Molecular Cytogenetic Classification of Down Syndrome and Screening of Somatic Aneuploidy in Mothers.

Down Syndrome (DS) caused by trisomy 21 results in various congenital and developmental complications in children. It is crucial to cytogenetically diagnose the DS cases early for their proper health management and to reduce the risk of further DS childbirths in mothers. In this study, we performed a cytogenetic analysis of 436 suspected DS cases using karyotyping and fluorescent in situ hybridization. We detected free trisomies (95.3%), robertsonian translocations (2.4%), isochromosomes (0.6%), and mosaics (1.2%). We observed a slightly higher incidence of DS childbirth in younger mothers compared to mothers with advanced age. We compared the somatic aneuploidy in peripheral blood of mothers having DS children (MDS) and control mothers (CM) to identify biomarkers for predicting the risk for DS childbirths. No significant difference was observed. After induced demethylation in peripheral blood cells, we did not observe a significant difference in the frequency of aneuploidy between MDS and CM. In conclusion, free trisomy 21 is the most common type of chromosomal abnormality in DS. A small number of DS cases have translocations and mosaicism of chromosome 21. Additionally, somatic aneuploidy in the peripheral blood from the mother is not an effective marker to predict DS childbirths.

Integrating Biomarker Outcomes into Clinical Trials for Alzheimer's Disease in Down Syndrome.

The NIH-funded Alzheimer's Biomarker Consortium Down Syndrome (ABC-DS) and the European Horizon 21 Consortium are collecting critical new information on the natural history of Alzheimer's Disease (AD) biomarkers in adults with Down syndrome (DS), a population genetically predisposed to developing AD. These studies are also providing key insights into which biomarkers best represent clinically meaningful outcomes that are most feasible in clinical trials. This paper considers how these data can be integrated in clinical trials for individuals with DS. The Alzheimer's Clinical Trial Consortium - Down syndrome (ACTC-DS) is a platform that brings expert researchers from both networks together to conduct clinical trials for AD in DS across international sites while building on their expertise and experience.

Evaluating the Risks and Benefits of Genetic and Pharmacologic Interventions for Down Syndrome: Views of Parents.

Researchers are investigating new technologies to mitigate or prevent symptoms of Down syndrome (DS), including chromosome silencing and pharmacotherapy. We surveyed parents of individuals with DS to assess their opinions on two hypothetical scenarios describing prenatal chromosome silencing and pediatric pharmacological intervention to improve neurocognition in children with DS. Although a slim majority of participants supported the availability of both therapies, respondent support was contingent on the risks presented, including the risk of miscarriage in the prenatal intervention and the impact of pharmaceuticals on their children's personality. Many parents expressed ambivalence, articulating a desire to improve their children's quality of life but requiring more safety and efficacy research before agreeing to a genetic or pharmacological intervention.

Effects of a Tripeptide on Mitogen-Activated Protein Kinase and Glycogen Synthase Kinase Activation in a Cell Line Derived from the Foetal Hippocampus of a Trisomy 16 Mouse: an Animal Model of Down Syndrome.

Down syndrome (DS) is a developmental disorder that results from the trisomy of chromosome 21. DS patients show several abnormalities including cognitive deficits. Here, we show enhanced activation of the extracellular signal-regulated kinase (ERK), a kinase that critically regulates synaptic plasticity and memory, in a hippocampal cell line derived from trisomy 16 mouse foetus. In addition, these cells show enhanced activation of p38 mitogen-activated protein kinase (p38 MAPK). The hyper-activation of ERK and p38 MAPK is significantly reduced by a small peptide, Gly-Pro-Glu (GPE), derived from insulin-like growth factor-1. In addition, the trisomic cells show reduced level of inhibitory phosphorylation of glycogen synthase kinase-3ß (GSK-3ß), which is enhanced by GPE. Furthermore, the trisomic cells do not show ERK activation in response to KCl depolarization or forskolin treatment. Importantly, ERK activation by these stimuli is observed after GPE treatment of the cells. These results suggest that GPE may help reduce aberrant signalling in the trisomic neurons by affecting MAPK and GSK-3ß activation.

[Ethics in the communication of down syndrome diagnosis]. / La ética en la comunicación del diagnóstico de síndrome de Down.

