Down+Syndrome



What it is Down syndrome (DS) has been identified in humans as an extra copy of a chromosome, specifically chromosome number 21. The karyotype can be seen in figure 1. In most cases, Down syndrome is not inherited, but is a random chance disease. In a normal embryo, there are two copies of each chromosome; one from each parent. When there is an extra copy of a chromosome, there are genes spread out between all three of the copies, leading to problems with brain development and natural body development (Searle, 2009). Physical features are altered when the development of a person is altered (Figure 2). Physical aspects include a shortened neck, flattened face, spots of white in the iris of the eye, and decreased size of hands and feet. People born with down syndrome are mentally slower, have problems with social behavior, and can be slower at learning motor skill activities. Due to their mental disability, their IQ's are much lower than the average person ("Down syndrome," 2012).



Diagnosis There is reason to believe that many of the irregularities in Down syndrome are due to gene dosage effects particularly over expression and under expression of certain genes. Only a subset of genes as gathered from experiments on transgenic mice may be involved. The child inheriting two copies of the mutant allele, known as disomic homozygosity, could be used to justify the increased risk of autoimmune disease in trisomy 21 (Soderberg et al., 2006). The risk of appearance of this trisomy is found to increase linearly and moderately in mothers 35 years of age or older. Diagnosis of the syndrome may be presented by analysis of fetal karyotype; for karyotype analysis, fetal cells obtained by biopsy of chorionic cups, amniocentesis, and cordocentesis may be used. Fluorescent in situ hybridization (FISH), a newly discovered method in molecular biology, has enabled the utilization of fetal erythrocytes found in a small amount in the circulation of maternal blood for analysis of karyotype ploidy. The nuchal translucency (NT) is formed by a layer of fluid beneath the nuchal skin extending for a variable distance over the head and neck. An increased amount of nuchal fluid can be used to pre-diagnose newborns as having Down syndrome.The extra chromosome 21 is the most often translocated with another acrocentric chromosome and recurrence of the problem might occur depending on the type of translocation. Ultrasound screening in the first trimester of pregnancy increases the effectiveness of detection of fetal chromosomal diseases (Dizdarevic et al., 2011). Video 1 below explains the nuchal test and how it is performed in the first trimester of the pregnancy. The correlation between DS genotype and phenotype has been investigated using mouse models trisomic for Has 210 homologs. media type="youtube" key="Y178viF068o" height="346" width="462" align="center"

Video 1- In this video, Dr, Flisser explains what the nuchal test is and when it is performed during the pregnancy (Flisser, 2009).

When the genetic risk is carried by mitochondrial DNA (mtDNA) it is said to be cytoplasmic inheritance. It has been found that the number of mtDNA mutations increases with age mostly in oocytes as does DS risk. mtDNA is almost always of maternal origin, as is the extra chromosome 21 in most cases. These mutations are associated with Alzheimer’s disease, diabetes and hypothyroidism. They can also be inherited and can be caused by both endogenous and exogenous factors. Mutations in mtDNA bring about a rise in the formation of free radicals while decreasing ATP levels, and thereby could affect the synaptonemal complex, chromosome segregation and division spindle. A defect in the function of the oxidant-antioxidant system has been found in DS mothers. Four never before labeled mutations causing amino acid changes have been established in mtDNA sequencing in a donor of the extra chromosome 21. The occurrence of mtDNA mutations could account for the free radical damage in DS (Arbuzova et al., 2001).

Genes Involved Superoxide dismutase (SOD) is an important gene because it creates hydrogen peroxide from the superoxide radicals. From that point, glutathione peroxidase and catalase change the hydrogen peroxide to water. The superoxide dismutase gene locus has been found on chromosome 21. This locus is very important in people with Down syndrome because there are more than two chromosomes, thus affecting the dosage of those genes components. With increased dosage of the SOD gene, it offsets the concentration of the glutathione peroxidase gene and can lead to “molecular aging” and can cause harm to the DNA and proteins in the patient (Pinto, Neves, Palha & Bicho, 1997).

