Dataset Information

MECP2 Duplications in Symptomatic Females: Report on 3 Patients Showing the Broad Phenotypic Spectrum.

ABSTRACT: Xq28 microduplications including the MECP2 gene constitute a 100% penetrant X-linked syndrome in males caused by overexpression of normal MeCP2 protein. A small number of cases of affected females have been reported. This can be due to the location of the duplicated material into an autosome, but it can also be due to the location of the duplicated material into one of the X chromosomes and random or unfavorable skewed X chromosome inactivation, which is much more likely to occur but may be underdiagnosed because of the resulting broad phenotypic spectrum. In order to contribute to the phenotypic delineation of Xq28 microduplications including MECP2 in symptomatic females, the authors present clinical and molecular data on 3 patients illustrating the broad phenotypic spectrum. Our finding underlines the importance of quantitative analysis of MECP2 in females with intellectual disability and raises the question of the indication in females with borderline intellectual performances or learning difficulties.

SUBMITTER: San Antonio-Arce V

PROVIDER: S-EPMC5417292 | biostudies-literature | 2016 Jan-Dec

REPOSITORIES: biostudies-literature

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<i>MECP2</i> Duplications in Symptomatic Females: Report on 3 Patients Showing the Broad Phenotypic Spectrum.

San Antonio-Arce Victoria V Fenollar-Cortés María M Oancea Ionescu Raluca R DeSantos-Moreno Teresa T Gallego-Merlo Jesús J Illana Cámara Francisco José FJ Cotarelo Pérez María Carmen MC

Child neurology open 20160101

Xq28 microduplications including the <i>MECP2</i> gene constitute a 100% penetrant X-linked syndrome in males caused by overexpression of normal MeCP2 protein. A small number of cases of affected females have been reported. This can be due to the location of the duplicated material into an autosome, but it can also be due to the location of the duplicated material into one of the X chromosomes and random or unfavorable skewed X chromosome inactivation, which is much more likely to occur but may ...[more]

PMID: 28503606

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Project description:Context17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.ObjectiveTo examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.DesignCase series.Patients and resultsWe assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.ConclusionOur findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.Significance statementHere we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.

Project description:Gut microbiome composition is different in males and females, but sex is rarely considered when prescribing antibiotics, and sex-based differences in gut microbiome recovery following antibiotic treatment are poorly understood. Here, we compared the effects of broad-spectrum antibiotics on both the stool and small bowel microbiomes in male and female rats. Adult male and female Sprague Dawley rats were exposed to a multi-drug antibiotic cocktail for 8 days, or remained unexposed as controls. Following cessation of antibiotics, rats were monitored for an additional 13-day recovery period prior to euthanasia. Baseline stool microbiome composition was similar in males and females. By antibiotic exposure day 8 (AbxD8), exposed male rats exhibited greater loss of stool microbial diversity compared to exposed females, and the relative abundance (RA) of numerous taxa were significantly different in exposed males vs. exposed females. Specifically, RA of phylum Proteobacteria and genera Lactobacillus, Sutterella, Akkermansia, and Serratia were higher in exposed males vs. exposed females, whereas RA of phyla Firmicutes and Actinobacteria and genera Turicibacter and Enterococcus were lower. By 13 days post antibiotics cessation (PAbxD13), the stool RA of these and other taxa remained significantly different from baseline, and also remained significantly different between exposed males and exposed females. RA of phyla Firmicutes and Actinobacteria and genus Enterococcus remained lower in exposed males vs. exposed females, and genus Sutterella remained higher. However, RA of phylum Proteobacteria and genus Akkermansia were now also lower in exposed males vs. females, whereas RA of phylum Bacteroidetes and genus Turicibacter were now higher in exposed males. Further, the small bowel microbiome of exposed rats on PAbxD13 was also significantly different from unexposed controls, with higher RA of Firmicutes, Turicibacter and Parabacteroides in exposed males vs. females, and lower RA of Bacteroidetes, Proteobacteria, Actinobacteria, Oscillospira, Sutterella, and Akkermansia in exposed males vs. females. These findings indicate that broad-spectrum antibiotics have significant and sex-specific effects on gut microbial populations in both stool and the small bowel, and that the recovery of gut microbial populations following exposure to broad-spectrum antibiotics also differs between sexes. These findings may have clinical implications for the way antibiotics are prescribed.

Dataset Information

MECP2 Duplications in Symptomatic Females: Report on 3 Patients Showing the Broad Phenotypic Spectrum.

Publications

<i>MECP2</i> Duplications in Symptomatic Females: Report on 3 Patients Showing the Broad Phenotypic Spectrum.

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