Down Syndrome diagnosis communication has got serious ethical implications, since the aim thereof can be either eugenic or therapeutic. The purpose of this paper is, on the one hand, to highlight the fundamental role which sanitary proffesionals play in diagnosis communication and the subsequent decission of the mother. On the other, recommendations on the way to communicate a diagnosis are set out. Finally, in order to analize the state of play in Spain the results of a cross-sectional descriptive study with a sample of 352 mothers are exposed. In this study the mothers express, by means of a survey, their personal experiencies of how they have received the news. It is concluded that the communication of Down syndrome diagnosis can be improved in many aspects.

[Longer oral contraception history as a possible preventive factor against fetal trisomy 21 in advanced maternal age pregnancies]. / A terhességet megelozoen alkalmazott hosszabb távú orális fogamzásgátlás mint a magzati 21-es triszómia lehetséges kockázatcsökkento tényezoje idos anyai életkorban vállalt terhességben.

Down syndrome is the most common autosomal chromosomal abnormality. According to the classical interpretation, it is the result of meiotic nondisjunction. Its occurrence is more common in advanced maternal age. Despite intensive research, pathophysiology of this genetic disorder is not fully understood. According to recent studies, a different kind of mechanism may be found in the background of trisomy 21 than was previously considered. Based on the ovarian mosaicism model, the cause of trisomy 21 (or any common trisomy) is a segregation error of a chromosome in premeiotic mitosis. The cell entering meiosis will be an oocyte with preexisting trisomy, where its (so-called "secondary") nondisjunction is essential. Maturation of the trisomic oocytes appears to fall behind the disomic oocytes, resulting in their relative accumulation in the ovaries as time progresses. The ratio of trisomic/disomic cells becomes less favorable in maternal maturity. If ovulation is inhibited - although the number of oocytes will continue to decline due to apoptosis - it can be assumed that the trisomic/disomic oocyte ratio remains more favorable with the progression of age. In our summary report, presenting and updating our previous data, we would like to propose that - according to ovarian mosaicism model - long-term oral contraception in the anamnesis may be beneficial in pregnancies with advanced maternal age. Orv Hetil. 2018; 159(28): 1146-1152.

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation.

Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aß) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

Prevalence trends of selected major birth defects: A multi-state population-based retrospective study, United States, 1999 to 2007.

BACKGROUND: We evaluated selected birth defects over a 9-year period to assess prevalence trends by selected maternal and infant factors. METHODS: Data were pooled from 11 population-based birth defects surveillance programs in the United States for children born between 1999 and 2007. Overall prevalence, as well as 3-year interval prevalence, was calculated for 26 specific birth defects, stratified by maternal age, maternal race/ethnicity, and infant sex. Average annual percent change (AAPC) was calculated for each birth defect. Poisson regression was used to determine change in AAPC, and joinpoint regression to identify breakpoints and changes in slope for prevalence of each defect over time. RESULTS: Between 1999 and 2001 and 2005 and 2007, four birth defects increased by 10% or more: coarctation of the aorta (17%), gastroschisis (83%), omphalocele (11%), and Down syndrome (10%). Among mothers <20 years of age, the gastroschisis AAPC increased 10.1% overall and, cross-classified by maternal race/ethnicity, the AAPC for mothers <20 years increased 9.2%, 25.7%, and 7.7% among non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic mothers, respectively. A small increase in Down syndrome (AAPC 4.4%) was found for NHB mothers ≥35 years. CONCLUSION: No significant trends in prevalence were identified for most birth defects. Gastroschisis prevalence increased significantly among NHW and NHB mothers <20 years of age, with the greatest increases in NHB mothers. Prevalence of Down syndrome among NHB mothers ≥35 years also increased slightly. Stratified results may suggest avenues of research in birth defect etiology and in evaluating prevention efforts. Birth Defects Research 109:1442-1450, 2017.© 2017 Wiley Periodicals, Inc.

