-
American Journal of Alzheimer's Disease... Jun 2018People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with... (Review)
Review
BACKGROUND
People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia.
OBJECTIVES
To explore the phenomenon of dementia in DS.
METHODS
Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer's disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references.
RESULTS AND CONCLUSIONS
Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer's disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions.
Topics: Aging; Alzheimer Disease; Down Syndrome; Early Diagnosis; Humans
PubMed: 29504408
DOI: 10.1177/1533317518761093 -
Scientific Reports Feb 2022The Down syndrome (DS) phenotype is usually characterized by relative strengths in non-verbal skills and deficits in verbal processing, but high interindividual...
The Down syndrome (DS) phenotype is usually characterized by relative strengths in non-verbal skills and deficits in verbal processing, but high interindividual variability has been registered in the syndrome. The goal of this study was to explore the cognitive profile, considering verbal and non-verbal intelligence, of children and adolescents with DS, also taking into account interindividual variability. We particularly aimed to investigate whether this variability means that we should envisage more than one cognitive profile in this population. The correlation between cognitive profile and medical conditions, parents' education levels and developmental milestones was also explored. Seventy-two children/adolescents with DS, aged 7-16 years, were assessed with the Wechsler Preschool and Primary Scale of Intelligence-III. Age-equivalent scores were adopted, and Verbal and Non-Verbal indices were obtained for each individual. The cognitive profile of the group as a whole was characterized by similar scores in the verbal and non-verbal domain. Cluster analysis revealed three different profiles, however: one group, with the lowest scores, had the typical profile associated with DS (with higher non-verbal than verbal intelligence); one, with intermediate scores, had greater verbal than non-verbal intelligence; and one, with the highest scores, fared equally well in the verbal and non-verbal domain. Three cognitive profiles emerged, suggesting that educational support for children and adolescents with DS may need to be more specific.
Topics: Adolescent; Adolescent Behavior; Adolescent Development; Age Factors; Biological Variation, Population; Child; Child Behavior; Child Development; Child Language; Cognition; Down Syndrome; Education of Intellectually Disabled; Educational Status; Female; Humans; Intelligence; Male; Persons with Mental Disabilities; Verbal Behavior; Vocabulary
PubMed: 35121796
DOI: 10.1038/s41598-022-05825-4 -
Biochimica Et Biophysica Acta.... Jun 2022Down syndrome (DS) is caused by trisomy 21, and it is characterized by developmental brain disorders and neurological dysfunction. Clinical studies and basic research...
Down syndrome (DS) is caused by trisomy 21, and it is characterized by developmental brain disorders and neurological dysfunction. Clinical studies and basic research have revealed that defects in mitochondrial function contribute to the pathogenesis of DS. However, the underlying mechanisms of mitochondrial dysfunction in DS remain unclear. In this study, we first generated GABAergic interneurons and medial ganglionic eminence (MGE) organoids from DS patients and control induced pluripotent stem cells. The mitochondria were abnormally clustered in the perinuclear region of GABA neurons and cell in MGE organoids from DS patients, which exhibited impaired mitochondrial function as assessed by seahorse oxidative phosphorylation assay. Inhibition of the DSCAM-PAK1 pathway by gene editing or treatment with a small molecule corrected mitochondrial perinuclear aggregation in cells from DS patients. Therefore, our study provides insight into the potential mechanism of mitochondrial dysfunction in DS.
Topics: Down Syndrome; Humans; Induced Pluripotent Stem Cells; Interneurons; Mitochondria; Organoids
PubMed: 35301086
DOI: 10.1016/j.bbadis.2022.166388 -
Mammalian Genome : Official Journal of... Dec 2016Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of... (Review)
Review
Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are as follows: (i) it is trisomic for 125 human protein-coding orthologs, but only 90 of these are Hsa21 orthologs and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret the results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review the functional information on Hsa21 protein-coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.
Topics: Animals; Chromosomes; Chromosomes, Human, Pair 21; Disease Models, Animal; Down Syndrome; Genome; Humans; Mice; Trisomy
PubMed: 27538963
DOI: 10.1007/s00335-016-9661-8 -
European Respiratory Review : An... Jan 2017Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with... (Review)
Review
Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations (particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.
Topics: Cardiovascular Diseases; Cardiovascular System; Cause of Death; Down Syndrome; Genetic Predisposition to Disease; Heart Defects, Congenital; Humans; Lung; Lung Diseases; Phenotype; Prognosis; Risk Factors
PubMed: 28223397
DOI: 10.1183/16000617.0098-2016 -
Neuropharmacology Jun 2021Cognition and behavior are tightly linked to synaptic function. A growing body of evidence suggests that aberrant neurotransmission, caused by changes in synaptic... (Review)
Review
Cognition and behavior are tightly linked to synaptic function. A growing body of evidence suggests that aberrant neurotransmission, caused by changes in synaptic protein expression levels, may be a major cause underlying different brain disorders. These changes in expression result in abnormal synaptic organization or function, leading to impaired neurotransmission and unbalanced circuit operations. Here, we review the data supporting the involvement of mutations in genes coding for kainate receptor (KAR) subunits in the pathogenesis of psychiatric disorders and Down syndrome (DS). We show that most of these mutations do not affect the biophysical properties or the receptors, but rather alter subunit expression levels. On the basis of reports studying KAR genes mutations in mouse models of autism spectrum disorders and DS, we illustrate how deviations from the physiological regulatory role that these receptors play in neurotransmitter release and plasticity give rise to synaptic alterations that lead to behavioral and cognitive deficits underlying these disorders.
