Plasma levels of nitric oxide related amino acids in demented subjects with Down syndrome are related to neopterin concentrations

Subjects with Down syndrome (DS) have abnormalities in virtually all aspects of the immune system and almost all will be affected with Alzheimer’s disease (AD). It is thought that nitric oxide (NO) is involved in the pathophysiology of AD. In the present study, including a total of 401 elderly DS subjects, the spectrum of plasma amino acids and neopterin was investigated and related to development of AD. Concentrations of nearly all amino acids in DS subjects differed significantly from those of healthy controls. Neopterin was increased in DS subjects, especially in dementia. The production of NO as reflected by an increased citrulline/arginine ratio (Cit/Arg ratio) was enhanced during development of clinical dementia. Neopterin concentrations correlated to the Cit/Arg ratio only in the group of prevalent demented subjects (ρ = 0.48, P = 0.006). The results of this study are suggestive for an increase in oxidative processes in DS subjects with AD

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study

Background Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome. Methods We did a multicentre cohort study, including adults with Down syndrome (>= 18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively;NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses. Findings Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia;ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3.6 years (SD 1.6, range 0.6-9.2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0.83 (95% CI 0.76-0.91) in the prodromal group and 0.94 (0.90-0.97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1.04-fold risk of clinical progression (95% CI 1.01-1.07;p=0.0034). Plasma NfL concentrations showed an annual increase of 3.0% (95% CI 0.4-5.8) per year in the asymptomatic non-progressors group, 11.5% (4.9-18.5) per year in the asymptomatic progressors group, and 16.0% (8.4-24.0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24.3% (15.3-34.1). Interpretation Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Plasma amino acids and neopterin in healthy persons with Down’s syndrome

In persons with Down’s syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

One carbon metabolism and trisomy 21: analysis of the impact of genetic polymorphism

Trisomy 21 is the most common chromosome abnormality characterized by the presence of three copies of chromosome 21 in the genome. The clinical disorder attributed to trisomy 21 is Down syndrome. Patients with Down syndrome are heterogeneous in their phenotypic expression. Due to the location of the cystathionine beta-synthase gene on chromosome 21, and its involvement in one carbon metabolism, homocysteine levels have been found to be decreased in children with Down syndrome. The study of the regulation of one carbon metabolism in Down syndrome becomes important in light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions. Thus, the importance of evaluating single nucleotide polymorphisms in genes involved in one carbon metabolism need to be addressed in individuals with trisomy 21. This review offers an analysis of the impact of these polymorphisms in Down syndrome and their possible implications for phenotypic heterogeneity

Update on Kleefstra syndrome

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric featur

The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome.

International audienceTrisomy 21 or Down syndrome is a chromosomal disorder resulting from the presence of all or part of an extra Chromosome 21. It is a common birth defect, the most frequent and most recognizable form of mental retardation, appearing in about 1 of every 700 newborns. Although the syndrome had been described thousands of years before, it was named after John Langdon Down who reported its clinical description in 1866. The suspected association of Down syndrome with a chromosomal abnormality was confirmed by Lejeune et al. in 1959. Fifty years after the discovery of the origin of Down syndrome, the term "mongolism" is still inappropriately used; persons with Down syndrome are still institutionalized. Health problems associated with that syndrome often receive no or little medical care, and many patients still die prematurely in infancy or early adulthood. Nevertheless, working against this negative reality, community-based associations have lobbied for medical care and research to support persons with Down syndrome. Different Trisomy 21 research groups have already identified candidate genes that are potentially involved in the formation of specific Down syndrome features. These advances in turn may help to develop targeted medical treatments for persons with Trisomy 21. A review on those achievements is discussed

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection