Zinc Nutritional Status in Adolescents with Down Syndrome

Studies have evidenced that zinc metabolism is altered in presence of Down syndrome, and zinc seems to have a relationship with the metabolic alterations usually present in this syndrome. In this work, the Zn-related nutritional status of adolescents with Down syndrome was evaluated by means of biochemical parameters and diet. A case–control study was performed in a group of adolescents with Down syndrome (n = 30) and a control group (n = 32), of both sexes, aged 10 to 19 years. Diet evaluation was accomplished by using a 3-day dietary record, and the analysis was performed by the NutWin program, version 1.5. Antropometric measurements were performed for evaluation of body composition. The Zn-related nutritional status of the groups was evaluated by means of zinc concentration determinations in plasma and erythrocytes, and 24-h urinary zinc excretion, by using the method of atomic absorption spectroscopy. The diet of both groups presented adequate concentrations of lipids, proteins, carbohydrates, and zinc. The mean values found for zinc concentration in erythrocytes were 49.2 ± 8.5 μg Zn/g Hb for the Down syndrome group and 35.9 ± 6.1 μg Zn/g Hb for the control group (p = 0.001). The average values found for zinc concentration in plasma were 67.6 ± 25.6 μg/dL for the Down syndrome group and 68.9 ± 22.3 μg/dL for the control group. The mean values found for zinc concentration in urine were 244.3 ± 194.9 μg Zn/24 h for the Down syndrome group and 200.3 ± 236.4 μg Zn/24 h for the control group. Assessment of body composition revealed overweight (26.7%) and obesity (6.6%) in the Down syndrome group. In this study, patients with Down syndrome presented altered zinc levels for some cellular compartments, and the average zinc concentrations were low in plasma and urine and elevated in erythrocytes.     

Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling

Background

The Down syndrome candidate region-1 gene (DSCR1, also known as RCAN1) is situated close to the Down Syndrome Critical Region (DSCR), which contains genes responsible for many features of Down syndrome. DSCR1 modulates calcineurin phosphatase activity, though its functional role is incompletely understood.

Methods

Here we investigated the role of DSCR1-1S isoform in IL-1 receptor (IL-1R)-mediated signaling by analyzing interaction between DSCR1-1S and the IL-1R pathway components Tollip, IRAK-1, and TRAF6.

Results

Co-immunoprecipitation analyses of HEK293 cells revealed that DSCR1-1S interacted with Tollip, an IRAK-1 inhibitor, leading to the dissociation of IRAK-1 from Tollip. Similarly, both DSCR1-1S and Tollip interacted with TRAF6, with DSCR1 reducing interaction between Tollip and TRAF6. DSCR1-1S also stimulated IL-1R-mediated signaling pathways, TAK1 activation, NF-κB transactivation, and IL-8 production, all downstream consequences of IL-1R activation.

General significance

Together, these results suggest that DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation.     

Systemic oxidative stress in children and teenagers with Down syndrome

Aims

The aim of this study was to evaluate the antioxidant status and oxidative stress biomarkers in the blood of children and teenagers with Down syndrome.

Main methods

The analysis of enzymatic antioxidant defenses, such as the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione transferase (GST), non-enzymatic antioxidants, such as levels of reduced glutathione (GSH), uric acid (UA) and vitamin E, as well as oxidative damage indicators, such as protein carbonyls (PC) levels and lipoperoxidation (TBARS), of DS individuals (n = 20) compared to healthy controls (n = 18). Except the vitamin E was measured by HPLC, all other markers were measured spectrophotometrically.

Key Findings

Antioxidant enzymes analysis showed significant increases in the SOD (47.2%), CAT (24.7%) and GR (49.6%) activities in DS subjects. No significant difference in GPx activity was detected while GST activity (61.2%) was decreased, and both responses may be consequence of the depletion of GSH (24.9%) levels. There were no significant differences in TBARS levels, while PC levels showed decreased (31.7%) levels compared to healthy controls, which may be related to the increase (16.1%) found in serum UA. Levels of vitamin E showed no significant differences between DS individuals compared to controls.