Teoría de la decisión y cribado del Síndrome de Down: cálculo individualizado del dintel de normalidad / Decision making and Down Syndrome screening: individualized cutoff

Objetivos: demostrar mediante la teoría de la decisión que el cribado bioquímico-ecográfico del síndrome de Down no debe aplicarse de forma universal sino teniendo en cuenta los umbrales de decisión. Desarrollar el cálculo matemático individualizado para cada gestante de los umbrales de decisión siguiendo el modelo de Pauker-Kassirer. Implementar un método simple para la obtención individualizada de las utilidades que intervienen. Material y métodos: definimos un diagrama de influencia con: variables aleatorias: tener Síndrome de Down, resultado del cribado, pérdida gestacional tras amniocentesis. Decisiones: aplicar el cribado, realizar amniocentesis. Utilidades relativas a los diferentes resultados posibles calculadas en un grupo de 10 gestantes consecutivas mediante diagramas de equivalencia temporal para el cálculo del tiempo de vida ajustado en calidad. Realizamos un análisis de sensibilidad comparando la utilidad de cada estrategia en función de la probabilidad a priori. Los cálculos fueron realizados con OpenMarkov (http://www.openmarkov.org). Resultados: con las utilidades obtenidas (tener un hijo sano 1; tener un hijo con síndrome de Down 0,57; interrumpir el embarazo por diagnóstico de síndrome de Down 0,90; pérdida gestacional secundaria a amniocentesis 0,80) en gestantes con una probabilidad a priori mayor de 0,014 (Odds de 1/70, corresponde al riesgo de una gestante de 41 años) se obtiene la máxima utilidad realizando directamente una amniocentesis. Al resto deberemos aplicar el cribado porque el umbral diagnóstico (0,0002) es menor que el riesgo en las gestantes más jóvenes. Discusión: la gran variabilidad interindividual de las utilidades aconseja que el cálculo de los umbrales de decisión se individualicen para cada gestante; para ello proponemos un método matemático basado en Pauker-Kassirer (AU)

Objectives: To evaluate by decision making if biochemical and ultrasonographic universal screening of Down syndrome is accurate, or they must be used in a selective way related to decision thresholds. To develope a probabilistic model to calcule the decision thresholds following Pauker-Kassirer model. To design a method of utility assessment to quantify women´s individual preferences. Material and methods: An influence diagram with uncertainty nodes (affected or unaffected birth, positive or negative screening, amniocentesis related miscarriage or no complicated technique), decision nodes (to perform screening, to perform amniocentesis) and utilities was developed. Utilities were the average of 10 consecutive pregnant women preference measures using the time trade-off model to obtain quality-adjusted life years. A sensitivity analysis comparing utility for every strategy related to prior probability was done. To perform mathematical results the free software programme OpenMarkov (http://www.openmarkov.org) was used. Results: Utilities were: unaffected birth 1, Down syndrome-affected birth 0.57, elective abortion after Down syndrome diagnosis 0.9 and amniocentesis procedure related miscarriage 0.8. Over 41 year-old risk (Odds 1/70) invasive diagnostic testing has the maximum expected utility. The testing threshold is lower than the lowest-risk women. Therefore, screening is the best option under that prior probability. Discussion: We agree with prior published data: current cutoff is not appropriate because it assumes that women value equally burdensome procedure-related miscarriage of a normal fetus and Down syndrome-affected birth. There was a substantial subject-to-subject variation; individual preferences should be used to stablish a personalised cutoff following Pauker-Kassirer model (AU)

Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring.

The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12-17months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.

Alzheimer's disease in people with Down's syndrome: the prospects for and the challenges of developing preventative treatments.

People with Down's syndrome (DS) are at high risk for developing Alzheimer's disease (AD) at a relatively young age. This increased risk is not observed in people with intellectual disabilities for reasons other than DS and for this reason it is unlikely to be due to non-specific effects of having a neurodevelopmental disorder but, instead, a direct consequence of the genetics of DS (trisomy 21). Given the location of the amyloid precursor protein (APP) gene on chromosome 21, the amyloid cascade hypothesis is the dominant theory accounting for this risk, with other genetic and environmental factors modifying the age of onset and the course of the disease. Several potential therapies targeting the amyloid pathway and aiming to modify the course of AD are currently being investigated, which may also be useful for treating AD in DS. However, given that the neuropathology associated with AD starts many years before dementia manifests, any preventative treatment must start well before the onset of symptoms. To enable trials of such interventions, plasma, CSF, brain, and retinal biomarkers are being studied as proxy early diagnostic and outcome measures for AD. In this systematic review, we consider the prospects for the development of potential preventative treatments of AD in the DS population and their evaluation.

