Down Syndrome: Trisomy 21
Jonathan Bettencourt
Biology Alive!
1998, Long Island University Virtual Classrooms
Printed with the permission of Eleanor Bettencourt
Copyright © 1998 Matthew S. Kerner. All rights reserved.

     Down syndrome is a genetic disorder that occurs because of abnormal chromosome structure. This abnormality is characterized by specific physical features and limited mental functions, along with several internal organ malformations. In Down syndrome, ninety-five percent of all cases are caused by the following event; one cell has two 21st chromosomes instead of one, so the resulting fertilized egg now has three sets of the 21st chromosomes. Because of this triplication of chromosome 21, the scientific name of Trisomy 21 became known.
     In 1866, a physician and geneticist named John Langdon Down, studied a small group of children who had common physical features, and were different than normal children. However, the difference was similar in those who had the disorder. He found out that the reason those children were physically abnormal was because there was the presence of an extra No. 21 chromosome, which altered the bodily structure along with its mental capabilities of that person, and thus the appearance. Because of Dr. J. L. Down's contribution to research, more than a hundred years ago, we know much more today of Down syndrome which was named after him. In other parts of the world today, Down syndrome is widely known as just "Downs."
     Dr. John Langdon Down wrote the first detailed description about the disorder. As time went by, many other people contributed to the study of Down syndrome as well. In 1930, Brewster and Cannon were the first to report an association between Down's observations and acute leukemia. In 1954, Schunk and Lehman were the first to report an association between Down's observations and transient leukemia. In 1959, Lejeune was the first to associate Down's observations with Trisomy 21 genetics. So you see, it all developed into a chain of research, but it was John Langdon Down who established the first solid base for the study of the disorder.
     Down syndrome's rate of occurrence is the highest of all the genetic disorders involving abnormal chromosomes. In 1997, 7000 children were born with DS in the United States alone. Worldwide, the rate of occurrence is one out of every 800 births. A huge role in the rate of occurrence is because of Trisomy 21 which has a ninety-five percent rate when a child is born with Down syndrome, and is therefore extremely common. This is due to non-disjunction during meiosis, maternal disjunction (80-90%), paternal disjunction (10-20%), with a 1% chance of recurrence. Twenty-five percenty of all miscarriages are caused by Trisomy 21. However, twenty-five percent of all children born with the symptom will go through the regular nine months of pregnancy and survive birth. The age of the mother also affects the rate of occurrence. For women between the ages of 35 and 40, the risk of having a baby with Down syndrome increases to one in 350. For women at the age of 40, the risk increases to one in 100. For women at the age of 45, the risk increases to a stunning one in 30; that's the basic Trisomy 21. Fifty percent of the people born with translocation are scattered, and another fifty percent are due to balanced translocation in one parent; thus, it's heredity. To this day, however, the reoccurrence rate is unknown.
     Down syndrome-Trisomy 21, is not really an inherited disorder but more of a genetic abnormality of the chromosome makeup in the body. Trisomy 21 has three genetic mechanism. The first and most common, is called non-disjunction, where there is an entire extra chromosome; 21 in all cells. The second is mosaic, where Trisomy 21 cells are mixed with a second cell line; usually "normal" (46, XX or 46, XY). Individuals with this form of Down syndrome are frequently, and slightly milder in their appearance; depending on the proportion of normal cells. The third is translocation, where part or all of chromosome 21 is translocated to another chromosome; usually number 14, 21, or 22. Only five percent of Down syndrome cases may be hereditary.
     Human cells divide in two ways; by mitosis and by meiosis. Mitosis is the name given to the ordinary cell division where one cell becomes two cells which have the exact same number and type of chromosomes as the parent cell. Meiosis is the name given to the other method of cell division that takes place in the ovaries and testicles and consists of one cell splitting in two, with the resulting cells having half the number of chromosomes of the parent cell. This happens so that normal eggs and sperms cells only have 23 chromosomes instead of 46. Nine percent of full Trisomy 21 is caused by paternal meiotic error and all full Trisomies are strongly associated with increasing maternal age, as well. So the disorder is seldom passed down, but there are many negative factors related to the passing down of Down syndrome.
     Down syndrome can be tested by doctors through a process called "Prenatal Testing," which examines the fetus in it's mother's womb. During this process, maternal serum alpha feto-protein (abbreviated MSAFP) is measured by a blood test in the pregnant woman at 15 to18 weeks of gestation. Alpha feto-protein is made in the fetal liver, and some escapes into the maternal circulation. This is important because doctors may use it in a screening test to find out whether the fetus has Down syndrome or not. MSAFP testing is a secondary option which is not always reliable. It involves maternal serum alpha feto-protein screening, which is also important to the welfare of the child. If the MSAFP screening test is low it suggests the risk of a Down syndrome fetus that is equal to the risk of a woman at the age of 35.
     Doctors can also test for the disease with procedures such as amniocentesis and chronic villi sampling. These two procedures involve taking cells from the tissues surrounding the fetus. The cells are placed in a culture medium to stimulate growth and then karyotypes are prepared.
     Down syndrome has numerous symptoms and affects on a person. Sometimes you can even point out a person with Down syndrome; just by looking at them. Most people with Down syndrome are short and have round faces with upper eyelids that cover the inner corners of the eyes. I say "most" because the physical appearance of the child may vary. It could be one, the other, none, or both. There may not be much to the physical appearance of a child, but the real defects occur inside the body and mentally. There is a wide range of mental retardation and developmental delay noted among children with Down syndrome. Heart defects are possible because of the difference in genes being triplicated. The genes are overexpressed and it's effect may depend on which "allele" is present in the person with Trisomy 21. "Alleles" are different, alternate forms of genes in the body.
     People with Down syndrome also tend to have multiple allergies and sensitivities, particularly in the integrity of the skin and respiratory systems. Why is this? This is because the body cannot properly process nutrients (particularly fats) and there are many defects in the such glands found in the adrenal, thyroid, and pituitary systems.
     In Down syndrome, the swallowing reflex doesn't work properly because of slow maturation and defects in the jaw (Tempero Mandibular).
     Although many medications and various therapies have been administered for treatment for people with Down syndrome, there has been no effective medical treatment available onto this day. However, recent advances in molecular biology make it possible to examine the genetic basis for Down syndrome. Once doctors can identify the genes on chromosome 21, and once they find the mechanism of how these genes interfere with normal developmental sequences, and if one could counteract these specific actions, a rational approach to medical therapy could emerge.
     Sadly, there is no cure for Down syndrome. In 1910, children with Down syndrome had an expected life span of nine years, and thanks to ongoing research resulting in medical advances. However, in this day and age, not many people die from it. It's not a fatal disorder. It brings on a life of pain, but seldom death. But the average person with Down syndrome lives up to the age of 55 and eventually ends up with "Alzheimer's disease". They're condemned, but not to death.
     As the human population increases, approaches can be taken to establish why the constant features of Down syndrome occur. Recent advances in technology allow geneticists to examine specific chromosome duplications in mice. This will help take apart the effects of "modifier loci" (apparent cause) through trait analysis. These genes most likely play a role in variability of human Down syndrome.
     Meanwhile, researchers are busy in their attempts to map out the full structure of the chromosome, including the Human Genome Database. Because of the small size of the 21st chromosome and its association with Down syndrome, it is the most thoroughly mapped human chromosome. Research is focusing on trying to identify genes and their effects when overexpressed. One of the primary goals of research is to identify the biochemical process which causes Trisomy 21 and decode it, leading to the development of a medical intervention.
     Scientists and doctors are still hard at work, but until they come to a solid conclusion, we have no other choice but to wait. Time can be torture, for some...

