Clinical characteristics.

The MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by infantile hypotonia, 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 related clinical findings, often associated with concomitant X-chromosomal abnormalities that prevent inactivation of the duplicated region. Generalized tonic-clonic seizures are most often observed; atonic seizures and absence seizures have also been described. One third of affected males are never able to walk independently. Almost 50% of affected males die before age 25 years, presumably from complications of recurrent infection and/or neurologic deterioration. In addition to the core features, autistic behaviors and gastrointestinal dysfunction have been observed in several affected boys. Although interfamilial phenotypic variability is observed, severity is usually consistent within families.

Diagnosis/testing.

Duplications of MECP2 ranging from 0.3 to 4 Mb and larger are found in all affected males and are identified by a variety of test methods. In fewer than 5% of affected males routine G-banded cytogenetic analysis detects duplications of Xq28 (the chromosomal locus of MECP2) larger than approximately 8 Mb.

Management.

Treatment of manifestations: Routine management of hypotonia, feeding difficulties, infections, developmental and speech delays, spasticity, and seizures.

Prevention of secondary complications: Physical therapy to maintain range of motion to reduce likelihood of contractures

Surveillance: Routine monitoring for progressive spasticity, autistic-like signs, loss of speech, seizure disorder and response to antiepileptic medications, infections, and gastrointestinal symptoms.

Genetic counseling.

MECP2 duplication syndrome is inherited in an X-linked manner. The vast majority of affected males have inherited the MECP2 duplication from a carrier mother; however, de novo cases 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 usually asymptomatic carriers. Preimplantation and prenatal testing for pregnancies at increased risk are possible if the diagnosis of MECP2 duplication syndrome has been confirmed in an affected family member.

Clinical Diagnosis

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

• Severe to profound intellectual disability, 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].

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis can be established by chromosomal microarray or another quantitative method such as quantitative PCR or MLPA.

Clinical Description

About 150 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].

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. 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.

Mild dysmorphic features including brachycephaly, midface retrusion, large ears, and depressed 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 with a median age at onset of six years. Generalized tonic-clonic seizures are most often observed; atonic seizures and absence seizures have also been described. There is no specific electroclinical phenotype, but in some individuals seizures can be refractory to treatment [Caumes et al 2014]. 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:

• 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]
• Autistic features, including anxiety, stereotypic hand movements, and decreased sensitivity to pain/temperature [Peters et al 2013].
• Mottled appearance of the skin
• Bladder dysfunction

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 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, about 150 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, 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, Tang et al 2012, Honda et al 2012, Sanmann et al 2012]. 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 and needs 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 intellectual 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)
• Consultation with a clinical geneticist and/or genetic counselor

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 seizures are resistant to the usual therapy, necessitating multi-drug therapy.

Predisposition to infections. Infections, especially of the respiratory tract, should be treated immediately with appropriate antibiotics. All vaccines should be given. If aspiration occurs, placement of a permanent gastrostomy should be considered.

Gastrointestinal 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 and response to antiepileptic medications
• Number and type of infections
• Autistic-like features
• Gastrointestinal symptoms

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 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 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. With few exceptions, carrier mothers show 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 variant" (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 proband represents a simplex case (i.e., a single occurrence in a family) and if the MECP2 duplication cannot be detected in the leukocyte DNA of the mother, 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.

Heterozygote (Carrier) Detection

Carrier testing of at-risk female relatives requires either (a) prior identification of the MECP2 duplication in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by duplication analysis.

Related Genetic Counseling Issues

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 females who are carriers or are 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the MECP2 duplication has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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 [Van Esch et al 2005, Ramocki & Zoghbi 2008].

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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

• 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