suggestive ofMECP2 classic Rett syndrome or variant Rett syndrome (based on clinical diagnostic criteria published byNeul et al [2010] [full text] prior to the widespread availability ofmolecular genetic testing), or mild learning disabilities.

Clinical findings ofMECP2classic 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 ofMECP2 mild learning disability. Typically mild and non-progressive. Note: Typically, females with mild learning disability are identified throughmolecular genetic testing following diagnosis of afirst-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; orsyndromic/nonsyndromic intellectual disability.

Clinical findings ofMECP2 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 ofMECP2 severe intellectual disability (including PPM-X syndrome)

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

Establishing the Diagnosis

Femaleproband. The diagnosis of aMECP2 disorderis usually established in a female proband withsuggestive findings and aheterozygous pathogenic (orlikely pathogenic) variant inMECP2 identified bymolecular genetic testing (seeTable 1).

Maleproband. The diagnosis of aMECP2 disorderis established in a male proband withsuggestive findings and ahemizygous pathogenic (orlikely pathogenic) variant inMECP2 identified bymolecular genetic testing (seeTable 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 thisGeneReview is understood to include likely pathogenic variants. (2) Identification of ahemizygous orheterozygousMECP2 variant ofuncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination ofgene-targeted testing (either single-gene,multigene panel) orcomprehensivegenomic testing (exome sequencing,exome array,genome sequencing) depending on thephenotype.

Gene-targeted testing requires that the clinician determine whichgene(s) are likely involved, whereasgenomic testing does not. Because thephenotype ofMECP2 disorders is broad, females with the distinctive findings described inSuggestive Findings are likely to be diagnosed using gene-targeted testing (seeOption 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 (seeOption 2).

Clinical Description

In females the spectrum ofMECP2-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 severesyndromic/nonsyndromic intellectual disability.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are inconsistent, due in part to the pattern ofX-chromosome inactivation (XCI); females who have aMECP2pathogenic 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:

• p.(Ala140Val). Thephenotype issyndromic (PPM-X) intellectual disability in males and very mild cognitive impairment in females [Dotti et al 2002,Klauck et al 2002,Gomot et al 2003,Venkateswaran et al 2014,Lambert et al 2016,Sheikh et al 2016].
• p.(Arg133Cys). Thephenotype is less severe than classic Rett syndrome in females; this variant can be present in affected males [Leonard et al 2003,Sheikh et al 2016].
• p.(Arg309Cys) is found in females and males with intellectual disability and some features ofMECP2 disorders, but not classic or variant Rett syndrome [Campos et al 2007,Schönewolf-Greulich et al 2016].

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].

Table 4.

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Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aMECP2 disorder, the evaluations summarized inTable 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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.

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.

Agents/Circumstances to Avoid

Because individuals withMECP2 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)

SeeCredibleMeds^® (free registration required) for a more extensive list of drugs to avoid.

Evaluation of Relatives at Risk

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic 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 seewww.rettsyndrome.org.

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

Mode of Inheritance

MECP2 disorders are inherited in anX-linked manner.

Risk to Family Members

Parents of aproband

• Approximately 99.5% of affected individuals representsimplex cases (i.e., a single occurrence in the family).
• Femaleproband.MECP2molecular genetic testing is recommended for both parents.
• Maleproband.MECP2molecular genetic testing is recommended for the mother. (Note: The father of an affected male will not have aMECP2 disorder nor will he behemizygous for theMECP2pathogenic variant; therefore, he does not require further evaluation/testing.)
• The mother of aproband who is found to beheterozygous for aMECP2 variant may have favorably skewedX-chromosome inactivation that results in her being unaffected or mildly affected.
• If theMECP2pathogenic variant found in theproband cannot be detected in the leukocyte DNA of either parent, possible explanations include ade novo pathogenic variant in the proband orgermline mosaicism in a parent. Maternal and paternal germline mosaicism have been reported [Amir et al 1999,Zeev et al 2002,Mari et al 2005].
  • Maternalgermline mosaicism was reported in one of nine pregnancies [Mari et al 2005,Venâncio et al 2007].
  • Paternalgermline mosaicism was reported in five fathers of affected daugthers from 21 families [Zhang et al 2019].