Antonarakis, S. E., Adelsberger, P. A., Peterson, M. B., Binkert, F., Schnizel, A. A. (1990). Analysis of DNA polymorphism suggests that most de novo dup (21q) chromosomes in patients with Down syndrome are isochromosomes and not translocations. Am J Hum Genet, 47, 968-972.
Antonarakis, S. E. (1993). Human chromosome 21: Genome mapping and exploration circa 1993. Trends Genet, 9, 142-148.
Eleanor Roosevelt Institute Chromosome 21 Sequence Database: Stanford Human Genome Center lab - Downs Syndrome Critical Region Sequencing Summary.
Human Chromosome 21 Project MPIMG Berlin. Genomic sequencing of Human Chromosome 21 - Overview of the sequencing status of Chromosome 21 world wide.
Korenberg, J., Kawashima, H., Pulst, S., Ikeuchi, T., Ogasawara, N., Yamamoto, K., Schonberg, S., Kojis, T., Allen, L., Magenis, E., Ikawa, H., Taniguchi, N., Epstein, C. (1990). Molecular definition of the region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet, 47, 236-246.
Lane, D., and Stratford, B. (Eds.) (1985). Down syndrome: Advances in medical care. New York: Wiley-Liss, Inc.
Molecular Genetics Labs at Cedars-Sinai Medical Center. The Chromosome 21 Sequence Database - Downs Syndrome Critical Region Sequencing Summary.
Selikowitz, M. (1990). Down syndrome: The facts. New York: Oxford University Press.
Van Dyke, D. C., Mattheis, P. Eberly, S. S., Williams, J. (Eds.). (1995). Medical and surgical care for children with Down Syndrome: A guide for parents. Bethesda MD: Woodbine House.

Revised: June 25, 2001.