Treatable Symptoms Down syndrome individuals (of middle age) have been found to develop “Alzheimer like” changes in neural activity which can be attributed to //chronic oxidative stress// stemming from the irregular configuration of expression within trisomy and the presence of nonfunctional mitochondria. Also, oxidative stress can be the causative agent of the appearance of cataracts, autoimmune diseases, and notable exceled aging. The scientific team of Jovanovic, Clements, and MacLeod (1998) conducted an experiment which tested urine samples from two siblings, one with DS and one without, to view which individual had a higher amount of biomarker for oxidative stress. The results showed that the siblings with DS had higher concentrations of the oxidative stress biomarker in their urine, indicating that they have a higher level of oxidative stress then do no affected members of the same family (Javonovic, Clements & MacLeod, 1998).

Treatments Proposed treatments for Down syndrome target the symptomatic realm of the disease. Predominately symptoms range from superficial characteristics, which are observable traits such as behavior and attitude, to physiological issues present on a microscopic scale.

In a study conducted by Schields et al., twenty adolescent Down syndrome patients were paired with physiotherapy students; of which half of the patient-student pairs would complete a ten week exercise regimen while the remaining half representing the control group did not participate in the ten week program. The exercise consisted of resistance training which was broken down into three upper body and three lower body exercises; both upper and lower body workouts were conducted for three sets of twelve repetitions with a two minute resting period after each set. The motivation provided by the physiotherapy students for the adolescent DS patients greatly encouraged them to progress through the workout. Experiments such as this, promote community action to enhance the livelihood of individuals with Down syndrome by aiding them in overcoming certain barriers (Schields et al., 2011).

<span style="font-family: Georgia,serif; font-size: 110%;">To counter the ruin that oxidative stress causes in a DS patient fortifying the diet with simple antioxidant compounds such as //vitamin E, BHT and propyl gallate// may prove beneficial; however this process of treatment is still viewed with controversy. Experiments based on the supplementation of antioxidant vitamins when conducted in vitro resulted in complete aversion to oxidative stress (Javonovic, Clements & MacLeod, 1998). Coenzyme Q10 (CoQ10) has been //well-acknowledged// for its //antioxidant properties// (Littaeeu & Tiano, 2010). In a prolonged study by Littaeeu, Tiano and others (2012) it was found that CoQ10 was capable of influencing //DNA repair mechanisms// in accordance to //age-specific reduction//. Twenty-eight subjects were recipients of oral CoQ10 treatments; during the 20 month experiment the patients made to routine doctor-patient visits where urine and blood samples were taken to test for the amount of hormones indicating the onset of puberty. The variation in CoQ10 treatment between pediatrics and post-puberty adolescents is based on which type of oxidized base was reduced; in pediatrics the amount of oxidized pyrimidines (cytosine or thymine) were decreased and the amount of oxidized purines (guanine or adenine) were reduced in post-puberty adolescents. The reduction of oxidized bases can be afforded to the bioenergetic activity of CoQ10 and its antioxidant capabilities along with lowering the effects of damaged mitochondria (Tiano et al., 2012). The coupling of multiple antioxidants such as vitamin E (discussed previously), CoQ10, and ubiquinol (a reactive oxygen species or ROS scavenger) is the most effective mechanism of limiting the effects of oxidative damage.

<span style="color: #009900; font-family: Georgia,serif; font-size: 150%;">Conclusion

<span style="font-family: Georgia,serif; font-size: 110%;"> Down syndrome occurs as a trisomy in chromosome 21 usually as a result of non-disjunction. Non-disjunction occurs at a higher rate in women who become pregnant at/over the age of 35. Issues in DS patients are characterized as abnormalities in cognitive development as well as distinct body characteristics. The irregularities observed in DS are most often attributed to over-expression and/or under expression of genes. The main gene involved in DS is the superoxide dismutase (SOD) gene that is present on chromosome 21; due to the trisomy of chromosome 21 the SOD gene is present in amplified amounts which increase the rate of molecular aging thus affecting DNA and proteins.

<span style="font-family: Georgia,serif; font-size: 110%;"> Proper diagnosis of DS can be accomplished fairly early in embryonic development via fetal karyotyping. There are multiple ways of harvesting chromosomes for a karyotype including obtaining a culture of cells from placental cells that invade the endometrium forming the chorionic girdle (chorionic cusp) anionic fluid and blood from the umbilical cord. Two methods of producing a karyotype from different cells are flourescent in situ hybridation and nuchal translucency fluid testing. Also ultrasound screening within the first trimester is a good indicator of a chromosome disorder. Mutations with mitochondrial DNA (mtDNA) also present an avenue in chromosome abnormalities as seen within DS; these mutations cause a rise in free radicals which promote oxidation in DNA.

