Trisomy 21, transposition of the great arteries and abnormal myelopoiesis

Cardiology in the Young ◽

10.1017/s1047951121002444 ◽

2021 ◽

pp. 1-2

Author(s):

Chandan Mishra ◽

Lamk Kadiyani ◽

Sivasubramanian Ramakrishnan ◽

Tushar Sehgal

Keyword(s):

Pulmonary Hypertension ◽

Down Syndrome ◽

Trisomy 21 ◽

Genetic Condition ◽

Transient Abnormal Myelopoiesis ◽

Poor Outcomes

Abstract Down syndrome is a well-recognised genetic condition associated with several comorbidities. Although CHD is common in Down syndrome, transposition of the great arteries is exceptionally rare. We describe a neonate with Down syndrome who presented with transient abnormal myelopoiesis and transposition of the great arteries. Down syndrome may accelerate pulmonary hypertension in transposition of the great arteries and is associated with poor outcomes.

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Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽

10.38192/1.6.1.c9 ◽

2019 ◽

Vol 6 (1) ◽

pp. c9

Author(s):

Triya Chakravorty ◽

Irene Roberts

Keyword(s):

Down Syndrome ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Trisomy 21 ◽

Children With Down Syndrome ◽

Transient Abnormal Myelopoiesis ◽

Increased Risk ◽

Leukaemic Cells ◽

Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

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Physiotherapy in Down Syndrome: A Literature Review

International Neuropsychiatric Disease Journal ◽

10.9734/indj/2021/v15i430160 ◽

2021 ◽

pp. 20-27

Author(s):

Yasmin Souza Silva ◽

Luciana Lane Gomes Da Silva ◽

Wellington Carlos Da Silva ◽

Agrinazio Geraldo Nascimento Neto ◽

Thalita De Sousa Pereira ◽

...

Keyword(s):

Systematic Review ◽

Down Syndrome ◽

Trisomy 21 ◽

Chromosomal Abnormalities ◽

Signs And Symptoms ◽

Scientific Basis ◽

Genetic Condition ◽

Main Research ◽

Children With Down Syndrome

Introduction: Down syndrome is a genetic condition arising from three chromosomal abnormalities, namely trisomy 21 (the most well-known); translocation, and/or mosaicism. This chromosome change occurs in the formation of the fetus, in more detail at the time of cell division, which will characterize the signs and symptoms of the syndrome. Objective: The purpose of this article is to research the main scientific findings in the last 10 years regarding physical therapy treatments, to verify the best techniques and their respective results, and to address the role of physiotherapy in the development of children with Down syndrome. Methods: The research only included studies published in the period from 2009 to 2019, systematic review articles and limited the Portuguese and English languages were excluded, excluding all incomplete articles, duplications, abstracts that did not address, and those works that do not have a scientific basis. Results: In this systematic review, it can be seen that the main research results were disseminated and stored in databases (SciELO, Medline, and LILACS), focusing on the study of and DS patients, specifical children in early childhood. There are few studies on down syndrome in adults. Another important aspect is the concentration of research in the field of sports physiotherapy, few studies have focused on other areas of physiotherapy, such as respiratory, cardiovascular, and cognitive physiotherapy, which go in the opposite direction. Conclusion: Physiotherapy for patients with DS can improve the quality and life expectancy of these individuals, but the needs of patients with this syndrome involve some physical, physiological and psychological aspects and require the attention of a multidisciplinary team.

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Transient Abnormal Myelopoiesis in a Neonate without Down Syndrome

Journal of Nepal Paediatric Society ◽

10.3126/jnps.v37i3.19186 ◽

2018 ◽

Vol 37 (3) ◽

pp. 296-299

Author(s):

Rupesh Shrestha

Keyword(s):

Down Syndrome ◽

Case Report ◽

Trisomy 21 ◽

Case Reports ◽

Spontaneous Remission ◽

Myeloproliferative Disorder ◽

Transient Abnormal Myelopoiesis ◽

Clonal Proliferation ◽

Leukemic Clone ◽

Normal Neonate

Transient abnormal myelopoiesis (TAM) also known as transient myeloproliferative disorder (TMD), a unique transient neonatal preleukaemic disorder characterized by clonal proliferation of megakaryoblasts, has been usually described to be associated with Down syndrome neonates. However, there are case reports of it occurring in neonates without Down phenotype, who are either mosaic for trisomy 21 or have trisomy 21 restricted to leukemic clone. This case report presents a case of TAM in a phenotypically normal neonate who presented in respiratory distress with features of tumour lysis syndrome (TLS) immediately after birth who was treated symptomatically and had spontaneous remission within three months.

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Introduction of STAG2 Mutation in an iPSC Model of Transient Abnormal Myelopoiesis Mimics Down Syndrome Myeloid Leukemia

Blood ◽

10.1182/blood-2021-151875 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1138-1138

Author(s):

Ishnoor Sidhu ◽

Sonali P. Barwe ◽

E. Anders Kolb ◽

Anilkumar Gopalakrishnapillai

Keyword(s):

