scholarly journals Susceptibility to Aneuploidy in Young Mothers of Down Syndrome Children

2009 ◽  
Vol 9 ◽  
pp. 1052-1060 ◽  
Author(s):  
Lucia Migliore ◽  
Francesca Migheli ◽  
Fabio Coppedè

We recently observed an increased frequency of binucleated micronucleated lymphocytes in women who had a Down syndrome (DS) child before 35 years of age and the fluorescencein situhybridization analysis revealed that micronuclei were mainly originating from chromosomal malsegregation events, including chromosome 21 malsegregation. That study indicated that women who have a DS child at a young age might have a genetic predisposition to chromosome malsegregation in both somatic and germ line cells. Further studies from our group confirmed increased chromosome damage in blood cells of women who had a DS child at a young age and pointed to a possible role for polymorphisms in folate-metabolizing genes in affecting both chromosome damage and DS risk. In the present article, we review the most recent findings on mechanisms and risk factors for chromosome 21 nondisjunction that lead to DS. Multiple risk factors are likely involved in chromosome nondisjunction; they act at different times in the meiotic process and can be of genetic or environmental (epigenetic) origin. We also discuss the increased risk of developing Alzheimer's disease (AD) later in life that was observed in women who had a DS child at a young age. Studies performed in the last years that have shown that the brain is, in fact, a complex genetic mosaic of aneuploid and euploid cells support the unified hypothesis trying to relate DS, trisomy 21, and AD.

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B Weber ◽  
D.W Biery ◽  
A Singh ◽  
S Divakaran ◽  
A.N Berman ◽  
...  

Abstract Background Autoimmune systemic inflammatory diseases are associated with an increased risk of cardiovascular disease, particularly myocardial infarction (MI). However, there are limited data on the prevalence and effects of inflammatory disease among U.S. adults who experience an MI at a young age. Purpose We sought to determine the prevalence and prognostic value of inflammatory disease in U.S. adults who experience an MI at a young age. Methods The YOUNG-MI registry is a retrospective cohort study of consecutive patients who experienced a Type 1 MI at or below the age of 50 years from 2000 to 2016 at two large medical centers. A diagnosis of rheumatoid arthritis (RA), psoriasis (PsO), systemic lupus erythematosus (SLE), or inflammatory arthritis was determined through physician review of electronic medical records (EMR). Demographic information, presence of cardiovascular (CV) risk-factors, medical procedures, and medications upon discharge were also ascertained from the EMR. Incidence of death was determined using a combination of EMR and national databases. Cox proportional hazard modeling was performed on a sub-sample following Mahalanobis Distance matching on age, sex, and CV risk factors. Results The cohort consisted of 2097 individuals (median age 45 years, 19% female, 53% ST-elevation MI). Among these, 53 (2.5%) individuals possessed a diagnosis of systemic inflammatory disease at or before their index MI (23% SLE, 9% RA, 64% PsO, 4% inflammatory arthritis). When compared to the remainder of the cohort, patients with a diagnosis of systemic inflammatory disease were more likely to be female (36% vs 19%, p=0.004) and be diagnosed with hypertension (62% vs 46%, p=0.025). There was, however, no significant difference in the prevalence of other CV risk factors – diabetes, smoking, dyslipidemia – or a family history of premature coronary artery disease. Despite these similarities, patients with inflammatory disease were less likely to be prescribed aspirin (88% vs 95%, p=0.049) or a statin (76% vs 89%, p=0.008) upon discharge. Over a median follow-up of 11.2 years, patients with inflammatory disease experienced an increased risk of all-cause mortality when compared with the full-cohort (Figure). Compared to the matched sample (n=138), patients with systemic inflammatory disease exhibited an increased risk of all-cause mortality (HR=2.68, CI [1.18 to 6.07], p=0.018), which remained significant after multivariable adjustment for length of stay and GFR (HR=2.38, CI [1.02 to 5.54], p=0.045). Conclusions Among individuals who experienced an MI at a young age, approximately 2.5% had evidence of a systemic inflammatory disease at or before their MI. When compared with a population of individuals with similar cardiovascular risk profiles, those with inflammatory disease had higher rates of all-cause mortality. Our findings suggest that the presence of a systemic inflammatory disorder is independently associated with worse long-term outcomes. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. 5T32 HL094301 NIH T32 Training Grant, “Noninvasive Cardiovascular Imaging Research Training Program”


F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 876 ◽  
Author(s):  
Lewis Buss ◽  
Elizabeth Fisher ◽  
John Hardy ◽  
Dean Nizetic ◽  
Jurgen Groet ◽  
...  

Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onsetAlzheimer’s disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein (APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called ‘dup-APP’, which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight.


2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Pilar Osuna-Marco ◽  
Mónica López-Barahona ◽  
Blanca López-Ibor ◽  
Águeda Mercedes Tejera

People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.


2013 ◽  
Vol 60 (4) ◽  
pp. 153-161 ◽  
Author(s):  
Fumihiro Yoshikawa ◽  
Yoh Tamaki ◽  
Hisa Okumura ◽  
Zenzo Miwa ◽  
Masaaki Ishikawa ◽  
...  

Abstract The purpose of this study was to identify the risk factors associated with low peripheral oxygen saturation (SpO2) and delayed recovery of dental patients with disabilities after intravenous sedation. A total of 1213 patients with disabilities were retrospectively investigated with respect to demographic parameters and sedation conditions. Multivariate logistic analyses were conducted for patients with an SpO2 <90% and a recovery period of >60 minutes to identify the risk factors for poor sedation conditions. A significant odds ratio related to decreased SpO2 was observed for age, sex, midazolam and propofol levels, concurrent use of nitrous oxide, cerebral palsy, Down syndrome, and mental retardation. The most problematic patients were those diagnosed with Down syndrome (odds ratio, 3.003–7.978; 95% confidence interval; P < .001). Decision tree analysis showed an increased risk of decreased SpO2 in males with Down syndrome or after administration of >0.493 mg/kg propofol in combination with midazolam. An increased risk of delayed awakening was seen in patients aged less than 21 years and in males administered >0.032 mg/kg of midazolam. Intravenous sedation for dental patients with disabilities, particularly those with cerebral palsy, Down syndrome, or mental retardation, increases the risk of decreased SpO2. In addition, delayed recovery is expected after midazolam administration.


2018 ◽  
Vol 36 (01) ◽  
pp. 079-085 ◽  
Author(s):  
Deana Hussamy ◽  
Christina Herrera ◽  
Diane Twickler ◽  
Donald Mcintire ◽  
Jodi Dashe

Objective The objective of this study was to evaluate risk factor prevalence in pregnancies with fetal Down syndrome, in an effort to characterize efficacy of population-based screening. Study Design Retrospective review of singleton pregnancies with delivery of live born or stillborn infant with Down syndrome from 2009 through 2015. Risk factor categories included maternal age ≥35 years, abnormal serum screening, identification of ≥1 ultrasound marker at 16 to 22 weeks (nuchal thickness ≥6 mm, echogenic intracardiac focus, echogenic bowel, renal pelvis dilatation, femur length <third percentile), and detection of a major fetal anomaly. Statistical analyses included χ2 test and Mantel–Haenszel χ2 test. Results Down syndrome infants represented 1:428 singleton births. All risk categories were assessed in 125 pregnancies and included abnormal serum screen in 110 (88%), ≥1 ultrasound marker in 66 (53%), and ≥1 anomaly in 41 (34%). The calculated risk was at least 1:270 in 93% of Down syndrome pregnancies. More pregnancies had multiple risk factors than had a single risk factor, 90 (72%) versus 30 (24%), p < 0.001. An abnormal ultrasound marker or anomaly was identified in >50% of fetuses in women <35 years and in >75% of those 35 years and older. Conclusion In a population-based cohort, sensitivity of second-trimester Down syndrome screening was 93%, with multiple risk factors present in nearly three-fourths of cases.


2021 ◽  
Vol 10 (21) ◽  
pp. 5125
Author(s):  
David Emes ◽  
Anke Hüls ◽  
Nicole Baumer ◽  
Mara Dierssen ◽  
Shiela Puri ◽  
...  

Adults with Down Syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19) than the general population, but evidence is required to understand the risks for children with DS, which is necessary to inform COVID-19 shielding advice and vaccination priorities. We aimed to determine the epidemiological and clinical characteristics of COVID-19 in children with DS. Using data from an international survey obtained from a range of countries and control data from the United States, we compared the prevalence of symptoms and medical complications and risk factors for severe outcomes between DS and non-DS paediatric populations with COVID-19. Hospitalised COVID-19 patients <18 years with DS had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than control patients without DS <18 years. Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS, and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), contrasting with previous findings in adults with DS (who exhibit higher mortality than those without DS). Children with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure the comprehensive and early detection of COVID-19 in this population and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Our results emphasize the importance of vaccinating children with DS as soon as they become eligible.


