Clinical Diagnosis

Duplication of the gene MECP2 (MECP2 duplication syndrome) in males results in the following:

• Severe to profound mental retardation, with limited or absent speech
• Early-onset hypotonia with slow motor development
• Progressive spasticity predominantly of the lower limbs
• Predisposition to infections in 75% of affected males, manifest as recurrent respiratory infections
• Epileptic seizures in 50% of affected males
• Other variably present features including autistic features, gastrointestinal dysfunction, mild facial dysmorphism

Although interfamilial phenotypic variability is observed, severity is usually consistent within families [Van Esch et al 2005, del Gaudio et al 2006, Friez et al 2006].

Testing

Cytogenetic testing. Routine G-banded cytogenetic analysis only detects duplications of Xq28 (the chromosomal locus of MECP2) larger than approximately 8 Mb. These large cytogenetically visible duplications are present in a minority of males (<5%) who exhibit a more severe phenotype [Sanlaville et al 2005].

Molecular Genetic Testing

Gene. MECP2 is the main gene known to be associated with MECP2 duplication syndrome. Duplication of MECP2 is usually the underlying mechanism; triplication has also been described [del Gaudio et al 2006].

Clinical testing

• Duplication testing. Duplications ranging from 0.3 to 4 Mb are found in 100% of affected males [Van Esch et al 2005, del Gaudio et al 2006, Smyk et al 2008, Clayton-Smith et al 2008, Lugtenberg et al 2009]. The duplications occur in the chromosome region Xq28, which includes the entire MECP2 gene.
  
  Duplication testing by quantitative methods such as quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), or array genome hybridization (array GH) can be used to detect the duplications.
  
  Array GH identifies duplications of MECP2 if the Xq28 chromosome region is well covered in that version of the array. Moreover, array GH can establish the exact size of the duplication if coverage of the affected region is sufficiently dense. Note: Because most of the duplications are too small to be detected by regular metaphase FISH, a PCR-based method of duplication testing should be used to verify the array GH results.

Table 1. Summary of Molecular Genetic Testing Used in MECP2 Duplication Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
MECP2	Duplication analysis 2	Whole-gene duplications	100%	Clinical
Not Applicable	Cytogenetic analysis	Cytogenetically visible duplications of Xq28	5%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Testing that identifies duplications; a variety of methods including quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis can be established by array GH and confirmed by duplication analysis using another quantitative method such as quantitative PCR or MLPA.

Carrier testing for at-risk relatives requires prior identification of the disease-causing duplication in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing duplication in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by duplication analysis.

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

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Other kinds of mutations and intragenic rearrangements of the MECP2 gene cause classic Rett syndrome, variant Rett syndrome, mild learning disabilities in females, and neonatal encephalopathy and syndromic or nonsyndromic mental retardation syndromes in males (see MECP2-Related Disorders).

Natural History

Duplication of MECP2 was recently discovered. Although about 120 affected males have been reported to date, the clinical findings are consistent in all reports [Meins et al 2005, Van Esch et al 2005, del Gaudio et al 2006, Friez et al 2006, Smyk et al 2008, Clayton-Smith et al 2008, Prescott et al 2009, Echenne et al 2009, Kirk et al 2009, Lugtenberg et al 2009, Velinov et al 2009].

Growth measurements at birth, including head circumference, are usually normal. During the first weeks of life, feeding difficulties resulting from hypotonia may become evident in affected males. The child is very hypotonic and may also exhibit difficulty with swallowing, gastro-esophageal reflux, failure-to-thrive, and extensive drooling. In some cases, nasogastric tube feeding becomes necessary.

Mild dysmorphic features including brachycephaly, midfacial hypoplasia, large ears, and flat nasal bridge may be present.