Down Syndrome ◽

Trisomy 21 ◽

Myeloid Leukemia ◽

Research Funding ◽

Double Mutant ◽

Stem Cell Marker ◽

Hematopoietic Differentiation ◽

Wild Type ◽

Transient Abnormal Myelopoiesis ◽

Gata1 Mutation

Abstract Background Children with Down syndrome (DS) have a high risk for acute myeloid leukemia (DS-ML). Genomic characterization of DS-ML blasts showed the presence of unique mutations in GATA1, an essential hematopoietic transcription factor, leading to the production of a truncated from of GATA1 (GATA1s). GATA1s together with trisomy 21 is sufficient to develop a pre-leukemic condition called transient abnormal myelopoiesis (TAM). Approximately thirty percent of these cases progress into DS-ML by acquisition of additional somatic mutations in a step-wise manner. We previously developed a model for TAM by introducing disease-specific GATA1 mutation in trisomy 21 induced pluripotent stem cells (iPSCs) leading to the production of N-terminally truncated short form of GATA1 (GATA1s) (Barwe et al., 2021). In this study, we introduced co-operating mutation in STAG2, a member of the cohesin complex recurrently mutated in DS-ML but not in TAM, and evaluated its effect on hematopoietic differentiation. Methods Two different iPSC lines with trisomy 21 with or without GATA1 mutation as described in Barwe et al., 2021, were used. CRISPR/Cas9 gene editing was performed to introduce STAG2 mutation to generate a knockout of STAG2. Hematopoietic differentiation of these iPSC lines was performed using STEMdiff Differentiation kit. ProteinSimple Wes system was used for western blot analysis. Multi-dimensional flow cytometry was used for immunophenotypic analysis of megakaryoblasts cultured in lineage expansion media for 5 days. Multi-lineage colony forming potential was assessed by Methocult colony forming assay using day 10 hematopoietic stem progenitor cells (HSPCs). Results Hematopoietic differentiation of GATA1 and STAG2 double mutants in two independent trisomy 21 iPSC lines confirmed GATA1s expression and the loss of functional STAG2 protein (Fig. 1A). GATA1s expressing HSPCs collected on day 12 post differentiation showed reduced erythroid (CD71+CD235+) and increased megakaryoid (CD34+CD41+ within CD41+ compartment) and myeloid (CD18+CD45+) population compared to disomy 21 HSPCs with wild-type GATA1, consistent with our previous study (Fig. 2B). STAG2 knockout HSPCs showed higher erythroid population (P=0.033 and 0.016 in T21-1S and T21-2S respectively) and reduced myeloid population while it had no significant effect on the megakaryoid population in both iPSC lines. The GATA1s/STAG2 knockout HSPCs showed reduced erythroid, but higher megakaryoid and myeloid population compared to wild-type HSPCs. Strikingly, the immature megakaryoid population was significantly higher in the double mutant HSPCs compared to single mutant alone in both iPSC lines (P=0.005 and 0.004 for T21-1GS and T21-2GS respectively), indicating that the STAG2knockout co-operated with GATA1s for increasing megakaryoid population. The trisomy 21 iPSC line with wild-type GATA1 developed CFU-GEMM (colony-forming unit granulocyte erythroid macrophage megakaryocyte), CFU-GM (CUF granulocyte-macrophage) and BFU-E (burst-forming unit erythroid) colonies in Methocult. GATA1 mutation, unlike STAG2 mutation, inhibited the formation of CUF-GEMM and BFU-E colonies. The number of CFU-GM colonies in T21-2GS was significantly reduced compared to T21-2G (Fig. 1C, p=0.002). Lineage expansion and immunophenotyping of these HSPCs in megakaryocyte-specific media showed that these cells expressed markers closely resembling DS-ML immunophenotype. Of note, the myeloid markers, CD13 and CD11b are the only two markers expressed on majority of DS-ML blasts compared to TAM blasts (Karandikar et al., 2001) (Yumura-Yagi et al., 1992). The percentage of CD13 and CD11b expressing cells was higher in megakaryoblasts expanded from iPSC lines with STAG2 GATA1 double mutant (Fig. 1D). The number of cells expressing CD117, a stem cell marker shown recently to be involved in DS-ML progression, were highest in T21-1GS and T21-2GS lines when compared to their respective isogenic family of GATA1 mutant lines. Conclusion GATA1s and STAG2 knockout co-operated to increase the megakaryoid population and the percentage of cells expressing DS-ML markers. We have developed a model system representing DS-ML, which can be used for understanding the individual and synergistic contribution of these gene mutations in disease initiation and progression. Figure 1 Figure 1. Disclosures Barwe: Prelude Therapeutics: Research Funding. Gopalakrishnapillai: Geron: Research Funding.

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‘The Stuff of Slow Constitution’: Reading Down Syndrome for Race, Disability, and the Timing that Makes Them So

Somatechnics ◽

10.3366/soma.2016.0193 ◽

2016 ◽

Vol 6 (2) ◽

pp. 235-248 ◽

Cited By ~ 2

Author(s):

Mel Y. Chen

Keyword(s):

Down Syndrome ◽

Trisomy 21 ◽

Historical Perspective ◽

Early History ◽

Present Moment ◽

History Of ◽

Living Being

In this paper I would like to bring into historical perspective the interrelation of several notions such as race and disability, which at the present moment seem to risk, especially in the fixing language of diversity, being institutionalised as orthogonal in nature to one another rather than co-constitutive. I bring these notions into historical clarity primarily through the early history of what is today known as Down Syndrome or Trisomy 21, but in 1866 was given the name ‘mongoloid idiocy’ by English physician John Langdon Down. In order to examine the complexity of these notions, I explore the idea of ‘slow’ populations in development, the idea of a material(ist) constitution of a living being, the ‘fit’ or aptness of environmental biochemistries broadly construed, and, finally, the germinal interarticulation of race and disability – an ensemble that continues to commutatively enflesh each of these notions in their turn.

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Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽

10.1093/genetics/163.2.571 ◽

2003 ◽

Vol 163 (2) ◽

pp. 571-580 ◽

Cited By ~ 1

Author(s):

William B Raich ◽

Celine Moorman ◽

Clay O Lacefield ◽

Jonah Lehrer ◽

Dusan Bartsch ◽

...

Keyword(s):

Down Syndrome ◽

Caenorhabditis Elegans ◽

Trisomy 21 ◽

Gene Dosage ◽

Inducible Promoters ◽

C Elegans ◽

Dual Specificity ◽

Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

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