Down Syndrome

The genetic component of an organism is delicately balanced, the most minor mistake regarding the content or location of the genetic material can have a tremendous impact on the phenotype or genotype and the chromosome mutation is one of the causes to lead to the imbalance. Chromosomal variations, aneuploidy, originates as the result of an error during mitosis or meiosis, such as nondisjunction where one progeny nucleus with more and one with less than the normal number of chromosomes is produced. If such nondisjunction occurs at meiosis II, anaphaseII one half of the gametes have the normal one set of chromosomes and one -quarter will have two sets of chromosomes and one quarter will have no chromosomes sets. Fusion of a gamete with two chromosome sets with a normal gamete will produce a polyploid zygote with three sets of chromosomes, triploid. However, the addition of an extra chromosome produces, to a certain extent, more viable individuals in animal and plant species compared to the loss of a chromosome does and so far, Down Syndrome is the only genetic disease that has a significant number of survivors passing the first year of their life after birth. The causes that lead to Down Syndrome have not been clearly elucidated , but studies have co- related the condition to a variety of environmental factors such as radiation, viral infection, hormone levels and obviously genetic predisposition naming genetic factors. A known fact established related to the development of Down Syndrome is the maternal age, therefore in younger mothers, up to 25 years old, the incidence of trisomy 21is lower than women having the maternal age over 30. ``The evidence that advanced maternal age is a risk factor for aneuploid offspring comes from studies on the parental origin of nondisjunction documented by chromosome banding of the affected child and both parents by studies using recombinant DNA technology.By examining banded chromosomes from the trisomic child and parents, the parental origin of the nondisjunction can be often determined. For trisomy21, the nondisjunction is maternal about 94%of the time and paternal about 6% . Studies have shown that the nondisjunction of the chromosome occurs in meiosis I which is not completed until ovulation so that eggs produced at an age up to 40 or over have been in meiosis for the same amount of time. Thus, during this time, metabolic errors or environmental factors can damage the cell so that abnormal processes occur when meiosis resumes. Most of the situations when Down Syndrome occurs is at the gametes stage before fertilisation, but there are situations when non-disjunction of chromosome 21 happens at an early stage of cell division of the blastocyst when some cells will contain a diploid set of chromosome and some others will be trisomics characteristic for mosaic Down Syndrome. Studies showed that trisomy 21 can happen not only after the nondisjunction of chromosome 21 but it can take place a translocation between chromosome 21 and chromosome14 (Robertsonian translocation) situation named familial Down Syndrome. The phenotypic features were first described by Langdon Down in 1886.He called the condition mongoloism due to the distinctive fold of skin in the corner of the eye, epicanthic fold and upslanting palpebral fissures. Affected individuals have a wide skull that is flatter than normal at the back, moth partially opened because of the furrowed and protruding tongue, small and poorly differentiated low set ears, flat face, micrognathia, broad neck, short limbs and palms with short fingers and single transverse palmar crease, shorter stature, poor muscle tone. Physical growth , behaviour and mental development is retarded and approximately 40% of all affected individuals have congenital heart defects , gastro-intestinal defects, thyroid dysfunctions and respiratory dysfunctions. Children with Down Syndrome are prone to develop leukemia due to weak immunity level, increased susceptibility to infection, hearing deficit, infertility(possible in females). Although most cases do not reach over 30-35 years old, recent studies have shown that the individuals that reach an older age are prone to develop Alzheimer Disease in their 50`s. Researchers identified around 350 genes on chromosome 21 with 33 genes responsible for development of Trisomy 21 located on the critical region 21q21-21q22.3 .Investigation on transenic mice made by Epstein et comp showed that 1.5 fold increased dosage of genes DRCR1 and DYRK1A, COL6A1 resulted in overexpression of these genes and induced heart defects and blocked transcri ption factor NFAT with an increased phosphorylation of NFATc4 in cortical neurons of embryos with Down Syndrome .Diverse studies monitoring brain disorders revealed that overexpression of DOPEY2 and APP genes on transgenic mice were correlated with cerebellar abnormalities and an increased length of the vermis and cognitive retardation. Weak muscular tonus and eye problems were associated with overexpression of CRYA 1. Several studies have reported at mRNA level that an overexpression of triplicated genes might underlie in phenotypic variation seen in Down Syndrome individual and their determination depends on the degree of gene expression variation but so far no gene has been directly linked as responsible for Down Syndrome but do play a role in determining some characteristic whereas do not trigger the disease on their own , it must be some more genes from chromosome 21 with unknown purposes.