MECP2 duplication syndrome is an X-linked neurodevelopmental disorder characterized by severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity, and recurrent infections. Only males are affected, although female carriers ... MECP2 duplication syndrome is an X-linked neurodevelopmental disorder characterized by severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity, and recurrent infections. Only males are affected, although female carriers may have some mild neuropsychiatric features, such as anxiety. Submicroscopic Xq28 duplications encompassing MECP2 are considered nonrecurrent events, because the breakpoint locations and rearrangement sizes vary among affected individuals (summary by Ramocki et al., 2010).
Lubs et al. (1999) reported a family in which 5 males had severe X-linked mental retardation and progressive, severe central nervous system deterioration. The patients also had hypotonia, mild myopathy, and a characteristic facies with downslanting palpebral fissures, ... Lubs et al. (1999) reported a family in which 5 males had severe X-linked mental retardation and progressive, severe central nervous system deterioration. The patients also had hypotonia, mild myopathy, and a characteristic facies with downslanting palpebral fissures, hypertelorism, and a short nose with a low nasal bridge. Three of the 5 affected males died of secondary complications before the age of 10 years, and no affected males had survived beyond the age of 10 years. Linkage analysis localized the gene for this condition to the distal 5 cM of Xq28. Meins et al. (2005) reported a boy with psychomotor retardation from birth. He showed features of Rett syndrome, including stereotypical hand movements at age 4 years, loss of purposeful hand movements at 6 years, and autistic features. He developed generalized epilepsy with absences and myotonia-astatic and tonic seizures. Other features included undescended testes, increased salivation, and bruxism. He never learned to speak, but could communicate basic needs. The extremities were frequently pink and cold, suggesting a mild peripheral vasomotor disturbance. There was no spasticity or scoliosis. Van Esch et al. (2005) reported a large Finnish family in which 6 males in 3 generations had a severe form of X-linked mental retardation associated with infantile axial hypotonia and childhood progressive spasticity. Other features included lack of speech development, seizures, recurrent respiratory infections, facial hypotonia, large, low-set ears, flat nasal bridge, and asymmetry of the skull. Three additional families with a similar phenotype were also described. Del Gaudio et al. (2006) reported 6 neurodevelopmentally delayed males with MECP2 duplication and 1 with MECP2 triplication, and reviewed 53 cases from the literature. The patient with the triplication had the most severe phenotype. All had developmental delay and infantile hypotonia. Absent speech was present in 84% (27/32) and 45% (14/31) lacked ambulation. A history of recurrent infections was present in 83% (40/48); 1 of the patients reported by del Gaudio et al. (2006) had absent swallowing with aspiration pneumonias. One of 53 (2%) in the literature had stereotypic hand movements. Three of the 7 reported by del Gaudio et al. (2006) had autistic-like features, but only 1 of 53 (2%) in the literature had such features. More than half had seizures, and 40% (19/48) had microcephaly. Del Gaudio et al. (2006) corroborated findings by others that infantile axial hypotonia in MECP2 duplication leads to progressive spasticity later in childhood. Using multiplex ligation-dependent probe amplification (MLPA), Friez et al. (2006) identified 6 families in which several males had mental retardation due to duplications of the MECP2 gene. One of the families had been reported by Lubs et al. (1999). The clinical presentation was similar in all patients and included recurrent infections, particularly pneumonia, infantile hypotonia giving way to spasticity in childhood, severe mental retardation, and lack of speech acquisition. Other features included gastroesophageal reflux, swallowing difficulties, facial hypotonia and excessive drooling, and inability or limited ability to walk. Four of 10 individuals had decreased serum IgA levels. About half of the patients died before age 25 years. The Xq28 duplications ranged in size from 400 to 800 kb and included MECP2 in all families. Five of the families had duplications including the L1CAM (308840) gene. Ramocki et al. (2009) reported 9 boys with MECP2 duplication syndrome from 8 families. All had severe to profound mental retardation, expressive language defects, and autism, with gaze avoidance and avoidance of social interactions. Other neuropsychologic features included difficulties with transition, rigidity, and anxiety. Neurologic features included hypotonia, seizures, choreiform movements, repetitive movements, and lower limb spasticity. The duplication size ranged from 0.32 to 0.71 Mb, and there was no correlation between the duplication size and phenotypic severity. Nine carrier females from the same families were also examined. About half had endocrine abnormalities, including irregular menses, premature menopause, adult-onset