Topics: Animals; Down Syndrome; Humans; Mental Disorders; Mice; Neuronal Plasticity; Receptors, Kainic Acid; Synaptic Transmission
PubMed: 33862031
DOI: 10.1016/j.neuropharm.2021.108558 -
Disease Markers 2021Oxidative stress plays an important role in Down syndrome (DS) pathology since the gene dose effect leads to abnormal levels of certain enzymes and metabolites. In this... (Review)
Review
Oxidative stress plays an important role in Down syndrome (DS) pathology since the gene dose effect leads to abnormal levels of certain enzymes and metabolites. In this review, we focused on relatively easy-to-obtain, peripheral markers of oxidative stress and inflammation, in order to compare the levels of these markers in DS patients and chromosomally healthy persons. Studies taking into account age- and sex-matched control groups were of particular interest in this context. We analyzed the factors that influence the levels of said markers in both groups (i.e., the usefulness of the markers), including the age of DS patients, occurrence of regular trisomy 21 or mosaicism, physical activity of patients, and the onset of Alzheimer's disease in DS. This paper was conceived as a handbook-to help for selecting suitable, easy-to-obtain markers for monitoring of the health status of DS patients (e.g., in nutritional studies and during dietary supplementation).
Topics: Biomarkers; Case-Control Studies; Down Syndrome; Health Status; Humans; Inflammation; Oxidative Stress; Patient Acuity; Phenotype
PubMed: 34257747
DOI: 10.1155/2021/5581139 -
Revista Chilena de Pediatria Oct 2020In Chile, Down syndrome has a prevalence of 2.5 in 1,000 live births. These patients present more congenital anomalies and comorbidities than the general population,...
INTRODUCTION
In Chile, Down syndrome has a prevalence of 2.5 in 1,000 live births. These patients present more congenital anomalies and comorbidities than the general population, increasing their hospitaliza tion rate.
OBJECTIVE
To describe congenital anomalies and comorbidities of neonates with Down syndrome born and/or hospitalized between 2008 and 2018.
PATIENTS AND METHOD
We conducted a retrospective review of patient's medical records born and/or hospitalized during their first 28 days of life between January 1st, 2008, and December 31st, 2018. For each patient, we recorded maternal age, familiar cases of Down Syndrome, pre and perinatal history, genetic study result, as well as age at admission, reason for hospitalization, comorbidities, length of stay, and death. Two patients that had more than 50% of incomplete medical records were excluded. We studied the associations between comorbidities, congenital anomalies, and death.
RESULTS
140 in 79,506 newborns (0.2%) were diagnosed at our center with Down Syndrome in their neonatal period. 24.7% were born preterm and 26.4% had low birth weight for gestational age. Morbidities and hospitalizations were present in 83.6% and 90%, of the study population, respectively. The main reason for hospitalization was polycythemia and the most frequent was hyperbilirubinemia. Four patients died (2.9%) and 70.7% presented at least one congenital anomaly, mainly heart disease. Median maternal age was 36 years and 57.1% of mothers were aged 35 or older.
CONCLUSIONS
This cohort of patients with Down Syndrome provides important information for the optimization of their perinatal management and follow-up.
Topics: Abnormalities, Multiple; Chile; Comorbidity; Down Syndrome; Female; Follow-Up Studies; Hospitalization; Humans; Infant, Newborn; Logistic Models; Male; Retrospective Studies
PubMed: 33399638
DOI: 10.32641/rchped.vi91i5.1518 -
EMBO Reports Jan 2015Trisomy 21, the commonest constitutional aneuploidy in humans, causes profound perturbation of stem and progenitor cell growth, which is both cell context dependent and... (Review)
Review
Trisomy 21, the commonest constitutional aneuploidy in humans, causes profound perturbation of stem and progenitor cell growth, which is both cell context dependent and developmental stage specific and mediated by complex genetic mechanisms beyond increased Hsa21 gene dosage. While proliferation of fetal hematopoietic and testicular stem/progenitors is increased and may underlie increased susceptibility to childhood leukemia and testicular cancer, fetal stem/progenitor proliferation in other tissues is markedly impaired leading to the characteristic craniofacial, neurocognitive and cardiac features in individuals with Down syndrome. After birth, trisomy 21-mediated premature aging of stem/progenitor cells may contribute to the progressive multi-system deterioration, including development of Alzheimer's disease.
Topics: Animals; Disease Models, Animal; Down Syndrome; Hematopoiesis; Humans; Induced Pluripotent Stem Cells; Phenotype; Stem Cells; Trisomy
PubMed: 25520324
DOI: 10.15252/embr.201439583 -
Current Alzheimer Research 2016
Topics: Alzheimer Disease; Down Syndrome; History, 19th Century; History, 20th Century; Humans
PubMed: 26487155
DOI: 10.2174/1567205012999151021102914