As a result of hypotonia, motor developmental milestones including sitting and crawling are severely delayed. Walking is also severely delayed; some individuals have an ataxic gait. One third of affected individuals never walk independently. Speech development is severely delayed and the majority of affected individuals (>70%) do not develop speech. In some individuals who were able to speak some words in early childhood, speech was progressively lost in adolescence. Most affected males function at the level of moderate to severe intellectual disability.

In 75% of affected males, hypotonia gives way to spasticity in childhood. The spasticity is more pronounced in the legs; mild contractures may develop over time. Often the use of a wheelchair is necessary in adulthood.

Seizures are seen in nearly 50% of affected individuals. Generalized tonic-clonic seizures are most often observed; atonic seizures and absence seizures have also been described. In some individuals seizures can be refractory to treatment. Often it is noted that the onset and the severity of the seizures correlate with neurologic deterioration, characterized by loss of speech, hand use, and/or ambulation.

Recurrent respiratory infections, especially recurrent pneumonia that may require assisted ventilation, occur in 75% of affected individuals. Other types of infections have also been described. Recurrent infections may be fatal; death before age 25 years is reported in almost 50% of affected individuals.

Growth, including head circumference, is usually within the normal range.

Other associated findings that can be observed include the following:

• Hypoplasia of the corpus callosum observed on brain imaging in three persons [Friez et al 2006, unpublished data]
• Autistic features, including anxiety and stereotypic hand movements
• Severe constipation and bowel obstruction
• Bladder dysfunction

Heterozygous females. Most females heterozygous for MECP2 duplication show extreme to complete skewing of X-chromosome inactivation and are asymptomatic. However, neuropsychiatric symptoms, including depression, anxiety, and autistic features, have been described in carriers who have normal intellectual abilities [Ramocki et al 2009].

Some symptomatic females with a Xq28 duplication without skewing of X-chromosome inactivation have been reported. In most of these individuals, the duplication arises from an unbalanced X-autosomal translocation or a genomic insertion elsewhere in the genome, explaining the absence of skewing of the aberrant X chromosome. These females present with severe developmental delay and other features similar to those observed in affected males [Lachlan et al 2004, Sanlaville et al 2005, Makrythanasis et al 2010].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation has been identified to date. However, the following have been noted:

• Individuals with a large, cytogenetically visible Xq28 duplication have growth retardation, microcephaly, and urogenital anomalies in addition to those findings described in Natural History, Heterozygous females [Lachlan et al 2004, Sanlaville et al 2005].
• A more important correlation with clinical severity is MECP2 copy number, as triplication of the MECP2 region apparently results in a more severe phenotype [del Gaudio et al 2006].

Penetrance

MECP2 duplications are believed to be completely penetrant in males.

Prevalence

To date, about 120 affected individuals from 36 different families have been reported [Meins et al 2005, Van Esch et al 2005, del Gaudio et al 2006, Friez et al 2006, Clayton-Smith et al 2008, Smyk et al 2008, Echenne et al 2009, Kirk et al 2009, Lugtenberg et al 2009, Prescott et al 2009, Velinov et al 2009]. The exact prevalence of MECP2 duplication syndrome is unknown, but data from several large array-based studies suggest a prevalence of approximately 1% in males with moderate to severe intellectual disability. When a clear X-linked inheritance pattern and/or additional findings are present, the likelihood of detecting a MECP2 duplication is much higher.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with MECP2 duplication syndrome, the following evaluations are recommended:

• Review of medical history for developmental progress, seizures, and recurrent infections
• Complete neurologic evaluation and EEG
• Complete neuropsychological evaluation of mental level and behavioral problems
• Assessment of feeding for swallowing difficulties in infants
• Analysis of the family pedigree for other possible affected individuals and carrier females (see Genetic Counseling)

Treatment of Manifestations

Cognitive impairment. Developmental stimulation including speech therapy is appropriate.

Note: Because developmental outcome is variable, individual counseling is important.

Spastic paraplegia. Treatment is nonspecific; general guidelines can be followed.