Significance

The results revealed a systemic pro-oxidant status in DS individuals, evidenced by the increased activity of some important antioxidant enzymes, together with decreased GSH levels in whole blood and elevated UA levels in plasma, probably as an antioxidant compensation related to the redox imbalance in DS individuals.     

Fluctuating dental asymmetry: A measure of developmental instability in Down syndrome

Subjects with Down syndrome provide a useful model for investigating the effect of chromosomal aneuploidy on developmental pathways. Studies suggest that a major effect of trisomy is a decrease in developmental stability. The present study examines fluctuating dental asymmetry in Down syndrome. Mesiodistal crown diameters were measured from dental casts of 114 Down syndrome subjects. Correlation coefficients for antimeric permanent teeth served as an index of dental asymmetry. These values were compared with normal values obtained from the literature. Fluctuating dental asymmetry is thought to reflect the relative success of developmental homeostasis in countering developmental disturbances. Down syndrome subjects have significantly increased dental asymmetry. In addition, they show a disproportionate increase in dental asymmetry for those teeth reported to have the least developmental stability. These results support the contention that the chromosomal imbalance in Down syndrome results in amplified developmental instability.     

Detection of gonadal mosaicism in parents of children with Down syndrome

The paper presents results of a revision of data of both conventional chromosome testing and a study of cytogenetic (QFQ) markers in families with Down syndrome. Retrospective analysis of 151 families found eight families with a carrier of gonadal mosaicism. In all cases, the mother was younger than 35 years old. Therefore a prevalence of parental mosaicism in young couples was estimated to be 6.5% (8/123). Conventional diagnostic testing, not followed by analysis of segregation of QHQ markers, would have resulted in a prevalence of only 1%. A comparison of the results ofcytogenetic analysis with those expected using molecular polymorphisms suggests that cytogenetic testing cannot be entirely replaced by molecular testing. A combination of both methods should be applied when gonadal mosaicism is suspected.     

Decreased HLA heterogeneity in parents of children with Down syndrome.

HLA-A and B antigens were determined in a study of 37 couples and their children with trisomy 21 Down syndrome (DS), using a standard microlymphocytotoxicity test. The comparison groups included 76 couples and their healthy children. All individuals were Caucasians from the same geographical area, and there was no history of consanguinity. The parents of children with DS did not show an association with a specific HLA antigen or haplotype. Sixteen of the 37 couples (43.24%) having children with DS share two or more antigens at the A and/or B locus. This was significantly higher than the proportion in the control group (6/76, or 7.88%). Of the 16 couples having children with DS and sharing two or more antigens, eight had a haplotype in common, in contrast with only two couples in the control group. The data suggest that sharing of parental HLA-A and B antigens may be related either to the occurrence of trisomy 21 zygotes or to prenatal survival of affected embryos and fetuses.     

The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome

Trisomy 21 (Down Syndrome, DS) is the most common chromosomal anomaly. Although DS is mostly perceived as affecting cognitive abilities and cardiac health, individuals with DS also exhibit dysregulated immune functions. Levels of pro-inflammatory cytokines are increased, but intrinsic alterations of innate immunity are understudied in DS. Furthermore, elevated Reactive Oxygen Species (ROS) are well documented in individuals with DS, further exacerbating inflammatory processes. Chronic inflammation and oxidative stress are often precursors of subsequent tissue destruction and pathologies, which affect a majority of persons with DS.Together with ROS, the second messenger ion Ca^2 + plays a central role in immune regulation. TRPM2 (Transient Receptor Potential Melastatin 2) is a Ca^2 +-permeable ion channel that is activated under conditions of oxidative stress. The Trpm2 gene is located on human Chromosome 21 (Hsa21). TRPM2 is strongly represented in innate immune cells, and numerous studies have documented its role in modulating inflammation. We have previously found that as a result of suboptimal cytokine production, TRPM2^?/? mice are highly susceptible to the bacterial pathogen Listeria monocytogenes (Lm). We therefore used Lm infection to trigger and characterize immune responsiveness in the DS mouse model Dp10(yey), and to investigate the potential contribution of TRPM2. In comparison to wildtype (WT), Dp10(yey) mice show an increased resistance against Lm infection and higher IFNγ serum concentrations. Using a gene elimination approach, we show that these effects correlate with Trpm2 gene copy number, supporting the notion that Trpm2 might promote hyperinflammation in DS.     

