MECP2 Mutations or Polymorphisms in Mentally Retarded Boys

Bourdon, Violaine; Philippe, Christophe; Martin, Dominique; Verloès, Alain; Grandemenge, Agnès; Jonveaux, Philippe

doi:10.1007/bf03260014

Cited by 19 publications

(17 citation statements)

References 26 publications

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“…The review of the literature also showed that males with MECP2 mutations present with a wide clinical spectrum including typical Rett or Rett-like phenotype, 3-7 mild to severe mental retardation, [11][12][13][14]22 and severe neonatal encephalopathy, 8-10 and results of the present report support the previous findings that males with MECP2 mutation also meet Rett-like phenotype.…”

Section: Discussionsupporting

confidence: 93%

“…Recently MECP2 mutations have been reported in males with a wide spectrum of neurological disorders including typical Rett syndrome or Rett-like phenotype, 3-7 neonatal encephalopathy, [8][9][10] and nonspecific mental retardation. [11][12][13][14] Large rearrangements including deletions and duplications have been detected by using quantitative analysis techniques, including multiplex ligation-dependent probe amplification 15 and real-time polymerase chain reaction (PCR), 16 and in Rett syndrome patients who were negative for MECP2 mutation on sequencing analysis. 17,18 Large duplications of MECP2 gene have been described frequently in male patients with severe mental retardation and with Rett-like phenotype.…”

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confidence: 99%

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A Novel MECP2 Change in an Indian Boy With Variant Rett Phenotype and Congenital Blindness: Implications for Genetic Counseling and Prenatal Diagnosis

et al. 2011

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Mutations in MECP2 gene are the primary cause of Rett syndrome, a neurodevelopmental disorder that primarily affects girls, and affect 90% to 95% patients with classical Rett syndrome. MECP2 mutations, once thought to be lethal in males, now present a broad spectrum of clinical manifestations in males. This article reports a family with a 9-year-old boy with Rett-like phenotype and congenital blindness, who inherited a novel MECP2 variant (p.P430S) from his asymptomatic mother. The variant was also identified in the asymptomatic maternal grandfather and maternal aunts of the proband, ruling out the possibility that the p.P430S was involved in the phenotype. Findings of the study suggest that a careful evaluation of the pathogenic nature of MECP2 variants identified in males be conducted before proposing genetic counseling or prenatal diagnosis to the family and that the interference of other factors like modifier genes, environment, epigenetics, and mosaicism be taken into account.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

A Novel MECP2 Change in an Indian Boy With Variant Rett Phenotype and Congenital Blindness: Implications for Genetic Counseling and Prenatal Diagnosis

et al. 2011

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“…Even when males with MECP2 have some of the distinctive features of RTT, such as loss of spoken language, loss of hand skills, or hand stereotypies, these features may be significantly subtler than those seen in females with RTT, further limiting specific clinical identification. This notion is borne out by MECP2 mutation studies of groups with neurodevelopmental delay that revealed mutations in 1.3–1.7% of males [Orrico, A. et al 2000, Couvert, P. et al 2001, Moncla, A.et al 2002, Yntema, H. G.et al 2002, Yntema, H. G.et al 2002, Bourdon, V.et al 2003, Kammoun, F.et al 2004, dos Santos, J. M.et al 2005, Ylisaukko-Oja, T.et al 2005, Donzel-Javouhey, A.et al 2006, Moog, U.et al 2006, Tejada, M. I.et al 2006], whereas few of these individuals were suspected as having MECP2 mutations. We expect that as whole exome or genome sequencing becomes commonly used to characterize males with neurodevelopmental disorders, it is likely that the identification of MECP2 mutations in these males will increase.…”

Section: Discussionmentioning

confidence: 99%

The array of clinical phenotypes of males with mutations in Methyl‐CpG binding protein 2

Neul

Benke

Marsh

et al. 2018

American J of Med Genetics Pt B

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Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome, primarily in girls. It had been suspected that mutations in MECP2 led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified thirty males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment. Two males with a somatic mutation in MECP2 had classic RTT. Of the remaining 28 subjects, 16 had RTT-causing MECP2 mutations, 9 with mutations that are not seen in females with RTT but are likely pathogenic, and 3 with uncertain variants. Two subjects with RTT-causing mutations were previously diagnosed as having atypical RTT; however, careful review of the clinical history determined that an additional 12/28 subjects met criteria for atypical RTT, but with more severe clinical presentation and course, and less distinctive RTT features, than females with RTT, leading to the designation of a new diagnostic entity, Male RTT Encephalopathy. Increased awareness of the clinical spectrum and widespread comprehensive genomic testing in boys with neurodevelopmental problems will lead to improved identification.

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“…Another X-linked gene, methyl-CpG binding protein 2 (MeCP2) (Vacca et al, 2001, Bourdon et al, 2003) has also been found to play a role in neuronal maturation and maintenance, including dendritic aborization (Kishi and Macklis, 2010). MeCP2 gene mutations have been identified in several disorders such as Rett syndrome, autism, and ADHD (Nagarajan et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Sex chromosome complement influences functional callosal myelination

Moore¹,

Patel²,

Hannsun³

et al. 2013

Neuroscience

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In addition to androgen differences between males and females, there are genetic differences that are caused by unequal dosage of sex chromosome genes. Using the cuprizone-induced demyelination model, we recently showed that surgical gonadectomy of adult mice resulted in decreased normal myelination and remyelination compared to gonadally intact animals, suggesting a supporting role for sex hormones in the maintenance of myelination. However, inherent sex differences in normal myelination and remyelination persisted even after gonadectomy, with males consistently remyelinating to a lesser extent relative to normal myelination as assayed by axon conduction and immunohistochemistry. This suggests a potential role for the sex chromosome complement in mediating the differential rates of remyelination observed in males and females. The present study focuses on the impact that sex chromosomes might have on these myelination differences. Making use of the four core-genotype \mice and cuprizone-diet induced demyelination/remyelination paradigm, our results demonstrate sex chromosome mediated asymmetry between XX and XY mice. The rate of functional remyelination following cuprizone diet-induced callosal demyelination in four core-genotype mice is attenuated in XY compared to XX animals of both gonadal sexes. Importantly, this difference arises only in the absence of circulating sex hormones following gonadectomy and confirms the role of sex hormones in the remyelination process reported earlier by our group. Because a genotype-mediated difference only arises following gonadectomy, the chromosomal contribution to myelination and remyelination is subtle yet significant. To explain this difference, we propose a possible asymmetry in expression of myelination-related genes in XX versus XY mice that needs to be investigated in future studies.

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MECP2 Mutations or Polymorphisms in Mentally Retarded Boys

Abstract: These results confirm that MECP2 mutations in males are far more rare than initially thought and call for a careful evaluation of the pathogenicity of the MECP2 missense mutations identified in mentally retarded males before genetic counseling is proposed to the relatives.

Cited by 19 publications

References 26 publications

A Novel MECP2 Change in an Indian Boy With Variant Rett Phenotype and Congenital Blindness: Implications for Genetic Counseling and Prenatal Diagnosis

A Novel MECP2 Change in an Indian Boy With Variant Rett Phenotype and Congenital Blindness: Implications for Genetic Counseling and Prenatal Diagnosis

The array of clinical phenotypes of males with mutations in Methyl‐CpG binding protein 2

Sex chromosome complement influences functional callosal myelination

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