Epilepsy. Seizures usually respond well to standard therapy with antiepileptic drugs; however, in some males the seizures are resistant to the usual therapy, resulting in secondary neurologic deterioration.

Predisposition to infections. Infections, especially of the respiratory tract, should be treated immediately with appropriate antibiotics.

Gastro-intestinal dysfunction. Feeding problems, gastroesophageal reflux, swallowing dysfunction, and obstipation require referral and treatment in the usual manner.

Prevention of Secondary Complications

Physical therapy with attention to stretching exercises can help maintain joint range of motion and prevent secondary contractures, thus prolonging the ability to walk.

Respiratory problems require early intervention.

Surveillance

The following should be monitored from early childhood:

• Developmental progress
• Neurologic features, with special attention to the onset of spasticity
• Onset and frequency of seizures
• Number and type of infections
• Autistic-like features
• Gastrointestinal symptoms

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

MECP2 duplication syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the MECP2 duplication.
• In a family with more than one affected individual, the mother of an affected male is an obligate MECP2 duplication carrier.
• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a MECP2 duplication carrier or the affected male may have a de novo MECP2 duplication, in which case the mother is not a carrier. (To date, all males known to have a pure MECP2 duplication (not an X/Y rearrangement) have inherited the duplication from a carrier mother. To date, all carrier mothers have shown extreme to complete skewing of X-chromosome inactivation.
• If a woman has more than one affected son and the MECP2 duplication cannot be detected in her DNA, she has germline mosaicism. (Germline mosaicism has not yet been documented, but numbers are too small to draw conclusions.) When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
  • His mother has a MECP2 duplication that she inherited from her mother.
  • His mother has a de novo MECP2 duplication, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body) or (b) or as "germline mosaicism" (i.e., present in some of her germ cells only).

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a MECP2 duplication, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the MECP2 duplication will be affected; female sibs who inherit the MECP2 duplication will be heterozygous carriers who are expected to be clinically normal unless they also have an X-chromosome abnormality that prevents inactivation of the duplication.
• If the MECP2 duplication cannot be detected in the DNA extracted from the leukocytes of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with MECP2 duplication syndrome do not reproduce.

Other family members of a proband. The proband's maternal aunts and other matrilineal relatives may be at risk of being MECP2 duplication carriers and having affected sons.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the MECP2 duplication has been identified in the family.

Related Genetic Counseling Issues

See Management, Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or at risk of being carriers.

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

Prenatal Testing

For pregnancies in which the mother has been identified as being heterozygous for the MECP2 duplication, the usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the duplication.

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

Preimplantation genetic diagnosis (PGD) may be available for families in which a MECP2 deletion has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Evidence suggests that overexpression of the MeCP2 protein could have detrimental effects on brain development and function as shown in mouse models [Collins et al 2004] and in the human [Shi et al 2005, Van Esch et al 2005, Ramocki & Zoghbi 2008].

