Classic rett syndrome in a boy as a result of somatic mosaicism for a <i>mecp2</i> mutation

Armstrong, Judith; Póo, Pilar; Pineda, Merçè; Aibar, Elena; Geán, Esther; Català, Vicenç; Monrós, Eugènia

doi:10.1002/ana.1272

Cited by 57 publications

(42 citation statements)

References 5 publications

(5 reference statements)

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“…in incontinentia pigmenti (IKBKG), Rett syndrome (MECP2), or chondrodysplasia punctata (EBP) (Metzenberg et al, 1999;Clayton-Smith et al, 2000;Armstrong et al, 2001;Kenwrick, 2001;Topçu et al, 2002). We assume that the paracentric inversion of the X chromosome occurred postzygotically in a particular subset of the patient's cells.…”

Section: Discussionmentioning

confidence: 99%

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

Kutsche

Werner²,

Bartsch³

et al. 2002

Cytogenet Genome Res

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The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder with male lethality. In the majority of the patients reported, the MLS syndrome is caused by segmental monosomy of the Xp22.3 region. To date, five male patients with MLS and 46,XX karyotype (“XX males”) have been described. Here we report on the first male case with MLS and an XY complement. The patient showed agenesis of the corpus callosum, histiocytoid cardiomyopathy, and lactic acidosis but no microphthalmia, and carried a mosaic subtle inversion of the short arm of the X chromosome in 15% of his peripheral blood lymphocytes, 46,Y,inv(X)(p22.13∼22.2p22.32∼22.33)[49]/46,XY[271]. By fluorescence in situ hybridization (FISH), we showed that YAC 225H10 spans the breakpoint in Xp22.3. End-sequencing and database analysis revealed a YAC insert of at least 416 kb containing the genes HCCS and AMELX, and exons 2–16 of ARHGAP6. Molecular cytogenetic data suggest that the Xp22.3 inversion breakpoint is located in intron 1 of ARHGAP6, the gene encoding the Rho GTPase activating protein 6. Future molecular studies in karyotypically normal female MLS patients to detect submicroscopic rearrangements including the ARHGAP6 gene as well as mutation screening of ARHGAP6 in patients with no obvious chromosomal rearrangements will clarify the role of this gene in MLS syndrome.

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Section: Discussionmentioning

confidence: 99%

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

Kutsche

Werner²,

Bartsch³

et al. 2002

Cytogenet Genome Res

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“…Although MECP2 mutations causing RTT in females lead to neonatal encephalopathy and death in males, other mutations that have not been associated with classic RTT in females give rise to mental retardation syndromes and are compatible with survival in males, presumably because the mutant protein retains partial function Orrico et al, 2000;Imessaoudene et al, 2001]. There are several instances of males with RTT-causing mutations that have survived and developed a RTT phenotype, but in all the known cases, either the males are mosaic for the mutation or they have a partial or complete 47,XXY karyotype to mitigate the effects of the mutation [Clayton-Smith et al, 2000;Armstrong et al, 2001;Hoffbuhr et al, 2001;Schwartzman et al, 2001].…”

Section: Introductionmentioning

confidence: 94%

Balanced X chromosome inactivation patterns in the Rett syndrome brain

Shahbazian¹,

Sun²,

Zoghbi³

2002

Am. J. Med. Genet.

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In Rett syndrome (RTT), an X-linked disorder essentially limited to females, neurological development goes awry. Causing this disarray in neuronal function is a mutated form of a protein known as methyl-CpG-binding protein 2 (MeCP2). Because the MECP2 gene is subject to X chromosome inactivation (XCI) in females, a number of studies have addressed whether the percentage of cells inactivating the normal vs. mutant chromosome in heterozygous females influences the phenotypic outcome of MECP2 mutations. Because most of these studies measured XCI in peripheral blood, however, interpretation of the results requires the assumption that XCI patterns in blood are representative of those in the brain, the primarily affected tissue. Here, we have analyzed the MECP2 sequence and XCI status in 13 brains of RTT patients. Mutations were identified in nine of the cases, with eight of these representing C to T transitions at CpG dinucleotides, and one being a novel frameshift mutation (765delA). Patterns of XCI were balanced in 10 of 10 cases for which the assay was informative. As previous studies have shown that a majority of RTT patients have balanced XCI patterns in peripheral blood, our results suggest that the pattern in blood is an accurate indicator of XCI patterns in the brain for a majority of cases, but there are some notable exceptions that this study may help explain. Given the correlation between balanced XCI and classic RTT, these results suggest that a certain percentage of neurons expressing the mutant MECP2 gene may be required for RTT to become manifest.

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“…In addition to germline mosaicism, the possibility of somatic mosaicism in the unaffected mother should also be considered [10]. This situation has not been described in females yet, but it has been found in 2 boys: a 14-year-old Armstrong/Aibar/Pineda/Pérez/Geá n/ Carrera/Casas/Martínez/Monró s boy with classical RTT [16] and a boy with a clinical phenotype of Angelman syndrome [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…These results have demonstrated the lethality of hemizygous MECP2 mutations causing RTT in females. Some of the rare cases of boys described to date with an RTT phenotype [11][12][13][14][15][16] had an associated Klinefelter syndrome [15] or else a somatic mosaicism for a MECP2 mutation [16], thus mimicking the phenomenon of X-chromosome inactivation in females.…”

Section: Introductionmentioning

confidence: 99%

Prenatal Diagnosis in Rett Syndrome

Armstrong

Aibar²,

Pineda³

et al. 2002

Fetal Diagn Ther

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Background/Aim: Rett syndrome (RTT) is an X-linked neurodevelopmental dominant disorder that affects almost exclusively girls. The disease is mainly sporadic, caused by de novo mutations at MECP2 gene (Xq28), but a low percentage of familial cases have been reported. We present the results of RTT prenatal diagnosis in three families and discuss the usefulness of such analyses in diseases caused mainly by de novo mutations. Methods: For adult individuals, DNA was extracted from peripheral lymphocytes; for fetus analysis it was obtained from cultured amniotic fluid or from chorionic biopsy specimens. Mutation detection at MECP2 gene was first carried out in the patients by SSCP/HD analysis and subsequent sequencing. Family studies and prenatal diagnoses were done by direct analysis of previously characterized patients’ mutations using SSCP/HD or restriction analysis. Results: Heterozygous mutations identified in the 3 patients were: 1061del96bp, 473C→T, and 763C→T, respectively. Mutations were not present in the mothers’ DNAs obtained from peripheral lymphocytes. None of the 3 fetuses analyzed carried the mutation of the affected sister. Conclusions: Recurrence within RTT families can be due to asymptomatic nonpenetrant carrier mothers or to parental germinal mosaicism for the MECP2 mutation. Since germline mosaicism can neither be predicted nor detected, families with 1 affected patient whose RTT-causing mutation has been previously identified can benefit from prenatal diagnosis which contributes to a decrease in the recurrence risk in a new pregnancy comparable to that of the normal population.

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Classic rett syndrome in a boy as a result of somatic mosaicism for a mecp2 mutation

Cited by 57 publications

References 5 publications

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

Balanced X chromosome inactivation patterns in the Rett syndrome brain

Prenatal Diagnosis in Rett Syndrome

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