Analysis of the origin of birth defects in pregnant women from the Kujawy-Pomerania Region.

OBJECTIVES: The aim of the study was to analyze the origin of birth defects in pregnant women from the Kujawy-Pomerania Region, and to identify factors affecting the formation of developmental disorders in the Province. MATERIAL AND METHODS: The correlation between maternal age and fetal defects was investigated. We also attempted to determine whether environmental or family factors play a role in the formation of fetal abnormalities. RESULTS: The analysis confirmed a correlation between the incidence of chromosomal aberrations and maternal age. CONCLUSIONS: Higher rates of neural tube defects were observed in fetuses born to mothers who did not take folic acid. The influence of other factors on developmental anomalies was not confirmed.

Risk factors for Down syndrome.

Down syndrome (DS) originates, in most of the cases (95 %), from a full trisomy of chromosome 21. The remaining cases are due to either mosaicism for chromosome 21 or the inheritance of a structural rearrangement leading to partial trisomy of the majority of its content. Full trisomy 21 and mosaicism are not inherited, but originate from errors in cell divisions during the development of the egg, sperm or embryo. In addition, full trisomy for chromosome 21 should be further divided into cases of maternal origin, the majority, and cases of paternal origin, less than 10 %. Among cases of maternal origin, a further stratification should be performed into errors that have occurred or originated during the first meiotic division in the maternal grandmother's body and errors that occurred later in life during the second maternal meiotic division. This complex scenario suggests that our understanding of the risk factors for trisomy 21 should take into account the above stratification as it reflects different individuals and generations in which the first error has occurred. Unfortunately, most of the available literature is focused on maternal risk factors, and the only certain risk factors for the birth of a child with DS are advanced maternal age at conception and recombination errors, even though the molecular mechanisms leading to chromosome 21 nondisjunction are still a matter of debate. This article critically reviews the hypotheses and the risk factors which have been suggested to contribute to the birth of a child with DS, including folate metabolism, dietary, lifestyle, environmental, occupational, genetic and epigenetic factors, with focus on maternal and paternal risk factors, and taking into account the possible contribution of the maternal grandmother and that of the developing trisomic embryo, in a complex scenario depicting the birth of a child with DS as the result of complex gene-environment interactions and selection processes involving different generations.

Demografía e inclusión social de las personas con síndrome de Down / No disponible

En este artículo realiza un retrato de la población con síndrome de Down en España. En primer término se ofrece una aproximación cuantitativa de la población a partir de fuentes estadísticas y otras bases de datos, a partir de las cuales se realiza una proyección demográfica hacia el año 2050. En una segunda parte se presentan los resultados de exclusión social de la población con síndrome de Down, a partir de diferentes indicadores de acceso al mercado laboral, nivel de estudios, recursos de apoyo, prestaciones y participación social. Por último, tomando como marco el modelo social de la discapacidad, se realiza una reflexión crítica en relación con su impacto presente y futuro sobre la población con síndrome de Down y otras discapacidades intelectuales

This article performs a portrait about people with Down’s syndrome in Spain. First, it provides a quantitative approach of the population from statistical sources and other databases, from which a demographic projection is done for the year 2050. In a second part it presents the results of social inclusion of the population with Down’s syndrome, from different indicators of access to the labor market, education level, social participation, performance, and support resources. Finally, taking as a framework the social model of disability, a critical reflection is done, about its present and future impact on people with Down syndrome and other intellectual disabilities

International Conference Barcelona Down. Jornadas Internacionales Barcelona Down. Discapacidad y deterioro cognitivo en la persona con síndrome de Down. Del nacimiento a la vejez / .Intellectual disability and cognitive impairment in Down syndrome. From birth to old age

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Anomalías cromosómicas: la experiencia del Registro de Anomalías Congénitas de la Comunitat Valenciana / Chromosomal anomalies: The experience of the Congenital Anomalies Registry of the Valencia Region

