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Biomolecules Apr 2020Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its... (Review)
Review
Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (HS), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used "CBS inhibitors" (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
Topics: Animals; Cystathionine beta-Synthase; Down Syndrome; Enzyme Inhibitors; Humans; Hydrogen Sulfide; Neoplasms; Tacrolimus
PubMed: 32365821
DOI: 10.3390/biom10050697 -
Frontiers in Endocrinology 2023To analyze and determine the safety and efficacy of growth hormone (GH) treatment in Down syndrome (DS) pediatric patients and to weigh ethical aspects involved. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To analyze and determine the safety and efficacy of growth hormone (GH) treatment in Down syndrome (DS) pediatric patients and to weigh ethical aspects involved.
DESIGN
Systematic review and mini meta-analysis of the literature.
METHODS
A search was performed in PubMed, Embase, Scopus, and PsycINFO through August 2022. Eligible studies included those who answered at least one of the following two questions: 1) What is the effect of growth hormone treatment in children with Down syndrome? 2) What are the ethical arguments in favor and against growth hormone treatment for children with Down syndrome? Multiple reviewers independently screened each article for eligibility.
RESULTS
In total sixteen reports detailed medical effects of GH treatment in pediatric DS patients and eight studies dealt with ethical aspects of GH treatment. Treatment with GH resulted in significantly higher growth velocity in patients with DS. The ethical complexity is great but does not present insurmountable difficulties to the therapeutic option.
CONCLUSIONS
As GH treatment is safe and effective for short-term height growth, GH therapy should be considered in long-term treatment of DS children.
Topics: Humans; Child; Human Growth Hormone; Down Syndrome; Body Height; Insulin-Like Growth Factor I
PubMed: 37152958
DOI: 10.3389/fendo.2023.1135768 -
Science Advances Jun 2023Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are...
Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS.
Topics: Humans; Down Syndrome; Proteomics; Interferons; Autoimmunity; Signal Transduction
PubMed: 37379383
DOI: 10.1126/sciadv.adg6218 -
Developmental Neurobiology Jul 2019Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically... (Review)
Review
Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Exosomes are one type of EVs that have demonstrated great potential in uncovering new biomarkers of neurodegeneration and disease, and also that appear to be intricately involved in the transsynaptic spread of pathogenic factors underlying Alzheimer's disease and other neurological diseases. Exosomes are nanosized vesicles, generated in endosomal multivesicular bodies (MVBs) and secreted by most cells in the body. Since exosomes are important mediators of intercellular communication and genetic exchange, they have emerged as a major research focus and have revealed novel biological sequelae involved in conditions afflicting the DS population. This review summarizes current knowledge on exosome biology in individuals with DS, both early in life and in aging individuals. Collectively these studies have demonstrated that complex multicellular processes underlying DS etiologies may include abnormal formation and secretion of extracellular vesicles such as exosomes.
Topics: Animals; Cell Communication; Down Syndrome; Endocytosis; Exosomes; Extracellular Vesicles; Humans
PubMed: 31347291
DOI: 10.1002/dneu.22712 -
Current Opinion in Immunology Oct 2021Down syndrome (DS) is characterized by a collection of clinical features including intellectual disability, congenital malformations, and susceptibility to infections... (Review)
Review
Down syndrome (DS) is characterized by a collection of clinical features including intellectual disability, congenital malformations, and susceptibility to infections and autoimmune diseases. While the presence of an extra chromosome 21 is known to cause DS, the precise genetic annotation linked to specific clinical features is largely missing. However, there is growing evidence that two genes located on chromosome 21, IFNAR1 and IFNAR2, play an important role in disease pathogenesis. These genes encode the two subunits of the receptor for type I interferons (IFN-I), a group of potent antiviral and pro-inflammatory cytokines. Human monogenic diseases caused by uncontrolled IFN-I production and response have been well characterized, and they clinically overlap with DS but also have notable differences. Herein, we review the literature characterizing the role of IFN-I in DS and compare and contrast DS to other IFN-mediated conditions. The existing IFN-I literature serves as a rich resource for testable hypotheses to elucidate disease mechanisms in DS and is likely to open novel therapeutic avenues.
Topics: Biomarkers; Disease Susceptibility; Down Syndrome; Gene Duplication; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Interferon Type I; Phenotype; Receptors, Interferon; Signal Transduction
PubMed: 34174697
DOI: 10.1016/j.coi.2021.06.006 -
Free Radical Biology & Medicine Jan 2018Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to... (Review)
Review
Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.
Topics: Alzheimer Disease; Biomarkers; Down Syndrome; Exosomes; Humans
PubMed: 28882786
DOI: 10.1016/j.freeradbiomed.2017.08.028 -
Journal of Neurodevelopmental Disorders Mar 2023Down syndrome (DS) is one of the most common genetic causes of intellectual disability, and it is associated with an increased incidence of numerous co-occurring...
BACKGROUND
Down syndrome (DS) is one of the most common genetic causes of intellectual disability, and it is associated with an increased incidence of numerous co-occurring conditions. Autism spectrum disorder (ASD) is common in persons with DS, with rates reported as high as 39%. However, little is known regarding co-occurring conditions in children with both DS and ASD.
METHODS
A single-center retrospective review of prospective longitudinally collected clinical data was performed. Any patient with a confirmed diagnosis of DS evaluated at a large, specialized Down Syndrome Program in a tertiary pediatric medical center between March 2018 and March 2022 was included. A standardized survey which included demographic and clinical questions was administered during each clinical evaluation.
