Michael Rose

Bio 101

Due 4/28/14
Down Syndrome Research Paper

Down Syndrome: Genetic Causes and Recent Advances

Down Syndrome is a very common genetic disorder, caused by the presence of a third
copy of chromosome 21. It is a cause of significant intellectual disability, with the average IQ of
a person with Down syndrome floating around 50. It also has many heightened risks, including
congenital heart disease, Alzheimers disease, leukemia, motor disorders, and physical anomalies
such as the characteristic slanted eyes and small chin. This is confusing to most, as the parents
of a child with Down syndrome are usually mostly genetically normal.
The extra chromosomal content can arise through a multitude of different ways. The most
common way that arises, in approximately 95% of the cases, is an extra chromosome 21 forming.
There are other forms as well though, such as some cells having trisomy 21, and others not. This
is called mosaic Down syndrome. Then there are even rarer cases, which are caused by
mechanisms such as isochromosomes which results when the long arms of a chromosome
separate together rather than the long and short arm separating together during meiosis.
Trisomy 21 can be clearly seen when scientists karyotype the genetic material of
chromosomes. It is usually caused from a failure of the 21st chromosome to separate during
meiosis. As a result of this failure to separate, the sperm or egg is produced with an extra copy of
chromosome 21 and has 24 chromosomes in total instead of the normal 23. This is in the form of
XX,+21 for females and XY,+21 for males. This creates a baby which has 47 chromosomes, and
3 copies of chromosome 21. About 88% of cases usually find that the non-separation of trisomy
21 come from the mother.

Michael Rose
Bio 101

Due 4/28/14
Down Syndrome Research Paper

The mechanism of action that trisomy 21 places on the cell is known to over express a
portion of 310 genes located in chromosome 21. Some of the genes in this area include genes for
amyloid, which produced an excess of amyloid beta peptide in the brain, which causes a
dementia that is similar to Alzheimers disease. This produced senile plaques and neurofibrillary
tangles in almost all people with Down syndrome by the age of 35, even if dementia symptoms
are not present. People with Down syndrome also tend to lack a normal number of lymphocytes
and produce much less antibodies, which lead to them having very high chances of producing
infections.
In recent research there has been a drive to increase the brain functionality in those that
are born with Down syndrome. The area of pharmacotherapy has recently, as of September 2013,
began looking into a variety of pharmacological ideas that could possibly allow for counteracting
the cognitive and adaptive deficits that those with Down syndrome possess. Some of the ideas
being looked at are Antioxidant agents, APP and gamma-secretase inhibitors, the polyphenol
epigallocatechin gallate, which is found most notably in green tea, fluoxetine, adrenergic
receptor agonists, modulation of GABA A and GABA B receptors, nerve growth factor, anticholinesterase agents, and antagonism of the NMDA receptors.
A lot of these ideas are quite interesting, and I will go over a few of the ideas and my
possible interpretation of what they could mean. To start with, antioxidant agents, including
epigallocatechin gallate could be very beneficial because people with Down syndrome tend to
have very high levels of cellular oxidative stress that occurs over their lifetime. When
chromosome 21 overexpresses its genes, there is a high level of oxidative stress and neuronal
apoptosis. This lack of balance related to the metabolism of free radicals may have a direct role

Michael Rose
Bio 101

Due 4/28/14
Down Syndrome Research Paper

in producing the neuropathology of Alzheimers disease and Dementia in people with Down
syndrome.
Another interesting finding in studies comes from a well-known drug called Fluoxetine,
or Prozac. In studies of a specific type of mouse known as the Ts65Dn mouse, the adult model of
down syndrome, scientists have seen that Down syndrome displays behavioral deficits that are
consistent with a dysfunctional hippocampus. When trying to find underlying mechanisms of the
dysfunctioning hippocampus, they have assessed neurogenesis in an area of the brain known as
the dentate gyrus. In normal situations, the Down syndrome brain shows very few of a specific
type of cell known as a BrdU cell when compared to other animals. Using antidepressants such
as Prozac over a period of 3 weeks has increased neurogenesis in the mouse model to
comparable levels, by augmenting and increasing the proliferation of the BrdU cells in the
hippocampus.
The last pharmacological treatment that Im going to discuss is NMDA receptor
antagonists. A drug that blocks the NMDA receptor known as memantine has been used recently
on the Ts65Dn mouse that has been shown to increase the learning and memory, as well as retain
some functionality of a form of hippocampus synaptic plasticity which usually dysfunctions in
the untreated Down syndrome brain. According to a randomized, double blind, placebo
controlled study, 16 week treatment with memantine or placebo on 40 young adults with Down
syndrome, the team of scientists working on this type of treatment ended up finding that there
was a significant improvement in the memantine group with only infrequent or mild adverse
effects noted. Given the importance of the NMDA receptor in a wide variety of processes, some
of which scientists understand, and some of which they dont, I would like to see further research
in this particular route tread carefully.

Michael Rose
Bio 101

Due 4/28/14
Down Syndrome Research Paper

Sources:
http://books.google.ca/books?id=JD7YLArg5ncC&pg=PA130#v=onepage&q&f=false
(Essentials of Rubins Pathology by Howard Reisner, Chapter 6: Developmental and Genetic
Diseases, Page 130)
http://books.google.ca/books?id=F_7QXO0ZBigC&pg=PA45#v=onepage&q&f=false
(Molecular Genetic Pathology by Liang Cheng, David Y. Zhang. Chapter 2, section 13
Principles of Clinical Cytogenetics)
http://www.ncbi.nlm.nih.gov/pubmed/23821040 (prospects for improving brain function in
individuals with Down syndrome)
http://www.ncbi.nlm.nih.gov/pubmed/16624293
http://www.ncbi.nlm.nih.gov/pubmed/19526251 (Molecular Genetic analysis of Down
syndrome)
http://www.ncbi.nlm.nih.gov/pubmed/22806212 (Antagonism of NMDA receptors as a potential
treatment for Down syndrome: a pilot randomized controlled trial)
http://www.ncbi.nlm.nih.gov/pubmed/22206998 (Antioxidants in Down Syndrome)
http://www.ncbi.nlm.nih.gov/pubmed/22789577 (Medical update for children with Down
syndrome for the pediatrician and family practitioner)