OBJETIVO: Describir la tendencia y la distribución de las anomalías congénitas (AC) cromosómicas en la Comunitat Valenciana, en menores de un año, durante el periodo 2007-2011. METODOLOGÍA: Se seleccionó a los nacidos vivos y muertos e interrupciones voluntarias del embarazo por AC entre 2007 y 2011 del Registro Poblacional de AC de la Comunitat Valenciana con AC cromosómica (códigos Q90-Q99.9 de la 10.ª Clasificación Internacional de Enfermedades-British Pediatric Asociation). Se calcularon la prevalencia por 10.000 nacidos y sus intervalos de confianza (IC) al 95% para el conjunto de AC cromosómica y algunos síndromes cromosómicos. El análisis se realizó mediante el cálculo de prevalencia y se compararon los datos utilizando la prueba de la chi al cuadrado de Pearson. RESULTADOS: Se identificaron 895 casos de AC cromosómicas, lo que supuso una prevalencia de 33,5 por 10.000 nacimientos (IC del 95%, 31,0-35,9), siendo los síndromes más frecuentes: Down, Edwards, Patau, Turner y Klinefelter. Las prevalencias de las AC cromosómicas y síndrome de Down fueron estables en el periodo, excepto en 2010. El Down fue la AC cromosómica más frecuente (67%) y las interrupciones voluntarias del embarazo por AC, el tipo de finalización del embarazo mayoritario (69%). Entre las AC asociadas, las cardiopatías congénitas representaban un 70,3%. La mayoría de las madres de niños con AC cromosómicas eran españolas (73,3%) y en el grupo de edad de madres mayores de 39 años se identificó la prevalencia más elevada (133,0 por 10.000 nacimientos). La provincia de Castellón presentó la prevalencia más elevada, 39,1 por 10.000 nacimientos. CONCLUSIONES: La prevalencia se ha mantenido estable durante el quinquenio, exceptuando el descenso significativo del año 2010, detectado para AC cromosómicas y 2 de los principales síndromes. Las AC cromosómicas son un importante problema de salud pública, ya que representan el 15% de todas las AC identificadas en la Comunitat Valenciana, coincidiendo con los valores de Europa

OBJECTIVE: To describe the temporal trend and distribution of chromosomal congenital abnormalities (CA) in the Valencia Region, in less than one year olds, during the period 2007-2011. METHODOLOGY: Live births, still births and termination of pregnancy due to foetal anomaly between 2007 and 2011 with chromosomal CA (Q90-Q99.9 codes of the 10th International Classification of Diseases -British Paediatric Association) were selected from the CA population-based Registry of Valencia Region The prevalence per 10,000 births for the chromosomal CA and for the different types of chromosomal syndromes with 95% confidence intervals was calculated. The analysis was performed by calculating prevalences and data were compared using Pearson Chi-squared test. RESULTS: A total of 895 cases were found, representing a prevalence of 33.5 per 10,000 births (95% CI: 31.0-35.9), highlighting five syndromes: Down's, Edward's, Patau, Turner and Klinefelter. The prevalence of chromosomal CA and Down's syndrome were stable over the period, except in 2010. Down's was the most frequent chromosomal CA (67% of the cases), and the most frequent termination of pregnancy type was for foetal anomaly (69%). Cardiac heart defects represented 70.3% of the associated congenital anomalies. Mothers of children with chromosomal CA were mainly Spanish (73.3%). The age group of mothers over 39 years had a higher prevalence (133.0 per 10,000 births). The province of Castellón had the highest prevalence, 39.1 per 10,000 births. CONCLUSIONS: The prevalence has remained stable over the five years, excluding the significant decline in 2010, for chromosomal CA detected and two of the major syndromes. The chromosomal CA are an important public health problem as they represent 15% of all CA identified in the Valencia Region, and agrees with the European data

El síndrome de Down en perspectiva 2016 / No disponible

Los progresos realizados en la atención, cuidados e investigación sobre el síndrome de Down han permitido avanzar considerablemente en la realidad vital de las personas. La visión optimista y esperanzadora que razonablemente nos captura, no debe ocultar los problemas que aún se plantean: la persistente visión negativa y excluyente que la sociedad continúa manteniendo; las diferencias en salud, habilidades, conducta, atención entre un individuo y otro; la problemática que plantea la irrupción de fármacos que pretenden mejorar las funciones cognitivas

Significant advances have been made in the research, care and attention to individuals with Down syndrome. The optimistic outlook should not overlook some persistent difficulties: the negative and rejecting vision of society; the inter-individual variability in medical, cognitive and behavioral concerns; and the challenges imposed by the use of incoming drugs positively tested in preclinical research