A review of trisomy X (47,XXX) Tartaglia, Nicole R; Howell, Susan; Sutherland, Ashley ...
Orphanet journal of rare diseases,
05/2010, Volume:
5, Issue:
1
Journal Article
Peer reviewed
Open access
Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal ...abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
The intertwining between spin, charge, and lattice degrees of freedom can give rise to unusual macroscopic quantum states, including high-temperature superconductivity and quantum anomalous ...Hall effects. Recently, a charge density wave (CDW) has been observed in the kagome antiferromagnet FeGe, indicative of possible intertwining physics. An outstanding question is that whether magnetic correlation is fundamental for the spontaneous spatial symmetry breaking orders. Here, utilizing elastic and high-resolution inelastic x-ray scattering, we observe a c-axis superlattice vector that coexists with the 2
$$\times$$
×
2
$$\times$$
×
1 CDW vectors in the kagome plane. Most interestingly, between the magnetic and CDW transition temperatures, the phonon dynamical structure factor shows a giant phonon-energy hardening and a substantial phonon linewidth broadening near the c-axis wavevectors, both signaling the spin-phonon coupling. By first principles and model calculations, we show that both the static spin polarization and dynamic spin excitations intertwine with the phonon to drive the spatial symmetry breaking in FeGe.
Sex chromosome aneuploidies (SCAs), including 47,XXY, 47,XXX, 47,XYY, and supernumerary variants, occur collectively in approximately one of 500 live births. Clinical phenotypes are highly variable ...resulting in previous ascertainment rates estimated to be only 10%–25% during a lifetime. Historically, prenatal SCA diagnoses were incidental findings, accounting for ≤10% of cases, with the majority of diagnoses occurring postnatally during evaluations for neurodevelopmental, medical, or infertility concerns. The initiation of noninvasive prenatal screening (NIPS) in 2012 and adoption into standardized obstetric care provides a unique opportunity to significantly increase prenatal ascertainment of SCAs. However, the impact NIPS has had on ascertainment of SCAs is understudied, particularly for those who may defer diagnostic testing until after birth. This study evaluates the timing of diagnostic testing following positive NIPS in 152 infants with SCAs and potential factors influencing this decision. Eighty‐seven (57%) elected to defer diagnostic testing after a positive NIPS until birth, and 8% (7/87) of those confirmed after birth were found to have discordant results on postnatal diagnostic testing, most of which would have influenced genetic counseling.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
is a major pathogen responsible for bovine mastitis, the most common and costly disease affecting dairy cattle.
naturally releases extracellular vesicles (EVs) during its growth. EVs play an ...important role in the bacteria-bacteria and bacteria-host interactions and are notably considered as nanocarriers that deliver virulence factors to the host tissues. Whether EVs play a role in a mastitis context is still unknown. In this work, we showed that
Newbould 305 (N305), a bovine mastitis isolate, has the ability to generate EVs
with a designated protein content. Purified
N305-secreted EVs were not cytotoxic when tested
on MAC-T and PS, two bovine mammary epithelial cell lines. However, they induced the gene expression of inflammatory cytokines at levels similar to those induced by live
N305. The
immune response to purified
N305-secreted EVs was tested in a mouse model for bovine mastitis and their immunogenic effect was compared to that of live
N305, heat-killed
N305 and to
lipoteichoic acid (LTA). Clinical and histopathological signs were evaluated and pro-inflammatory and chemotactic cytokine levels were measured in the mammary gland 24 h post-inoculation. Live
induced a significantly stronger inflammatory response than that of any other condition tested. Nevertheless,
N305-secreted EVs induced a dose-dependent neutrophil recruitment and the production of a selected set of pro-inflammatory mediators as well as chemokines. This immune response elicited by intramammary
N305-secreted EVs was comparable to that of heat-killed
N305 and, partly, by LTA. These results demonstrated that
N305-secreted EVs induce a mild inflammatory response distinct from the live pathogen after intramammary injection. Overall, our combined
and
data suggest that EVs are worth to be investigated to better understand the
pathogenesis and are relevant tools to develop strategies against bovine
mastitis.
Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5' untranslated ...region of the fragile X mental retardation 1 (
) gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABA
) receptor
subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a
-subunit-selective, extrasynaptic GABA
receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS.
This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg once (QD), twice (BID), or three-times daily (TID) when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors.
A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD (
= 8), 5 mg BID (
= 8), or 5 mg TID (
= 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (
= 4), headache (
= 3), diarrhea (
= 2), and irritability (
= 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement.
Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group.
www.ClinicalTrials.gov, identifier: NCT03697161.
Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual ...disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the β isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The “inactive” X chromosome (Xi) has been assumed to have little impact, in trans, on the “active” X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to ...three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes.
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•Analyzed gene expression in sex chromosome aneuploidy samples using linear models•Xi and Xa transcriptomes are modular•38% of X chromosome genes are affected by Xi copy number—in cis and in trans•10 X chromosome genes likely contribute to male-female differences in somatic tissues
Through RNA sequencing of individuals with sex chromosome aneuploidy, San Roman et al. identify modular “active” (Xa) and “inactive” (Xi) X chromosome transcriptomes. Looking beyond classical X inactivation, which acts in cis, they find that Xi modulates Xa transcript levels in trans. They identify 10 X chromosome genes most likely to contribute to male-female differences in common disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exfoliative toxins are serine proteases secreted by Staphylococcus aureus that are associated with toxin-mediated staphylococcal syndromes. To date, four different serotypes of exfoliative toxins ...have been identified and 3 of them (ETA, ETB, and ETD) are linked to human infection. Among these toxins, only the ETD structure remained unknown, limiting our understanding of the structural determinants for the functional differentiation between these toxins. We recently identified an ETD-like protein associated to S. aureus strains involved in mild mastitis in sheep. The crystal structure of this ETD-like protein was determined at 1.95 Å resolution and the structural analysis provide insights into the oligomerization, stability and specificity and enabled a comprehensive structural comparison with ETA and ETB. Despite the highly conserved molecular architecture, significant differences in the composition of the loops and in both the N- and C-terminal α-helices seem to define ETD-like specificity. Molecular dynamics simulations indicate that these regions defining ET specificity present different degrees of flexibility and may undergo conformational changes upon substrate recognition and binding. DLS and AUC experiments indicated that the ETD-like is monomeric in solution whereas it is present as a dimer in the asymmetric unit indicating that oligomerization is not related to functional differentiation among these toxins. Differential scanning calorimetry and circular dichroism assays demonstrated an endothermic transition centered at 52 °C, and an exothermic aggregation in temperatures up to 64 °C. All these together provide insights about the mode of action of a toxin often secreted in syndromes that are not associated with either ETA or ETB.
•First crystal structure of Staphylococcus aureus exfoliative toxin D.•Specificity and dynamics of exfoliative toxins ETA, ETB and ETD.•Cis/trans conformation dependent hydrolysis of desmoglein-1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Liquid Argon (LAr) Time Projection Chambers (TPC) operating in double-phase can detect the nuclear recoils (NR) possibly caused by the elastic scattering of WIMP dark matter particles via ...light signals from both scintillation and ionization processes. In the scenario of a low-mass WIMP (< 2 GeV/c 2 ), the energy range for the NRs would be below 20 keV, thus making it crucial to characterize the ionization response in LAr TPCs as the lone available detection channel at such low energy. The Recoil Directionality (ReD) project, within the Global Argon Dark Matter Collaboration, aims to measure the ionization yield of a LAr TPC in the recoil energy range of 2–5 keV. The measurement was performed in winter 2023 at the INFN Sezione of Catania and the analysis is ongoing.
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