Mitochondrial alterations and tendency to apoptosis in peripheral blood cells from children with Down syndrome

Different types of cells from subjects with Down syndrome (DS) have an increased susceptibility to cell death. We have studied apoptosis and mitochondrial (mt) membrane potential (DeltaPsi(m)) in peripheral blood mononuclear cells (PBMC) from DS children and age-matched healthy donors after in vitro treatment with apoptogenic molecules, along with mtDNA content. We found that PBMC from DS and healthy controls had a similar tendency to undergo apoptosis and a similar amount of mtDNA. However, in cells from DS subjects, mitochondria showed a higher loss of DeltaPsi(m), underlying the presence of an increasing susceptibility of these organelles to damaging agents.     

A 19-kb CpG Island Associated with Single-minded Gene 2 in Down Syndrome Chromosomal Region

To help in isolating the genes involved in Down syndrome, wesought CpG islands in 4 Mb cosmid/PAC contigs spanning mostof the 21q.22.2 band using seven rare cutting enzymes. A strikingfeature was observed upstream of hSIM2 where at least 41 rare-cuttingsites were clustered within a 20-kb region. To investigate thestructure of the cluster, a cosmid containing hSIM2 was submittedto shotgun sequencing. Sequence analysis revealed that the clusterwas a long CpG island extending 19, 128 nucleotides which includesin the first and second exons of hSIM2. Taken together withour observation in which the CpG islands were concentrated within1.2 Mb around hSIM2, we propose that this region functions asan R-band, and the cluster provides a unique element for markingof DNA for the spatial and temporal expression of the hSIM2locus.     

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND: Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS: As part of the population‐based case‐control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS: Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08–2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11–2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85–1.87; p = 0.124). CONCLUSIONS: Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011. © 2011 Wiley‐Liss, Inc.     

Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

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Prevalence of methylenetetrahydrofolate reductase 677 C-T polymorphism among mothers of Down syndrome children

INTRODUCTION:

The relationship between chromosomal non-disjunction leading to aneuploidy and folate metabolism has drawn attention in the recent years. In this study, we examined the polymorphism in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), namely, 677 C-T in women having Down syndrome (DS) children.

MATERIALS AND METHODS:

The prevalence of these variant genotypes (MTHFR 677 C-T polymorphism) in women having DS children (case mothers) (n = 110) was compared with controls (n = 111) from Punjab. Genotyping was done using the polymerase chain reaction method followed by restriction fragment length polymorphism.

RESULTS:

In the present study, 1.8% of case mothers had TT genotype while none of the control mothers showed this genotype. T allele frequency among cases was 0.13 and 0.11 in controls. The Chi-square value showed a non-significant difference between cases and controls.

CONCLUSION:

No association has been observed between 677 C-T polymorphism and risk of non-disjunction in case mothers. Detection of polymorphisms in more genes of folate pathway is required to find out the exact cause of non-disjunction.     

A Novel Gene Isolated from Human Placenta Located in Down Syndrome Critical Region on Chromosome 21

Down syndrome is the most common birth defect, which is causedby trisomy 21. We identified a novel gene in the so-called Downsyndrome critical region by EST mapping to genomic DNA and followingcDNA cloning. The gene, designated DCRB (Down syndrome CriticalRegion gene B), consisted ofthree exons of1095 bp in total andencoded a large open reading frame of118 amino acid residues.The amino acids sequence ofDCRB showed no significant homologyto any known protein. Northern blot analysis showed that DCRBis mainly expressed in the placenta, in which a major 1.1-kbband and a minor 2.0-kb band were detected. Minor bands of 1.4kb and 2.2 kb were also detected in adult heart and skeletalmuscle.     