Author(s):  
Linda Juel Ahrenfeldt ◽  
Camilla Riis Nielsen ◽  
Sören Möller ◽  
Kaare Christensen ◽  
Rune Lindahl-Jacobsen

Abstract Aim: International health authorities suggest that individuals aged 65 years and above and people with underlying comorbidities such as hypertension, chronic lung disease, cardiovascular disease, cancer, diabetes, and obesity are at increased risk of severe Coronavirus Disease 2019 (COVID-19); however, the prevalence of risk factors is unknown in many countries. Therefore, we aim to describe the distribution of these risk factors across Europe. Subject and Methods: Prevalence of risk factors for severe COVID-19 was identified based on interview for 73,274 Europeans aged 50+ participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) in 2017. Burden of disease was estimated using population data from Eurostat. Results: A total of 75.3% of the study population (corresponding to app. 60 million European men and 71 million women) had at least one risk factor for severe COVID-19, 45.9% (app. 36 million men and 43 million women) had at least two factors and 21.2% (app. 17 million men and 20 million women) had at least three risk factors. The prevalences of underlying medical conditions ranged from 4.5% for cancer to 41.4% for hypertension, and the region-specific prevalence of having at least three risk factors ranged from 18.9% in Northern Europe to 24.6% in Eastern Europe. Conclusions: Information about the prevalences of risk factors might help authorities to identify the most vulnerable subpopulations with multiple risk factors of severe COVID-19 disease and thus to decide appropriate strategies to mitigate the pandemic.


2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Biray Erturk ◽  
Emin Karaca ◽  
Ayca Aykut ◽  
Burak Durmaz ◽  
Ahmet Guler ◽  
...  

Background. Currently, the data available on the utility of miRNAs in noninvasive prenatal testing is insufficient in the literature. We evaluated the expression levels of 14 miRNAs located on chromosome 21 in maternal plasma and their utility in noninvasive prenatal testing of Down Syndrome.Method. A total of 56 patients underwent invasive prenatal testing; 23 cases were carrying Down Syndrome affected fetuses, and 33 control cases carrying unaffected, normal karyotype fetuses were included for comparison. Indications for invasive prenatal testing were advanced maternal age, increased risk of Down Syndrome in screening tests, and abnormal finding in the sonographic examination. In both the study and control groups, all the pregnant women were at 17th and 18th week of gestation. miRNA expression levels were measured using real-time RT-PCR.Results. Significantly increased maternal plasma levels of miR-3156 and miR-99a were found in the women carrying a fetus with Down Syndrome.Conclusion. Our results provide a basis for multicenter studies with larger sample groups and microRNA profiles, particularly with the microRNAs which were found to be variably expressed in our study. Through this clinical research, the utility of microRNAs in noninvasive prenatal testing can be better explored in future studies.


Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 767-775 ◽  
Author(s):  
Gina Kirsammer ◽  
Sarah Jilani ◽  
Hui Liu ◽  
Elizabeth Davis ◽  
Sandeep Gurbuxani ◽  
...  

Children with Down syndrome (DS) display macrocytosis, thrombocytosis, and a 500-fold increased risk of developing megakaryocytic leukemia; however, the specific effects of trisomy 21 on hematopoiesis remain poorly defined. To study this question, we analyzed blood cell development in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for 104 orthologs of Hsa21 genes and are the most widely used mouse model for DS. We discovered that Ts65Dn mice display persistent macrocytosis and develop a myeloproliferative disease (MPD) characterized by profound thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocyte morphology, and myelofibrosis. In addition, these animals bear distorted hematopoietic stem and myeloid progenitor cell compartments compared with euploid control littermates. Of the 104 trisomic genes in Ts65Dn mice, Aml1/Runx1 attracts considerable attention as a candidate oncogene in DS–acute megakaryoblastic leukemia (DS-AMKL). To determine whether trisomy for Aml1/Runx1 is essential for MPD, we restored disomy at the Aml1/Runx1 locus in the Ts65Dn strain. Surprisingly, trisomy for Aml1/Runx1 is not required for megakaryocyte hyperplasia and myelofibrosis, suggesting that trisomy for one or more of the remaining genes can promote this disease. Our studies demonstrate the potential of DS mouse models to improve our understanding of chromosome 21 gene dosage effects in human hematologic malignancies.


Science ◽  
2021 ◽  
Vol 373 (6551) ◽  
pp. eabf6202 ◽  
Author(s):  
Elvin Wagenblast ◽  
Joana Araújo ◽  
Olga I. Gan ◽  
Sarah K. Cutting ◽  
Alex Murison ◽  
...  

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.


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