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

• If the mother of theproband has aMECP2pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Females who inherit thepathogenic variant are at high risk of developing aMECP2 disorder, although skewedX-chromosome inactivation may result in a variablephenotype.
  • 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 theproband represents asimplex case (i.e., a single occurrence in a family) and if theMECP2pathogenic 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 parentalgermline mosaicism [Amir et al 1999,Zeev et al 2002,Mari et al 2005,Venâncio et al 2007,Zhang et al 2019].

Offspring of aproband

• Each child of a femaleproband with aMECP2 disorder has a 50% chance of inheriting theMECP2pathogenic variant. Females with more severeMECP2 disorders do not reproduce; mildly affected females have reproduced.
• Males with aMECP2 disorder are not known to reproduce.

Other family members. The risk to other family members depends on the genetic status of theproband's mother: if the mother is affected or has a pathogenicMECP2 variant, her family members may be at risk.

Related Genetic Counseling Issues

First-degree female relatives. Once the pathogenicMECP2 variant has been identified in aproband, 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 aMECP2 disorder may beheterozygous for theMECP2 variant present in their sister but have few to no manifestations because of skewedX-chromosome inactivation. Genetic counseling should address this possibility as clinically unaffected sisters may be at risk of transmitting the pathogenicMECP2 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 offergenetic 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 pathogenicMECP2 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, seeHuang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once theMECP2pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing are possible. Males with aMECP2 variant who survive infancy will most likely have severe intellectual disability. Thephenotype in a female with aMECP2 variant is difficult to predict and can range from apparently normal to severely affected.

Note: Because parentalgermline mosaicism for aMECP2pathogenic variant has been reported in multiple families, it is appropriate to offerprenatal testing to the parents of a child with aMECP2 disorder whether or not theMECP2 pathogenic variant has been identified in the leukocyte DNA of either parent.

Table A.

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Table B.

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Molecular Pathogenesis

Loss of the protein MeCP2 leads toepigenetic aberrations of chromatin, suggesting that MeCP2 deficiency could lead to loss ofimprinting, 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:

• Methyl bindingdomain (MBD): binds specifically to DNA at symmetrically methylated CpGs within chromatin [Hansen et al 2010,Casas-Delucchi et al 2012]
• Transcription repressiondomain (TRD): responsible for recruiting other proteins that mediate transcription repression
• A-T hookdomain: basic residues that bind A-T rich DNA [Baker et al 2013,Heckman et al 2014]
• WWdomain: conserved C-terminal domain [Buschdorf & Stratling 2004]

It has also been shown that MeCP2 plays a role ingenesplicing [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 pathogenicMECP2 variants occurde novo. It has been suggested that pathogenic variants result in loss of protein function; some functional studies show that pathogenicMECP2 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: encodesMECP2_e1, includes exons 1, 3, and 4 but notexon 2 (498 amino acids)
• NM_004992.3: encodesMECP2_e2, includes exons 2, 3, and 4 but notexon 1 (486 amino acids)

Although theisoforms 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:

• Exon 1 (MECP2_e1): pathogenic variants inexon 1 are rare and include variants in the start codon (p.Met1?) and p.Ala2 as well as variant frameshift changes [Amir et al 2005,Evans et al 2005,Poirier et al 2005,Ravn et al 2005,Saxena et al 2006,Saunders et al 2009,Sheikh et al 2017].
• Exon 2 (MECP2_e2): apathogenic variant in the start codon (p.Met1?) has been reported inexon 2 [Gauthier et al 2005].

The majority of pathogenic variants occur in the region encoding the methyl bindingdomain (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 recurrentnonsense 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).

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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