RESULTS
In total, 562 individuals with DS were included. The median age was 10 years (IQR: 6.18-13.92). Of this group, 72 (13%) had a co-occurring diagnosis of ASD (DS+ASD). Individuals with DS+ASD were more likely to be male (OR 2.23, CI 1.29-3.84) and had higher odds of a current or prior diagnosis of constipation (OR 2.19, CI 1.31-3.65), gastroesophageal reflux (OR 1.91, CI 1.14-3.21), behavioral feeding difficulties (OR 2.71, CI 1.02-7.19), infantile spasms (OR 6.03, CI 1.79-20.34) and scoliosis (OR 2.73, CI 1.16-6.40). There were lower odds of congenital heart disease in the DS+ASD group (OR 0.56, CI 0.34-0.93). There was no observed difference in prematurity or Neonatal Intensive Care Unit complications between groups. Individuals with DS+ASD had similar odds of having a history of congenital heart defect requiring surgery to those with DS only. Furthermore, there was no difference in rates of autoimmune thyroiditis or celiac disease. There was also no difference in rates of diagnosed co-occurring neurodevelopmental or mental health conditions in this cohort, including anxiety disorders and attention-deficit/hyperactivity disorder.
CONCLUSIONS
This study identifies a variety of medical conditions which are more frequent in children with DS+ASD than DS alone, providing important information for the clinical management of these patients. Future research should investigate the role of some of these medical conditions in the development of ASD phenotypes, and whether there may be distinct genetic and metabolic contributions towards these conditions.
Topics: Male; Humans; Female; Autistic Disorder; Down Syndrome; Autism Spectrum Disorder; Retrospective Studies; Prospective Studies
PubMed: 36864370
DOI: 10.1186/s11689-023-09478-w -
International Journal of Molecular... Oct 2023The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic...
The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic mutations, epigenetic alterations, and changes in selection dynamics. Myeloid leukemia associated with DS (ML-DS) is preceded by a preleukemic phase called transient abnormal myelopoiesis driven by gene mutations and progresses to ML-DS via additional mutations in cohesin genes, , , or pathway genes. DS-related ALL (ALL-DS) differs from non-DS ALL in terms of cytogenetic subgroups and genetic driver events, and the aberrant expression of , mutations, and pathway-activating mutations are frequent in ALL-DS. Recent advancements in single-cell multi-omics technologies have provided unprecedented insights into the cellular and molecular heterogeneity of DS-associated hematologic neoplasms. Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment's role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies.
Topics: Humans; Down Syndrome; Janus Kinases; Signal Transduction; STAT Transcription Factors; Mutation; Hematologic Neoplasms; Tumor Microenvironment
PubMed: 37895004
DOI: 10.3390/ijms242015325 -
Medicina (Kaunas, Lithuania) Mar 2021The role of bruxism in children and adolescents with Down syndrome, the most often diagnosed congenital syndrome, is still unclear. Therefore, this study aims to conduct... (Review)
Review
The role of bruxism in children and adolescents with Down syndrome, the most often diagnosed congenital syndrome, is still unclear. Therefore, this study aims to conduct a narrative review of the literature about bruxism in children and adolescents with Down syndrome to identify the prevalence, risk factors, and possible treatments of this disorder. Although an accurate estimate of its prevalence could not be inferred, it appears that bruxism is more prevalent in Down syndrome individuals rather than in the general pediatric population. No gender difference was observed, but a reduction in its prevalence was described with increasing age (around 12 years). The variability in the diagnostic techniques contributed to the heterogeneity of the literature data. Clinicopathological features of Down syndrome, such as muscle spasticity, oral breathing, and a predisposition to obstructive sleep apnea, may suggest a higher prevalence of bruxism in this patient group. Finally, given the paucity of studies on the management of bruxism in this population, it was not possible to outline a standard protocol for the non-invasive treatment of cases in which an observational approach is not sufficient.
Topics: Adolescent; Child; Down Syndrome; Humans; Prevalence; Risk Factors; Sleep Apnea, Obstructive; Sleep Bruxism
PubMed: 33804484
DOI: 10.3390/medicina57030224 -
Molecular Medicine (Cambridge, Mass.) Mar 2018Trisomy of chromosome 21 (TS21) is the most common autosomal aneuploidy compatible with postnatal survival with a prevalence of 1 in 700 newborns. Its phenotype is... (Review)
Review
Trisomy of chromosome 21 (TS21) is the most common autosomal aneuploidy compatible with postnatal survival with a prevalence of 1 in 700 newborns. Its phenotype is highly complex with constant features, such as mental retardation, dysmorphic traits and hypotonia, and variable features including heart defects, susceptibility to Alzheimer's disease (AD), type 2 diabetes, obesity and immune disorders. Overexpression of genes on chromosome-21 (Hsa21) is responsible for the pathogenesis of Down syndrome (DS) phenotypic features either in a direct or in an indirect manner since many Hsa21 genes can affect the expression of other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function and energy conversion, and play a central role in the mitochondrial dysfunction and chronic oxidative stress, consistently observed in DS subjects.Recent studies highlight the deep interconnections between mitochondrial dysfunction and DS phenotype. In this short review we first provide a basic overview of mitochondrial phenotype in DS cells and tissues. We then discuss how specific Hsa21 genes may be involved in determining the disruption of mitochondrial DS phenotype and biogenesis. Finally we briefly focus on drugs that affect mitochondrial function and mitochondrial network suggesting possible therapeutic approaches to improve and/or prevent some aspects of the DS phenotype.
Topics: Animals; Down Syndrome; Humans; Mitochondria
PubMed: 30134785
DOI: 10.1186/s10020-018-0004-y