The growth capacity of bone marrow CD34 positive cells in culture is drastically reduced in a murine model of Down syndrome

Human trisomy 21, Down syndrome (DS), is characterized by mental retardation. In addition, high risks of developing hematological and immune disorders, as well as cardiac, skeletal and other abnormalities are life-long concerns. Recent data suggested that bone marrow contains progenitors, hematopoietic or stromal cells, which may have the potential of generating non hematopoietic tissue such as neural cells, cardiac cells or osteoblasts. Therefore we have used a model of Down syndrome, Ts65Dn mice, to investigate their bone marrow. We have found that the vast majority of CD34(+) cells in the bone marrow of adult Ts65Dn mice, but not of the CD34(-) cells, exhibit a drastic reduction in their in vitro growth capacity. In addition to neural antigens, cultured CD34(+) cells from trisomic and diploid mice also expressed mast cell markers.     

Quantitative methylation-sensitive arbitrarily primed PCR method to determine differential genomic DNA methylation in Down Syndrome

Relative levels of DNA hypermethylation were quantified in DS individuals using a new method based on a combination of methylation-sensitive arbitrarily primed polymerase chain reaction (MS-AP-PCR) and quantification of DNA fragments with the Agilent 2100 bioanalyzer. Four of the DS individuals had low plasma total homocysteine (tHcy) level (4.3 +/- 0.3 micromol/l) and 4 other had high-tHcy level (14.1 +/- 0.9 micromol/l). Eight healthy control individuals were matched to the DS cases for age, sex, and tHcy levels. We have identified and quantified six hypermethylated fragments. Their sizes ranged from 230-bp to 700-bp. In cases and controls, low-tHcy did not affect methylation level of identified fragments, mean methylation values were 68.0 +/- 39.7% and 52.1 +/- 40.3%, respectively. DNA methylation in DS individuals did not change significantly (59.7+/-34.5%) in response to high-tHcy level in contrast to controls (23.4 +/- 17.7%, P = 0.02). Further, the quantitative MS-AP-PCR using this microfludic system is a useful method for determining differential genomic DNA methylation.     

A Review of Ultrasound Imaging Techniques for the Detection of Down Syndrome

Down syndrome is the most common chromosomal disorder that affects the life of a person. Early detection of Down syndrome is important and significant for a better assessment of the fetus. The detection can be performed by identifying various parameters from the ultrasound images recorded during the 1st (11-14 weeks) and 2nd trimester (15-22 weeks) of the gestational period. The most important features are short Nasal bone (Hypoplasia) or absence of nasal bone, increased thickness of the back of the neck, fetal heart rate (FHR), crown-rump length (CRL) and shortening of arm bone or thigh-bone. The Diagnosis of Down syndrome is performed using invasive and noninvasive screening tests. There are many reported studies on the diagnosis of Down syndrome. This paper reviews the work on various imaging methods, and a technique reported for the detection of Down syndrome and introduces the use of Deep Learning techniques in identifying the presence of Down syndrome.     

Evaluation of maternal health and labor and delivery conditions as risk factors for childhood leukemias in children with Down syndrome

Children with Down syndrome (DS) have a remarkably high risk of developing leukemia during childhood; the mechanisms driving that risk are not well understood, and no clear prevention strategies exist. We conducted a nested case-control study in a Texas DS birth cohort to investigate possible links between maternal health, labor/delivery conditions, and leukemia risk. For most of the factors studied there was no evidence of an increased risk of total leukemias, or the subtypes acute lymphoid or acute myeloid leukemia. Ultrasound use showed an almost 2-fold increased odds of leukemia, but this result is likely an example of confounding by indication. There was a pattern of increased risk seen for presence of co-occurring heart anomalies, including tetralogy of Fallot, ventricular septal defects, atrial septal defects, and patent ductus arteriosus. Further investigation of the links between co-occurring heart defects in children with DS and development of leukemia may provide new understanding of cancer mechanisms, and ultimately lead to prevention opportunities for this high-risk population.