Alternative titles; symbols
SNOMEDCT: 702816000; ORPHA: 1762; DO: 0060799;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Intellectual developmental disorder, X-linked syndromic, Lubs type | 300260 | X-linked recessive | 3 | MECP2 | 300005 |
A number sign (#) is used with this entry because Lubs-type X-linked syndromic intellectual developmental disorder (MRXSL) is caused by duplication or triplication of the gene encoding methyl-CpG-binding protein-2 (MECP2; 300005) on chromosome Xq28.
The MECP2 gene is also mutated in Rett syndrome (RTT; 312750) and in X-linked syndromic intellectual developmental disorder-13 (MRXS13; 300055).
X-linked Lubs-type syndromic intellectual developmental disorder (MRXSL) is a neurodevelopmental disorder characterized by severely to profoundly impaired intellectual development, 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, 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 stereotypic 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 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 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.
Collins et al. (2004) generated transgenic mice that overexpressed wildtype human MECP2. Detailed neurobehavioral and electrophysiologic studies in these mice, which expressed MECP2 at 2-fold wildtype levels, demonstrated onset of phenotypes around 10 weeks of age. Mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, mice developed seizures, hypoactivity, and spasticity, and 30% of mice died by 1 year of age. Collins et al. (2004) concluded that MECP2 levels must be tightly regulated in vivo and that even mild overexpression of this protein may be detrimental.
Samaco et al. (2012) found that transgenic mice expressing double or 3-fold levels of MECP2 showed heightened anxiety behavior and impaired socialization compared to wildtype mice. Microarray analysis of these mice showed increased amygdala expression of Crh (122560) and Oprm1 (600018), both of which are directly regulated by the binding of MECP2 to their promoters. Anxiety-like behavior was reduced in transgenic mice lacking 1 copy of Crh or its receptor Crhr1 (122561), but anxiety-related behavior was unchanged in mice lacking 1 copy of Oprm1. In contrast, reduction of Oprm1 expression improved abnormal social behavior. These data indicated that increased MECP2 levels affect distinct molecular pathways underlying anxiety and social behavior.
Sztainberg et al. (2015) proposed that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, Sztainberg et al. (2015) showed that correction of MeCP2 levels largely reverses the behavioral, molecular, and electrophysiologic deficits. The authors also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with mRNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. Sztainberg et al. (2015) found that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.
Liu et al. (2016) reported that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviors and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by Western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wildtype monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wildtype monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviors. Liu et al. (2016) generated 5 F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from 1 F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wildtype monkeys of similar age.
Belligni, E. F., Palmer, R. W., Hennekam, R. C. M. MECP2 duplication in a patient with congenital central hypoventilation. Am. J. Med. Genet. 152A: 1591-1593, 2010. [PubMed: 20503343] [Full Text: https://doi.org/10.1002/ajmg.a.33311]
Carvalho, C. M. B., Zhang, F., Liu, P., Patel, A., Sahoo, T., Bacino, C. A., Shaw, C., Peacock, S., Pursley, A., Tavyev, Y. J., Ramocki, M. B., Nawara, M., Obersztyn, E., Vianna-Morgante, A. M., Stankiewicz, P., Zoghbi, H. Y., Cheung, S. W., Lupski, J. R. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum. Molec. Genet. 18: 2188-2203, 2009. [PubMed: 19324899] [Full Text: https://doi.org/10.1093/hmg/ddp151]
