Antioxidants in Down syndrome

Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Antioxidants in Down syndrome

Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Sex ratio in Down syndrome

Data from 55 publications providing the sex ratio (SR), i.e. ratio between male and female cases of Down syndrome (DS), are presented. In general, SR was skewed toward an excess of males in the majority of studied populations, either in populations with a high level of cases ascertainment (epidemiological studies) or in selected groups. No significant correlation involving the age of either patients or mothers was found. Some other factors which might influence the sex ratio in DS at birth are mentioned. Meta-analysis of data from epidemiological studies suggests the phenomenon is not restricted to free trisomy 21 alone but appears in translocation cases, both in mutant and inherited translocation carriers (SR = 1.31 and 1.36, respectively). In contrast to nonmosaic 47, +21 cases, where SR is close to 1.3, an excess of females was observed in mosaics 46/47, +21 (SR = 0.83). No male predominance was found among patients with DS not tested cytogenetically (SR = 0.98), which may be explained by female predominance in false-positive cases. In populations with a fraction of clinically diagnosed cases of 30% and over, SR has intermediate value of 1.1. The ratio showed a tendency to increase since 1940's, reaching a mean value of 1.35 in 1980's varying from 1.3 to 1.62 in different populations), which might be a consequence of the growing use of karyotyping to confirm diagnosis and of a real increase in proportion of males. In the 1990's, the ratio fell to 1.22 varying from 1.03 to 1.27. As SR is assumed to reflect a proportion of paternal contribution, the discrepancy between the proportions of paternal errors in cytogenetic studies on parental origin of the extra chromosome (24% in the 1980's) and in molecular studies (5-10% in the 1990's) discussed in the literature might be explained by temporal changes alone. Genetic mechanisms of male predominance in trisomy 21 are reviewed, among them models for joint segregation of chromosome 21 and Y chromosome in spermatogenesis, and the chromosome 21 nondisjunction during 2nd meiotic division of oogenesis caused by Y chromosome-bearing spermatozoa.     

Reproductive behavior and Down syndrome

Coital rates and contraception practice were investigated in mothers of 160 newborns with Down syndrome (DS) in comparison with the same aged (+/- 1 year) mothers of 160 healthy newborns. A considerable lowering of sexual activity is typical for parents, especially young ones, of children with DS. No relationship between parental sexual behavior and maternal hormonal dysfunction was found. Study on children sex ratio (SR) in relation to parental sexual activity revealed that the prevalence of boys in the DS children was due to the excess of boys (SR = 1.85) in the small group of children from sexually active couples. These data are discussed as evidence of association of a high coital rate with chromosome malsegregation in spermatogenesis.     

Obstacle avoidance in Down syndrome

IntroductionThe ability to avoid obstacles requires to represent the properties of the obstacle, represent the location of the obstacle relative to the body and update these representations as the body moves. Individuals with Down syndrome (DS) often have trouble avoiding obstacles, leading to increased frequency of trips and falling. The aim of the present study was to deeply analyze obstacle avoidance strategies in normally developed young adults (N) and in young adults with DS, at different levels of obstacle heights, with particular attention to the strategies used for clearing the obstacle and to how the walking pattern was modified by obstacle perception.Methods10 DS and 16 age-matched N walked along a walkway in three conditions: plain walking, walking with obstacle at ground level, walking with obstacle at 10% of the subject’s height. Spatiotemporal parameters were analyzed.ResultsThere was evidence for a different avoidance strategy in DS, and for a difficulty in regulating gait parameters when challenged with a complex situation as the presence of an obstacle. This may lead to an increased risk of fall. The results in addition suggested a lack in anticipatory movement adjustments in DS and provided further evidence of the presence of difficulties in perceptual–motor coupling in DS.     

Exosome release and cargo in Down syndrome

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.     

Trisomy 21 Down syndrome

Summary The lymphocyte chromosomes of trisomy 21 Down syndrome patients and their parents in a random series of 374 families were analyzed, the objective being the identification of parental mosaicism. The numbers of parents in whom at least two trisomy 21 cells were detected were seven mothers and three fathers, a frequency of 2.7% of families. Confirmation of mosaicism was by identification of parental transmission of the extra chromosome to the progeny, by repeat chromosome analysis, and/or by the presence of more than one affected child. If to these are added six others in whom only one trisomic cell was detected, but with no other supporting evidence, the frequency could be as high as 4.3%. Differences in parental age at the birth of Down syndrome progeny may be accounted for by differences in frequencies of mosaicism in germ cells and somatic tissue. Mosaicism was found more frequently in the mothers than in the fathers, but more data are required for confirmation of a real difference.     