Literature Cited

1. Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, David Sweatt J, Zoghbi HY. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet. 2004;13:2679–89. [PubMed: 15351775]
2. Clayton-Smith J, Walters S, Hobson E, Burkitt-Wright E, Smith R, Toutain A, Amiel J, Lyonnet S, Mansour S, Fitzpatrick D, Ciccone R, Ricca I, Zuffardi O, Donnai D. Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. Eur J Hum Genet. 2008;17:434–43. [PMC free article: PMC2986219] [PubMed: 18854860]
3. del Gaudio D, Fang P, Scaglia F, Ward PA, Craigen WJ, Glaze DG, Neul JL, Patel A, Lee JA, Irons M, Berry SA, Pursley AA, Grebe TA, Freedenberg D, Martin RA, Hsich GE, Khera JR, Friedman NR, Zoghbi HY, Eng CM, Lupski JR, Beaudet al Cheung SW, Roa BB. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med. 2006;8:784–92. [PubMed: 17172942]
4. Echenne B, Roubertie A, Lugtenberg D, Kleefstra T, Hamel BC, Van Bokhoven H, Lacombe D, Philippe C, Jonveaux P, de Brouwer AP. Neurologic aspects of MECP2 gene duplication in male patients. Pediatr Neurol. 2009;41:187–91. [PubMed: 19664534]
5. Friez MJ, Jones JR, Clarkson K, Lubs H, Abuelo D, Bier JA, Pai S, Simensen R, Williams C, Giampietro PF, Schwartz CE, Stevenson RE (2006) Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics. 118:e1687-95. [PubMed: 17088400]
6. Kirk EP, Malaty-Brevaud V, Martini N, Lacoste C, Levy N, Maclean K, Davies L, Philip N, Badens C. The clinical variability of the MECP2 duplication syndrome: Description of two families with duplications excluding L1CAM and FLNA. Clin Genet. 2009;75:301–3. [PubMed: 19018795]
7. Lachlan KL, Collinson MN, Sandford RO, van Zyl B, Jacobs PA, Thomas NS. Functional disomy resulting from duplications of distal Xq in four unrelated patients. Hum Genet. 2004;115:399–408. [PubMed: 15338277]
8. 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]
9. Makrythanasis P, Moix I, Gimelli S, Fluss J, Aliferis K, Antonarakis SE, Morris MA, Béna F, Bottani A (2010) De novo duplication of MECP2 in a girl with mental retardation and no obvious dysmorphic features. Clin Genet [Epub ahead of print] [PubMed: 20236124]
10. 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]
11. Prescott TE, Rødningen OK, Bjørnstad A, Stray-Pedersen A. Two brothers with a microduplication including the MECP2 gene: rapid head growth in infancy and resolution of susceptibility to infection. Clin Dysmorphol. 2009;18:78–82. [PubMed: 19057379]
12. Ramocki MB, Zoghbi HY. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature. 2008;455:912–8. [PMC free article: PMC2696622] [PubMed: 18923513]
13. 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]
14. Sanlaville D, Prieur M, de Blois MC, Genevieve D, Lapierre JM, Ozilou C, Picq M, Gosset P, Morichon-Delvallez N, Munnich A, Cormier-Daire V, Baujat G, Romana S, Vekemans M, Turleau C. Functional disomy of the Xq28 chromosome region. Eur J Hum Genet. 2005;13:579–85. [PubMed: 15741994]
15. Shi J, Shibayama A, Liu Q, Nguyen VQ, Feng J, Santos M, Temudo T, Maciel P, Sommer SS. Detection of heterozygous deletions and duplications in the MECP2 gene in Rett syndrome by Robust Dosage PCR (RD-PCR). Hum Mutat. 2005;25:505. [PubMed: 15841480]
16. Smyk M, Obersztyn E, Nowakowska B, Nawara M, Cheung SW, Mazurczak T, Stankiewicz P, Bocian E. Different-sized duplications of Xq28, including MECP2, in three males with mental retardation, absent or delayed speech, and recurrent infections. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:799–806. [PubMed: 18165974]
17. 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]
18. Velinov M, Novelli A, Gu H, Fenko M, Dolzhanskaya N, Bernardini L, Capalbo A, Dallapiccola B, Jenkins ES, Brown WT. De novo 2.15 Mb terminal Xq duplication involving MECP2 but not L1CAM gene in a male patient with mental retardation. Clin Dysmorphol. 2009;18:9–12. [PubMed: 19090026]

Author Notes

Hilde Van Esch is a clinical geneticist and researcher with focus on genetics of intellectual disability and brain malformations.

Acknowledgments

The author's research has received funding by Fonds voor Wetenschappelijk Onderzoek, Vlaanderen.

Revision History

• 24 June 2010 (me) Comprehensive update posted live
• 18 January 2008 (me) Review posted to live Web site
• 12 October 2007 (hve) Original submission