diabetes, and hypothyroidism. Psychologic evaluation revealed variable depression, anxiety, compulsive behaviors, rigidity, hostility, psychoticism, somatization, and autistic features. Some had difficulties with language. Informative studies of 8 carrier females showed 100% skewed X inactivation and normal levels of MECP2 mRNA in peripheral blood. Ramocki et al. (2009) suggested that tight regulation of MECP2 levels is critical for appropriate neuronal development and function, and that female duplication carriers also show psychiatric manifestations. Belligni et al. (2010) reported a 5-year-old boy who demonstrated severe central hypotonia and central hypoventilation at birth, necessitating a tracheostomy. He showed severe developmental delay with poor head control. He also had a persistent ductus arteriosus and chronic constipation, without evidence of Hirschsprung disease. Brain MRI showed decreased white matter bulk and bilateral optic nerve hypoplasia. Genetic analysis identified a 0.5 to 0.8-Mb interstitial duplication of Xq28 including the MECP2 gene (300005.0030), which was inherited from his asymptomatic mother. Belligni et al. (2010) suggested that MECP2 be evaluated in patients with features of the congenital hypoventilation syndrome (209880).
In a boy with mental retardation and features of Rett syndrome, Meins et al. (2005) found a submicroscopic duplication of Xq28, including the MECP2 gene (300005.0030). Dosage analysis of family members showed 2 gene copies in the boy ... In a boy with mental retardation and features of Rett syndrome, Meins et al. (2005) found a submicroscopic duplication of Xq28, including the MECP2 gene (300005.0030). Dosage analysis of family members showed 2 gene copies in the boy and 3 copies in his healthy mother, who had severely skewed X inactivation. Quantification of transcript levels suggested a double dose of MECP2 in the boy, but not in his mother. Further analysis showed that the duplication included 12 genes, from AVPR2 (300538) to TKTL1 (300044); the L1CAM gene was excluded. By array comparative genomic hybridization (array CGH), Van Esch et al. (2005) identified a small duplication at Xq28 in a large Finnish family with a severe form of mental retardation associated with progressive spasticity and seizures. Screening by real-time quantification of 17 additional patients with mental retardation who had similar phenotypes revealed 3 more duplications. The duplications in the 4 patients varied in size from 0.4 to 0.8 Mb and harbored several genes, including L1CAM and MECP2. The proximal breakpoints were located within a 250-kb region centromeric to L1CAM, whereas the distal breakpoints were located in a 300-kb interval telomeric of MECP2. Although the size and location of each duplication was different in the 4 patients, the duplications segregated with the disease and asymptomatic carrier females showed complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enabled refinement of the genotype-phenotype correlation and strongly suggested that increased dosage of MECP2 results in the mental retardation phenotype. Lugtenberg et al. (2009) identified duplication of the MECP2 gene in 3 (1%) of 283 male probands with X-linked mental retardation and in 3 (2%) of 134 males with mental retardation and severe, mostly progressive, neurologic symptoms. An examination of 13 affected males from these 6 families showed that all had moderate to severe mental retardation and childhood hypotonia, and the majority also presented with absent speech, seizures, and progressive spasticity. Ataxia and cerebral atrophy were also observed. No Xq28 duplications were found in 329 females with mental retardation. The duplications ranged from 100 to 900 kb, and some also included the IRAK1 gene (300283), but the severity of the disorder did not correlate with the size of the duplication. Carvalho et al. (2009) investigated the potential mechanisms for MECP2 duplication and examined whether genomic architectural features may play a role in their origin using a 4-Mb tiling-path oligonucleotide array CGH assay. The 30 male patients analyzed showed a unique duplication varying in size from 250 kb to 2.6 Mb. In 77% of these nonrecurrent duplications, the distal breakpoints grouped within a 215-kb genomic interval, located 47 kb telomeric to the MECP2 gene. The genomic architecture of this region contains both direct and inverted low-copy repeat (LCR) sequences; this same region undergoes polymorphic structural variation in the general population. Array CGH analysis revealed complex rearrangements in 8 patients; in 6 patients the duplication contained an embedded triplicated segment, and in the other 2, stretches of nonduplicated sequences occurred within the duplicated region. Breakpoint junction sequencing was achieved in 4 duplications and identified an inversion in 1 patient, demonstrating further complexity. Carvalho et al. (2009) proposed that the presence of LCRs in the vicinity of the MECP2 gene may generate an unstable DNA structure that can induce DNA strand lesions, such as a collapsed fork, and facilitate a fork stalling and template switching (FoSTeS) event producing the complex rearrangements involving the MECP2 gene.
