Clinical characteristics.

MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by early-onset hypotonia, feeding difficulty, gastrointestinal manifestations including gastroesophageal reflux and constipation, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in ~75% of affected individuals), and seizures (in ~50%). MECP2 duplication syndrome is 100% penetrant in males. Occasionally females have been described with a MECP2 duplication and a range of findings from mild intellectual disability to a phenotype similar to that seen in males. In addition to the core features, autistic behaviors, nonspecific neuroradiologic findings on brain MRI, mottled skin, and urogenital anomalies have been observed in several affected boys.

Diagnosis/testing.

The diagnosis of MECP2 duplication syndrome is established in an individual by identification of a heterozygous whole-gene duplication of MECP2 on molecular genetic testing.

Management.

Treatment of manifestations: Routine management of feeding difficulties, constipation, developmental and speech delays, spasticity, and seizures. Physical therapy to maintain range of motion to reduce likelihood of contractures. Prompt antibiotic treatment for respiratory infections; all vaccines should be given; consider gastrostomy tube if aspiration is present. Social work and care coordination as indicated.

Surveillance: Routine monitoring for growth, feeding issues, constipation, reflux, loss of speech, progressive spasticity, seizure disorder and response to anti-seizure medication, infections, and autistic-like features.

Genetic counseling.

MECP2 duplication syndrome is inherited in an X-linked manner. The majority of affected males have inherited the MECP2 duplication from a heterozygous mother; however, de novo genetic alterations have been reported. If the mother of the proband has a MECP2 duplication, the chance of transmitting it in each pregnancy is 50%. Males who inherit the MECP2 duplication will be affected; females who inherit the MECP2 duplication are typically asymptomatic but may exhibit clinical manifestations ranging from mild nonspecific intellectual disability to a severe phenotype similar to that observed in males. If the mother of the proband has a balanced structural chromosome rearrangement involving the Xq28 region, the risk to sibs depends on the specific chromosome rearrangement. Once the MECP2 duplication has been identified in an affected family member (and/or the mother of the proband is found to be a carrier of a balanced translocation), prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

MECP2 duplication syndrome should be considered in males with the following clinical findings:

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

Note: MECP2 duplication syndrome occurs rarely in females because of skewing of X inactivation against the X chromosome that carries the duplicated fragment (see Clinical Characteristics, Heterozygous Females). In rare instances, however, females can be as severely affected as males and similar clinical findings can be observed.

Establishing the Diagnosis

The diagnosis of MECP2 duplication syndrome is established in an individual with suggestive findings and a heterozygous whole-gene duplication of MECP2 identified by molecular genetic testing (see Table 1).

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). Note: Single-gene testing is rarely useful and typically NOT recommended.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including MECP2 duplications).

Note: Routine G-banded cytogenetic analysis only detects duplications of Xq28 (the chromosomal locus of MECP2) larger than approximately 8 Mb; therefore, this testing is not considered first-tier testing and individuals with MECP2 duplication syndrome may have a normal G-banded karyotype.

An intellectual disability multigene panel that includes duplication analysis of MECP2 and other genes of interest (see Differential Diagnosis) is 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 if CMA were not performed. 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 an intellectual disability 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.

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome array (when clinically available) may be considered to detect (multi)exon duplications.

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

Clinical Description

MECP2 duplication syndrome is an X-linked disorder, mainly affecting males. The core phenotype includes developmental delay / intellectual disability, infantile hypotonia, speech and motor delay, recurrent infections, seizures, and gastrointestinal dysfunction. Additional, less frequent clinical features have been described.

More than 300 affected males have been reported to date and 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 2009, Echenne et al 2009, Kirk et al 2009, Lugtenberg et al 2009, Prescott et al 2009, Velinov et al 2009, Breman et al 2011, Sanmann et al 2012, Tang et al 2012, Lim et al 2017, Miguet et al 2018, Pascual-Alonso et al 2020].

