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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 -
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 -
Physiological Research Mar 2022Down syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Individuals with Ds demonstrate...
Down syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Individuals with Ds demonstrate cognitive deficits in addition to comorbidities including cardiac defects, pulmonary arterial hypertension (PAH), low blood pressure (BP), and differences in autonomic regulation. Many individuals with Ds are born with heart malformations and some can be surgically corrected. Lower BP at rest and in response to exercise and other stressors are a prevalent feature in Ds. These reduced cardiovascular responses may be due to underlying autonomic dysfunction and have been implicated in lower exercise/work capacity in Ds, which is an important correlate of morbidity, mortality and quality of life. Exercise therapy can be beneficial to normalize autonomic function and may help prevent the development of co-morbidities in Ds. We will review cardiovascular physiology and pathophysiology in individuals with Ds, along with exercise therapy and special considerations for these individuals.
Topics: Autonomic Nervous System; Down Syndrome; Exercise; Heart Rate; Humans; Quality of Life
PubMed: 35043643
DOI: 10.33549/physiolres.934791 -
Genes Feb 2021Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic... (Review)
Review
Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic syndromes associated with immunity disorders are common and represent an interesting model for a better understanding of the underlying mechanism of autoimmunity predisposition. Among these conditions, Down syndrome (DS) certainly deserves special attention as it represents the most common genetic syndrome associated with immune dysregulation, involving both innate and adaptive immunity. Autoimmunity represents a well-known complication of DS: it is estimated that people affected by this disease present a risk four to six times higher than the normal population to develop autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and hypo- or hyperthyroidism. Several factors have been considered as possible etiology, including genetic and epigenetic modifications and immune dysregulation. In times in which the life expectancy of people with DS has been extremely prolonged, thanks to improvements in the diagnosis and treatment of congenital heart disease and infectious complications, knowledge of the mechanisms and proper management of autoimmune diseases within this syndrome has become essential. In this short review, we aim to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.
Topics: Autoimmune Diseases; Autoimmunity; Diabetes Mellitus, Type 1; Down Syndrome; Epigenesis, Genetic; Genetic Predisposition to Disease; Humans
PubMed: 33668420
DOI: 10.3390/genes12020268 -
Paediatric Anaesthesia May 2022Approximately one in every 700 babies in the United States is born with Down syndrome, or 0.14%. Children with Down syndrome have cognitive impairment and congenital... (Review)
Review
Approximately one in every 700 babies in the United States is born with Down syndrome, or 0.14%. Children with Down syndrome have cognitive impairment and congenital malformations necessitating frequent occurrences of general anesthesia and surgery. The thoughtful perioperative care of children with Down syndrome is relevant and acutely complex for the pediatric anesthesiologist. Behavior, sedation, hypotonia, upper airway obstruction, venous access, and bradycardia are omnipresent concerns apart from the surgical pathology. Down syndrome is also associated with autonomic nervous system dysfunction, a comorbidity that is overlooked in discussions of perioperative care and is described thus far in adults. Autonomic nervous system function or dysfunction may explain the phenotypical features of the perioperative challenges listed above. For this reason, understanding the development and measurement of autonomic nervous system function is important for the pediatric anesthesiologist. Definition and quantification of sympathetic and parasympathetic function will be reviewed.
Topics: Adult; Anesthesia, General; Anesthesiologists; Autonomic Nervous System; Bradycardia; Child; Down Syndrome; Humans; Sympathetic Nervous System
PubMed: 35156260
DOI: 10.1111/pan.14416 -
BMC Pediatrics Jul 2022Down syndrome is associated with various congenital anomalies and metabolic alterations such as hematological alterations. Values for the major hematological indicators...
INTRODUCTION
Down syndrome is associated with various congenital anomalies and metabolic alterations such as hematological alterations. Values for the major hematological indicators vary with age and sex, but these values have not been described for Mexican children with Down syndrome.
OBJECTIVE
To describe the complete blood count (CBC) values of pediatric patients with Down syndrome in México and report the most common non-malignant hematological alterations.
MATERIALS AND METHODS
The analysis includes data from 450 patients with Down syndrome, 55.5% ware males, aged 0-18 years who were patients at the Mexican National Institute of Pediatrics and whose clinical charts included CBC panel results for the period January 2008 through March 2018.
RESULTS
A total of 3438 CBC panels were analyzed with descriptive statistics to find the values and statistical dispersion of the major indicators, with percentiles, and reported separately by sex and age group. The most common non-malignant hematological alterations found were macrocytic anemia, leukopenia, lymphopenia, and thrombocytosis. There were differences in values in all three series.
CONCLUSIONS
The CBC panels and hematological alterations are summarized for patients with Down syndrome.
Topics: Blood Cell Count; Child; Down Syndrome; Female; Humans; Leukopenia; Male; Mexico; Thrombocytopenia
PubMed: 35778676
DOI: 10.1186/s12887-022-03450-8 -
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