Trisomy 21 Down syndrome

Summary In a series of 374 families with Down syndrome progeny, structural chromosome rearrangements were detected in the parents of six children with regular trisomy. The aberrations were reciprocal translocations and inversions. In all three informative families, the parent who transmitted the extra chromosome was not the one with the structural rearrangement. Among the three non-informative families there was one in which both parents carried different reciprocal translocations. In two other families a chromosome aberration was detected: a triple X mother and a father with a Philadelphia chromosome. Omitting the four parents with possible biased asccrtainment, 0.4% had a chromosome rearrangement. When the parents with constitutional chromosome aberrations and those with mosaicism, described previously, are combined, the frequency of chromosomally abnormal parents lies between 1.9% and 3.2%. When correlated with parental transmission of the extra chromosome, mosaicism rather than structural rearrangements appears to be of ctiologic significance.     

Palate vault morphology in Down syndrome

Moire topography was used to quantitatively determine the shape of the palatal vault in 57 Spanish patients with Down syndrome (DS) (38 males and 19 females; age range 18-36 years) and in 100 normal controls (N) (76 males and 24 females; age range 20-29 years). The topographic image for each palatal vault was analyzed and approximately 40 sets of coordinates (x, y, z) were recorded. Other parameters, including length, width and maximum height, were recorded from the palate vault images. No appreciable sexual dimorphism in palate dimensions was observed in DS subjects versus the situation in N subjects. Globally, the average N dimensions were significantly greater than those in the DS patients (P < 0.005). A special palatal morphology was found to be associated with DS, with different ratios for the three dimensions (mean factor 0.88 for length, 0.81 for width and 0.73 for height), versus the healthy palatal vaults. It is concluded that palatal morphology in DS fits an elliptic paraboloid. On the other hand, no lineal correlation was observed between height, width and length in the DS and N groups. The scatter plots of bivariate data exhibited a shapeless morphology. The lineal correlation coefficients ranged from 0.008 to 0.33 for the DS and N groups.     

Paternal age and Down syndrome.

The frequency of Down syndrome (DS) in infants of older fathers has been examined in two sets of data. The effect of maternal age was controlled by single years of age. Lack of tight control has been an important weakness of other studies on this subject. Data obtained in metropolitan Atlanta by an intensive case-ascertainment program showed no overall excess of DS infants born to older fathers. Nor was there evidence of such an effect in recent birth certificate data made available by the National Center for Health Statistics. The Atlanta data suggest an increased number of DS infants born to older fathers who had children by women less than or equal to 34 years. However, there was a small deficiency of DS infants born to older fathers by women greater than or equal to 35 years. The possibility of a paternal-age effect remains open, but the available data suggest that, if it exists, it is quite small.     

Cigarette smoking and Down syndrome.

A matched case-control study of 100 mothers of Down syndrome children, 100 mothers of children with other defects (defect controls), and 100 mothers of children with no defects (normal controls) was carried out. All infants were born in upstate New York in 1980 and 1981. Matching was very close on maternal age for the normal controls but not for the defect controls. The risk ratios for the association of cigarette smoking around the time of conception with Down syndrome was 0.58 (90% confidence interval of 0.34-0.98) in the case-defect control comparison and 0.56 (90% confidence interval of 0.33-0.95) in the case-normal control comparison. Stratification by alcohol ingestion and maternal age did not abolish the negative trend to association. The results are contrary to that of an earlier study of others that found a positive association of older age and trisomy in spontaneous abortions. In fact, among mothers of Down syndrome cases over age 30 in this analysis, the risk ratio was lower than for younger mothers. (For case-normal control comparisons, the value was 0.39 [90% confidence interval of 0.17-0.87]). If not due to chance or confounding, the negative association in our data may be attributable to, among other factors, a selective effect of smoking upon survival or fertilizability of +21 gametes prior to conception or upon survival of +21 conceptuses after fertilization.     

Accelerated epigenetic aging in Down syndrome

Down Syndrome (DS) entails an increased risk of many chronic diseases that are typically associated with older age. The clinical manifestations of accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for this hypothesis has been sparse. Here, we utilize a quantitative molecular marker of aging (known as the epigenetic clock) to demonstrate that trisomy 21 significantly increases the age of blood and brain tissue (on average by 6.6 years, P = 7.0 × 10⁻¹⁴).     

Protein expression in Down syndrome brain

Down syndrome (DS) is the most common chromosomal abnormality associated with early mental retardation and neurological abnormalities followed by precocious age dependent Alzheimer-type neurode generation later in life. Knowledge of the pathological mechanisms involved in DS is far from complete, but overexpression of genes residing in chromosome 21 was considered to be the central point for the DS phenotype. In this regard, beta amyloid precursor protein (APP), CuZn superoxide dismutase (SOD1) and S100beta have been implicated in causing apoptosis, a mechanism thought to be responsible for neuronal loss in DS, in one way or another. The gene dosage hypothesis has been challenged, however, and dysregulation of expression of genes located on other chromosomes has been described, which may well be secondary to chromosomal imbalance or a direct consequence of the disease process. The present review focuses on the protein expression profile in DS and we postulate that abnormalities in the coordinated expression, as well as interaction of proteins may be responsible for the neuropathology of DS. A series of candidate proteins are discussed that may be directly causing or reflecting the DS phenotype, in particular the brain abnormalities in DS.