Feeding/gastrointestinal manifestations. During the first weeks of life, feeding difficulties resulting from hypotonia may become evident in affected males. Children with MECP2 duplication syndrome are very hypotonic and may also exhibit difficulty with swallowing, gastroesophageal reflux, failure to thrive, and extensive drooling. In some cases, nasogastric tube feeding becomes necessary. In some affected individuals, fundoplication or permanent gastrostomy becomes necessary later in life to improve feeding conditions and prevent aspiration of fluids. Clinically important constipation is reported in more than one third of affected individuals.

Development. 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; the majority of affected individuals (>60%) 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 65% 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 with a median age at onset of six years. Multiple seizure types have been observed, the most frequently reported include atonic, tonic-clonic, tonic, and atypical absence seizures [Marafi et al 2019]. There is no specific electroclinical phenotype or specific effective monotherapy or polytherapy. Seizures resistant to treatment have been reported in about 82% of affected males with epilepsy [Marafi et al 2019]. 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 infections. 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.

Mild dysmorphic features including brachycephaly, midface retrusion, large ears, and depressed nasal bridge may be present.

Growth measurements at birth, including head circumference, are usually normal. Growth throughout childhood, including head circumference, is usually within the normal range.

Other associated findings that can be observed include the following:

• Nonspecific neuroradiologic findings on brain MRI including hypoplasia of the corpus callosum, enlarged ventricles, nonspecific changes in the white matter, and cerebellar hypoplasia [Friez et al 2006, Philippe et al 2013, El Chehadeh et al 2016]
• Autistic features including anxiety, stereotypic hand movements, and decreased sensitivity to pain/temperature [Miguet et al 2018, Giudice-Nairn et al 2019, Pascual-Alonso et al 2020]
• Mottled appearance of the skin
• Urogenital anomalies including bladder dysfunction, cryptorchidism, and small penis [Clayton-Smith et al 2009, Miguet et al 2018]

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 deficiency, microcephaly, and urogenital anomalies in addition to those findings described in 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, Tang et al 2012].

Penetrance

MECP2 duplications are believed to be completely penetrant in males.

Prevalence

To date, more than 300 affected individuals have been reported [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 2009, Echenne et al 2009, Kirk et al 2009, Lugtenberg et al 2009, Prescott et al 2009, Velinov et al 2009, Honda et al 2012, Sanmann et al 2012, Tang et al 2012, Lim et al 2017, Miguet et al 2018, Pascual-Alonso et al 2020]. 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. A recent Australian study calculated that the birth prevalence of MECP2 duplication syndrome in Australia was 0.65:100,000 for all live births and 1:100,000 for males, with a median age at diagnosis of 23.5 months (range: birth - 13 years) [Giudice-Nairn et al 2019]. When a clear X-linked inheritance pattern is present, the likelihood of detecting a MECP2 duplication is higher.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MECP2 duplication syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation 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 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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have MECP2 duplication syndrome nor will he be hemizygous for the MECP2 duplication; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is either an obligate heterozygote for an interstitial MECP2 duplication or a carrier of a balanced translocation involving Xq28.
  Note: If a woman has more than one affected child and no other affected relatives and if the MECP2 duplication (or a predisposing balanced translocation) cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for a MECP2 duplication or have a balanced translocation involving Xq28; or the causative genetic alteration may have occurred de novo in the affected male.
  In the majority of males who have an interstitial MECP2 duplication (not an X/Y rearrangement, or insertion elsewhere in the genome), the duplication is inherited from a heterozygous mother. However, de novo duplications have been described in several males [Giudice-Nairn et al 2019, Pascual-Alonso et al 2020].
• Recommendations for the evaluation of the mother of a male proband include molecular genetic testing for the MECP2 duplication identified in the proband and chromosome analysis to determine if a balanced chromosome rearrangement involving the Xq28 region is present.
• Typically, mothers who are heterozygous for a MECP2 duplication show extreme-to-complete skewing of X-chromosome inactivation and are asymptomatic. However, neuropsychiatric symptoms including depression, anxiety, and autistic features were described in heterozygous females with normal intellectual abilities [Ramocki et al 2009] (see Clinical Characteristics, Heterozygous Females).

