scholarly journals Intracerebral haemorrhage in Down syndrome: protected or predisposed?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 876 ◽  
Author(s):  
Lewis Buss ◽  
Elizabeth Fisher ◽  
John Hardy ◽  
Dean Nizetic ◽  
Jurgen Groet ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intracerebral Haemorrhage ◽  
Early Onset ◽  
Epidemiological Data ◽  
Haemorrhagic Stroke ◽  
Brain Parenchyma ◽  
Chromosome 21 ◽  
Clinical Consequence ◽  
Increased Risk ◽  
The Central Nervous System

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.

scholarly journals Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Pilar Osuna-Marco ◽  
Mónica López-Barahona ◽  
Blanca López-Ibor ◽  
Águeda Mercedes Tejera
Keyword(s):  
Down Syndrome ◽  
Solid Tumors ◽  
Tumor Suppressor Genes ◽  
Wilms Tumor ◽  
Extra Chromosome ◽  
Germ Cell Tumors ◽  
Chromosome 21 ◽  
Testicular Tumors ◽  
Unique Pattern ◽  
Increased Risk

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.

scholarly journals Prenatal Evaluation of MicroRNA Expressions in Pregnancies with Down Syndrome

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Biray Erturk ◽  
Emin Karaca ◽  
Ayca Aykut ◽  
Burak Durmaz ◽  
Ahmet Guler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prenatal Testing ◽  
Maternal Plasma ◽  
Chromosome 21 ◽  
Screening Tests ◽  
Sonographic Examination ◽  
Noninvasive Prenatal Testing ◽  
Abnormal Finding ◽  
Expression Levels ◽  
Increased Risk

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.

scholarly journals Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 767-775 ◽  
Author(s):  
Gina Kirsammer ◽  
Sarah Jilani ◽  
Hui Liu ◽  
Elizabeth Davis ◽  
Sandeep Gurbuxani ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Gene Dosage ◽  
Hematologic Malignancies ◽  
Chromosome 21 ◽  
Myeloproliferative Disease ◽  
Ts65dn Mouse ◽  
Hematopoietic Stem ◽  
Megakaryoblastic Leukemia ◽  
Increased Risk

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.

scholarly journals Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Justin L. Tosh ◽  
◽  
Elena R. Rhymes ◽  
Paige Mumford ◽  
Heather T. Whittaker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Mouse Models ◽  
Early Onset ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Early Onset Alzheimer’S Disease

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

scholarly journals Mapping the cellular origin and early evolution of leukemia in Down syndrome

Science ◽  
2021 ◽  
Vol 373 (6551) ◽  
pp. eabf6202 ◽  
Author(s):  
Elvin Wagenblast ◽  
Joana Araújo ◽  
Olga I. Gan ◽  
Sarah K. Cutting ◽  
Alex Murison ◽  
...  
Keyword(s):  
Stem Cells ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Chromosome 21 ◽  
Hematopoietic Stem ◽  
Developmental Context ◽  
Cellular Origin ◽  
Increased Risk ◽  
Stem And Progenitor Cells

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.

scholarly journals Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

2021 ◽  
Author(s):  
Claudia Cannavo ◽  
Karen Cleverley ◽  
Cheryl Maduro ◽  
Paige Mumford ◽  
Dale Moulding ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Cell Biology ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
App Processing ◽  
Cellular Models ◽  
Increased Risk ◽  
Primary Mouse

Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer’s disease – dementia. Alzheimer’s disease is characterised by the accumulation in the brain of amyloid-β plaques that are a product of amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-β accumulation is within endosomes and changes to endosome biology occur early in disease. Here we determine if primary mouse embryonic fibroblasts isolated from two mouse models of Down syndrome can be used to study endosome and APP cell biology. We report that in these cellular models of Down syndrome endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in these models, despite three copies of App .

scholarly journals Mapping the Cellular Origin and Early Evolution of Leukemia in Down Syndrome

2020 ◽  
Author(s):  
Elvin Wagenblast ◽  
Joana Araújo ◽  
Olga I. Gan ◽  
Sarah K. Cutting ◽  
Alex Murison ◽  
...  
Keyword(s):  
Stem Cells ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Fetal Liver ◽  
Chromosome 21 ◽  
Hematopoietic Stem ◽  
Cellular Origin ◽  
Increased Risk ◽  
Stem And Progenitor Cells ◽  
Cellular Context

AbstractChildren with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. As Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 miRNAs triggers 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 cells mediated the propagation of preleukemia and leukemia, and functional KIT inhibition targeted preleukemic stem cells, blocking progression to leukemia.

The Search for Biomarkers of Alzheimer's Disease in Down Syndrome

2020 ◽  
Vol 125 (2) ◽  
pp. 97-99 ◽  
Author(s):  
Benjamin L. Handen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Longitudinal Study ◽  
High Risk ◽  
Amyloid Precursor Protein ◽  
Current Knowledge ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Increased Risk

Abstract Adults with Down syndrome are at high risk for Alzheimer's disease (AD), with most individuals developing clinical dementia by their late 60s. This increased risk for AD has been attributed, at least in part, to triplication and overexpression of the gene for amyloid precursor protein (APP) on chromosome 21, leading to elevated levels of amyloid β peptides. This article offers a brief overview of our current knowledge of AD in the DS population. In addition, information on a NIA/NICHD-funded, multicenter longitudinal study of biomarkers of AD in adults with DS is provided.

scholarly journals Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view

2021 ◽  
Vol 23 ◽  
Author(s):  
K. A. L. Hasaart ◽  
E. J. M. Bertrums ◽  
F. Manders ◽  
B. F. Goemans ◽  
R. van Boxtel
Keyword(s):  
Down Syndrome ◽  
Fetal Liver ◽  
Chromosome 21 ◽  
Children With Down Syndrome ◽  
Selection Dynamics ◽  
Oncogenic Mutations ◽  
Increased Risk ◽  
Evolutionary View ◽  
Selective Forces ◽  
Rate Limiting

Abstract Children show a higher incidence of leukaemia compared with young adolescents, yet their cells are less damaged because of their young age. Children with Down syndrome (DS) have an even higher risk of developing leukaemia during the first years of life. The presence of a constitutive trisomy of chromosome 21 (T21) in DS acts as a genetic driver for leukaemia development, however, additional oncogenic mutations are required. Therefore, T21 provides the opportunity to better understand leukaemogenesis in children. Here, we describe the increased risk of leukaemia in DS during childhood from a somatic evolutionary view. According to this idea, cancer is caused by a variation in inheritable phenotypes within cell populations that are subjected to selective forces within the tissue context. We propose a model in which the increased risk of leukaemia in DS children derives from higher rates of mutation accumulation, already present during fetal development, which is further enhanced by changes in selection dynamics within the fetal liver niche. This model could possibly be used to understand the rate-limiting steps of leukaemogenesis early in life.

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
Keyword(s):  
Risk Factors ◽  
Down Syndrome ◽  
Germ Line ◽  
Young Age ◽  
Chromosome 21 ◽  
Chromosome Damage ◽  
Multiple Risk Factors ◽  
Genetic Mosaic ◽  
Increased Risk ◽  
Age Studies

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.

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