Collins, A. L., Levenson, J. M., Vilaythong, A. P., Richman, R., Armstrong, D. L., Noebels, J. L., Sweatt, J. D., Zoghbi, H. Y. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Molec. Genet. 13: 2679-2689, 2004. [PubMed: 15351775] [Full Text: https://doi.org/10.1093/hmg/ddh282]
del Gaudio, D., Fang, P., Scaglia, F., Ward, P. A., Craigen, W. J., Glaze, D. G., Neul, J. L., Patel, A., Lee, J. A., Irons, M., Berry, S. A., Pursley, A. A., and 12 others. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 8: 784-792, 2006. [PubMed: 17172942] [Full Text: https://doi.org/10.1097/01.gim.0000250502.28516.3c]
Friez, M. J., Jones, J. R., Clarkson, K., Lubs, H., Abuelo, D., Blaymore Bier, J.-A., Pai, S., Simensen, R., Williams, C., Giampietro, P. F., Schwartz, C. E., Stevenson, R. E. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 118: e1687, 2006. Note: Electronic Article. [PubMed: 17088400] [Full Text: https://doi.org/10.1542/peds.2006-0395]
Liu, Z., Li, X., Zhang, J.-T., Cai, Y.-J., Cheng, T.-L., Cheng, C., Wang, Y., Zhang, C.-C., Nie, Y. H., Chen, Z.-F., Bian, W.-J., Zhang, L., and 14 others. Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2. Nature 530: 98-102, 2016. [PubMed: 26808898] [Full Text: https://doi.org/10.1038/nature16533]
Lubs, H., Abidi, F., Bier, J.-A. B., Abuelo, D., Ouzts, L., Voeller, K., Fennell, E., Stevenson, R. E., Schwartz, C. E., Arena, F. XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28. Am. J. Med. Genet. 85: 243-248, 1999. [PubMed: 10398236] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990730)85:3<243::aid-ajmg11>3.0.co;2-e]
Lugtenberg, D., Kleefstra, T., Oudakker, A. R., Nillesen, W. M., Yntema, H. G., Tzschach, A., Raynaud, M., Rating, D., Journel, H., Chelly, J., Goizet, C., Lacombe, D., and 12 others. Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy. Europ. J. Hum. Genet. 17: 444-453, 2009. Note: Erratum: Europ. J. Hum. Genet. 17: 697 only, 2009. [PubMed: 18985075] [Full Text: https://doi.org/10.1038/ejhg.2008.208]
Meins, M., Lehmann, J., Gerresheim, F., Herchenbach, J., Hagedorn, M., Hameister, K., Epplen, J. T. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. (Letter) J. Med. Genet. 42: e12, 2005. Note: Electronic Article. [PubMed: 15689435] [Full Text: https://doi.org/10.1136/jmg.2004.023804]
Ramocki, M. B., Peters, S. U., Tavyev, Y. J., Zhang, F., Carvalho, C. M. B., Schaaf, C. P., Richman, R., Fang, P., Glaze, D. G., Lupski, J. R., Zoghbi, H. Y. Autism and other neuropsychiatric symptoms are prevalent in individuals with MECP2 duplication syndrome. Ann. Neurol. 66: 771-782, 2009. [PubMed: 20035514] [Full Text: https://doi.org/10.1002/ana.21715]
Ramocki, M. B., Tavyev, Y. J., Peters, S. U. The MECP2 duplication syndrome. Am. J. Med. Genet. 152A: 1079-1088, 2010. [PubMed: 20425814] [Full Text: https://doi.org/10.1002/ajmg.a.33184]
Samaco, R. C., Mandel-Brehm, C., McGraw, C. M., Shaw, C. A., McGill, B. E., Zoghbi, H. Y. Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. Nature Genet. 44: 206-211, 2012. [PubMed: 22231481] [Full Text: https://doi.org/10.1038/ng.1066]
Sztainberg, Y., Chen, H., Swann, J. W., Hao, S., Tang, B., Wu, Z., Tang, J., Wan, Y.-W., Liu, Z., Rigo, F., Zoghbi, H. Y. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature 528: 123-126, 2015. [PubMed: 26605526] [Full Text: https://doi.org/10.1038/nature16159]
Van Esch, H., Bauters, M., Ignatius, J., Jansen, M., Raynaud, M., Hollanders, K., Lugtenberg, D., Bienvenu, T., Jensen, L. R., Gecz, J., Moraine, C., Marynen, P., Fryns, J.-P., 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. 77: 442-453, 2005. [PubMed: 16080119] [Full Text: https://doi.org/10.1086/444549]