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

• If the mother of the proband has an interstitial MECP2 duplication, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the MECP2 duplication will be affected.
  • Females who inherit the MECP2 duplication will be heterozygous and will typically be asymptomatic (with extreme to complete skewing of X-chromosome inactivation). However, heterozygous females may rarely exhibit clinical manifestations ranging from neuropsychiatric symptoms and mild nonspecific intellectual disability to a severe phenotype similar to that observed in males [El Chehadeh et al 2017]. It is not possible to correctly predict clinical outcome in a heterozygous female as clinical severity does not necessarily correlate with the X-chromosome inactivation pattern in blood [El Chehadeh et al 2017].
• If the mother of the proband has a balanced structural chromosome rearrangement involving the Xq28 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If a male proband represents a simplex case (i.e., a single occurrence in a family) and if testing of maternal leukocyte DNA does not detect a MECP2 duplication or chromosome rearrangement involving the Xq28 region, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.

Offspring of a male proband. No affected male has reproduced.

Other family members. If a MECP2 duplication or chromosome rearrangement is identified in the mother of a male proband, the proband's maternal aunts may be at risk of also having the genetic alteration and the aunts' offspring, depending on their sex, may be at risk of being heterozygous or hemizygous for the genetic alteration.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the causative genetic alteration has been identified in the proband.

Note: Females who are heterozygous for a MECP2 duplication will typically be asymptomatic (with extreme-to-complete skewing of X-chromosome inactivation). However, heterozygous females may rarely exhibit clinical manifestations ranging from neuropsychiatric symptoms and mild nonspecific intellectual disability to a severe phenotype similar to that observed in males [El Chehadeh et al 2017] (see Clinical Characteristics, Heterozygous Females).

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, 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 females who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the MECP2 duplication has been identified in an affected family member (and/or the mother of the proband is found to be a carrier of a balanced translocation), prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Note: X-inactivation analysis of amniotic cells is not informative because the X-inactivation pattern in amniotic cells may not correlate with X inactivation in the fetal body and brain.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MECP2 encodes MeCP2, a chromatin-bound nuclear protein that binds methylated DNA and hence plays an important role in gene regulation. In addition to the well-accepted role of MeCP2 as transcriptional repressor, recent studies have shown MeCP2 to be involved in RNA processing and active transcription as well. Studies have shown that hundreds of genes may be regulated by MeCP2 in a cell-specific manner [Shahbazian & Zoghbi 2002, Chahrour et al 2008, Skene et al 2010, Connolly & Zhou 2019]. While MeCP2 is ubiquitously present in various human tissues, it is expressed abundantly in the brain [Shahbazian & Zoghbi 2002], and within the brain, neurons express the highest levels. During embryogenesis, the neuronal level of MeCP2 is initially low, increases during the course of postnatal development, and reaches its maximum with maturation [Skene et al 2010]. Both loss of MECP2 (see Genetically Related Disorders) and duplication of MECP2 lead to intellectual disability syndrome, indicating that a correct dose of the protein is essential for normal brain development.

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 [Van Esch et al 2005, Ramocki & Zoghbi 2008]. A more recent human neuronal in vitro model, using the induced pluripotent stem (iPS) cell technology, showed that human iPS-derived neurons, carrying the duplication, have an abnormal morphology and altered electrophysiologic behavior [Nageshappa et al 2016].

Mechanism of disease causation. The genomic duplication involving MECP2 leads to increased protein expression.

MECP2-specific laboratory technical considerations. As this is a copy number variation (CNV), it can only be diagnosed by using a quantitative method such as chromosomal microarray analysis (CMA) or CNV calling using whole-genome data.

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 from Fonds voor Wetenschappelijk Onderzoek, Vlaanderen.

Revision History

• 21 May 2020 (sw) Comprehensive update posted live
• 9 October 2014 (me) Comprehensive update posted live
• 24 June 2010 (me) Comprehensive update posted live
• 18 January 2008 (me) Review posted live
• 12 October 2007 (hve) Original submission

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