<span style="font-family: Georgia,serif; font-size: 110%;"> Current treatments for DS only work against the symptoms; they do not reverse the disorder. Supplementation with antioxidants works to prevent oxidative stress that can wreak havoc on the genetic material of the individual leading to early aging and degeneration of cognitive functions. Providing an comfortable and accepting environment for individuals with Down syndrome is also very helpful. Often time support can be the best treatment for a person with Down syndrome.

<span style="font-family: Georgia,serif; font-size: 110%;">media type="youtube" key="XGZnO5Im5bM" height="321" width="428" align="center"

<span style="font-family: Georgia,serif; font-size: 110%;">Video 2- Summary of non-Familial Down Syndrome (Health guru, 2011)

<span style="color: #7030a0; font-family: Georgia,serif; font-size: 150%;">References

<span style="font-family: Georgia,serif; font-size: 110%;">Arbuzova,S., Chuckle, H., Mueller, R., & Sehmi, I. (2001). Familial Down Syndrome: evidence supporting cytoplasmic inheritance. Clinical Genetics, 60(6),456-462

<span style="font-family: Georgia,serif; font-size: 110%;">Dizdarevic, J., Izetbegovic, S., Dekovic, S., Stojkanovi, G., (2011). Nuchal translucency screening for fetal Down’s syndrome. HealthMed, 5. <span style="font-family: Georgia,serif; font-size: 110%;">Javonovic, S. V., Clements, D., & MacLeod, K. (1998). Biomarkers of oxidative stress are significantly elevated in Down syndrome. //Free Radical Biology & Medicine, 25//(9).

<span style="font-family: Georgia,serif; font-size: 110%;">Flisser, A. (Performer) (2009). Prenatal testing: Nuchal test (pregnancy health guru) [Web]. Retrieved from http://www.youtube.com/watch?v=Y178viF068o

<span style="font-family: Georgia,serif; font-size: 110%;">Health guru.(Performer) (2011). Understanding Down Syndrome [Web]. Retrieved from [] <span style="font-family: Georgia,serif; font-size: 110%;">Littaeeu, G., & Tiano L. (2010). Clinical aspects of coenzyme Q10: an update. //Nutrition 26.//

<span style="font-family: Georgia,serif; font-size: 110%;">Mayo Clinic. (Photographer). (2011). //The genetic basis of down syndrome//. [Web Photo]. Retrieved from []

<span style="font-family: Georgia,serif; font-size: 110%;">National Institute of Child Health & Human Development, Eunice Kennedy Shriver. (2012). //Down syndrome//. Retrieved from National Institute of Health website: []

<span style="font-family: Georgia,serif; font-size: 110%;">Pinto, M., Neves, J., Palha, M., & Bicho, M. (1997). //Oxidative stress in portuguese children with down syndrome//. Retrieved from []

<span style="font-family: Georgia,serif; font-size: 110%;">Searle, B. (2009, September 30). //Chromosomes and rare chromosome disorders in general//. Retrieved from []

<span style="font-family: Georgia,serif; font-size: 110%;">Soderbergh, A., Gustafsson, J., Ekwall, O., Hallgren, A., Nilsson, T., Kampe, O., Rorsman, F., Anneren, G., (2006). Autoantibodies linked to autoimmune polyendocrine syndrome type 1 are prevalent in Down syndrome. Acta Paediatrica, 95.

<span style="font-family: Georgia,serif; font-size: 110%;">Smida, V. (Photographer). (2011). //The clinical presentation of down syndrome (signs and symptoms)//. [Web Photo]. Retrieved from []

<span style="font-family: Georgia,serif; font-size: 110%;">Tiano, L., Padella, L., Santoro, L., Carnevali, P., Principi, F., Bruge, F.,. . . Littarru P. (2012). Prolonged coenzyme Q10 treatment in Down syndrome patients, effect on DNA oxidation. //Neurology of Aging, 33//.