The MECP2 duplication syndrome may explain about 1% of cases of X-linked mental retardation, but this number may increase up to 15% when males with specific features, such as progressive spasticity, are studied (Ramocki et al., 2010). Lugtenberg ... The MECP2 duplication syndrome may explain about 1% of cases of X-linked mental retardation, but this number may increase up to 15% when males with specific features, such as progressive spasticity, are studied (Ramocki et al., 2010). Lugtenberg et al. (2009) identified duplication of the MECP2 gene in 3 (1%) of 283 male probands with X-linked mental retardation and in 3 (2%) of 134 males with mental retardation and severe, mostly progressive, neurologic symptoms, and Ramocki et al. (2010) stated that MECP2 duplications were found in 19 (0.41%) of 4,683 males referred for developmental delay or mental retardation. However, Friez et al. (2006) found that 2 (11.8%) of 17 males with X-linked mental retardation linked to Xq28 had MECP2 duplications, and Van Esch et al. (2005) found that 3 (17.6%) of 17 males with mental retardation and progressive spasticity had MECP2 duplications.
Duplication of the gene MECP2 (MECP2 duplication syndrome) in males results in the following:...
DiagnosisClinical DiagnosisDuplication 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 dysmorphismAlthough 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].TestingCytogenetic 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 TestingGene. 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 testingDuplication 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMECP2Duplication analysis 2Whole-gene duplications100%ClinicalNot ApplicableCytogenetic analysis Cytogenetically visible duplications of Xq28 5% Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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. Testing StrategyTo 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.Genetically Related (Allelic) DisordersOther 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).
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]. ...
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 obstructionBladder dysfunctionHeterozygous 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].
No clear genotype-phenotype correlation has been identified to date. However, the following have been noted: ...
Genotype-Phenotype CorrelationsNo 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].
Alpha-Thalassemia X-Linked Intellectual Disability Syndrome (formerly alpha-thalassemia X-linked mental retardation [ATRX] syndrome) is characterized by distinctive craniofacial features, genital anomalies, and severe developmental delays with hypotonia and cognitive impairment. Especially in early infancy before the facial features become evident, the early and severe hypotonia and developmental delay overlap with the MECP2 duplication syndrome phenotype. ATRX syndrome is caused by mutations in ATRX and the inheritance is also X-linked. MECP2 duplication syndrome and ATRX syndrome are easily distinguished by molecular genetic testing. ...
Differential DiagnosisAlpha-Thalassemia X-Linked Intellectual Disability Syndrome (formerly alpha-thalassemia X-linked mental retardation [ATRX] syndrome) is characterized by distinctive craniofacial features, genital anomalies, and severe developmental delays with hypotonia and cognitive impairment. Especially in early infancy before the facial features become evident, the early and severe hypotonia and developmental delay overlap with the MECP2 duplication syndrome phenotype. ATRX syndrome is caused by mutations in ATRX and the inheritance is also X-linked. MECP2 duplication syndrome and ATRX syndrome are easily distinguished by molecular genetic testing.
To establish the extent of disease in an individual diagnosed with MECP2 duplication syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 EEGComplete 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 ManifestationsCognitive 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 ComplicationsPhysical 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.SurveillanceThe 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 symptomsEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. MECP2 Duplication Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMECP2Xq28Methyl-CpG-binding protein 2RettBASE MECP2 @ LOVD CCHMC - Human Genetics Mutation DatabaseMECP2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for MECP2 Duplication Syndrome (View All in OMIM) View in own window 300005METHYL-CpG-BINDING PROTEIN 2; MECP2 300260LUBS X-LINKED MENTAL RETARDATION SYNDROME; MRXSLMolecular Genetic PathogenesisEvidence 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].