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Down Syndrome is one of the most common genetic disorders in people today. Down
Syndrome is caused by either a partial or full third copy of chromosome 21. Also known as trisomy 21,
Down Syndrome is estimated to effect one in seven-hundred babies born each year. Because of the
huge importance of the genetic material in the development of humans, people with Down Syndrome
are often associated with physical growth delays, unique facial features, and a wide range of
intellectual disability. Even though Down Syndrome is a genetic disorder, evidence has not shown it to
be inherited and most often the parents have a normal genetic make-up.
Down Syndrome has been a very common disorder among humans for probably the whole of
our existence, but little has been known or documented about it until 1862 when John Langdon Down
was the first to describe it as a distinct mental disability. Over the next hundred years, Down syndrome
would grow to be one of the most well known mental disabilities. Before the work of John Down,
infants with down syndrome were often killed or abandoned people didn't understand the mental
disorder. Because of our lack of understanding, individuals that had Down Syndrome in the 20th century
were often institutionalized, never receiving any sort of treatment for their disorder are rarely made it
past their early adult life. During the movement of Eugenics in the early 20th century, people with down
syndrome were even subject to programs of forced sterilization.
Down syndrome is caused by having three copies of the genes from chromosome 21. This
partial or full copy of chromosome 21 is made by chance when chromosome 21 isn't fully split during
meiosis, and either the original sperm or egg cell of an individual retains the extra copy. The extra
chromosome can arise in a few different ways. The most common cause constituting about 95% of
Down syndrome cases is a full extra copy of chromosome 21. Much more rare at about 2% of cases is
something called Mosaic Down Syndrome, where some of the cells in the body are normal and some
contain the extra 21st chromosome. Other causes include Robertsonain translocation, and
isochromosome. Robertsonian translocation happens when the chromosomes break at their centromeres
and the long arms fuse to form one long single chromosome with one centromere. An isochromosome
happens when the two long arms of a chromosome separate together, instead of the long and short arms
separating together in egg or sperm development.
Because of the extra genetic material present with chromosome 21, the genes over express
themselves at around 50%. This results in many unique characteristics in people with down syndrome
including many physical conditions affecting major organs and moderate to sever mental disability.
Among the physical characteristics that we can see include a small chin, slanted eyes, poor muscle
tone, a flay nasal bridge, and a crease in the palm of the hand. A protruding tongue is also common, due
to small mouth size and a large tongue. Because of the changes in airway due to the unique nose bridge
and tongue size, around half of those with down syndrome experience some form of sleep apnea.
Growth height is also lower in those with down syndrome, resulting in a short stature.
Mental characteristics of an individual with down syndrome include a moderate to mild IQ
(around 35-69), and in some cases having an even lower IQ of 20-35. Individuals with Mosaic Down
Syndrome where not every cell has the extra chromosome 21 often have a slightly higher IQ than those
with trisomy 21. As individuals with down syndrome age, they often don't perform as well as their
same aged peers. In some cases, individuals with Down Syndrome lose their ability to speak after they
reach about 30 years old. Delay in developmental skills are also very common, with children that have
Down Syndrome learning to crawl, walk, etc. at a much slower rate than that of their same age peers.
Between 20%-40% of individuals have speech impediments often constituting stuttering or irregular
speech. In those that reach age 60, 50%-70% develop Alzheimer's disease.

In recent years much research has been done so that scientists can better understand Down
Syndrome, especially in the field of molecular genetics. While there is still so much that scientists don't
know about Down Syndrome and molecular genetics in general, research has helped scientists to
identify where to look. In 1959, the cause of Down syndrome was identified as an extra copy of
chromosome 21 by Dr. Marthe Gautier. The trisomy of chromosome 21 influences almost every area of
human body tissue, which results in a very broad phenotype. Even though this has been researched for
many years due to how common Down Syndrome is, we still don't know the specifics behind the
mechanisms involved. Everyone that has down syndrome has some form of intellectual disability,
while almost all people with down syndrome develop Alzheimer's disease late in life. Alterations in
neurogenesis, neuronal differentiation, myelination, dendritogenesis, synaptogenesis and other
mechanisms are suggested to underlie the cognitive impairment. However, the exact mechanisms
responsible remain little understood. (Newton, 2015) It is assumed that chromosome 21 gene
overdosage plays a major role in Down syndrome-related neurodegeneration. Yet, the wide range of
variation in the degree of intellectual disability in Down syndrome is difficult to explain with a gene
overdose hypothesis. (Newton 2015) While we understand that having an extra chromosome 21 causes
some of the neurological issues, we can't explain the whole spectrum of symptoms simply from having
an extra chromosome 21.
“It is hypothesized that there are two pathophysiological mechanisms which may cause Down
Syndrome. Both hypotheses which may act through altered gene transcription, tissue-specific gene
transcription, genetic interaction, DNA methylation, altered microRNA activity , posttranscriptional
mechanisms and altered chromosome territories. (Newton 2015) Many more mechanisms, currently
undetected, may be present. Neither hypothesis rules out the other, and they may well influence one
another. The first of these hypotheses is called Dosage effect. The unifying simplified description of
this hypothesis is that a 1.5-fold increase of dosage results in a 1.5-fold increase of chromosome 21
gene expression causing the Down Syndrome phenotype that scientists recognize today. The dosage
effect hypothesis does not describe specific genes, subsets of genes or molecular pathways which are
responsible for specific Down syndrome features. Down syndrome mouse model experiments show
that a trisomy of the Down Syndrome critical region (DSCR) can explain some, but not all, phenotypic
features of Down Syndrome. (Newton 2015) In addition, expression levels of chromosome 21 genes
can differ between tissues. In 2011, GENCODE identified 696 genes on chromosome 21. Proteins
encoded by these genes are involved in 636 different biological processes, have 304 different molecular
function and are present in 163 cellular components. (Letourneau and Antonarakis 2012) The
neurological Down syndrome phenotype cannot be explained by changes determined within a single
pathway, but instead it is more likely a result of a complex interaction with disturbed regulation of
several pathways.
The second hypothesis described is called Amplified developmental instability. This hypothesis
says that there is a phenotypic instability due to extra genetic information, and that dosage imbalances
of genes located on chromosome 21 are responsible for a non-specific disturbance of overall genomic
regulation and expression. Because of this global balance disruption of gene expression in
developmental pathways, normal developmental processes are altered finally resulting in the
establishment of the Down Syndrome phenotype. This hypothesis has a significant overlap with the
dosage effect hypothesis but describes in a broad sense that the presence of extra genetic information
will result in a global cellular disturbance. (Newton 2015) However it is also known that other
autosomal trisomy syndromes (trisomy 13, trisomy 18) can lead to a similar global disturbance of
cellular molecular processes but do not lead to a phenotype similar to Down Syndrome. (Newton
2015) While much research has been done in recent years to understand Down Syndrome more, there is
still so many questions that must be answered in order to gain a better understanding.


Courtney, A. P. (2013). Down syndrome. Magill’S Medical Guide (Online Edition),

Newton, R. W., Puri, S., & Marder, L. (2015). Down Syndrome : Current Perspectives. London [England]:

Mac Keith Press

Havercamp, S. M., Tassé, M. J., Navas, P., Benson, B. A., Allain, D., & Manickam, K. (2017). Exploring

the Weight and Health Status of Adults with Down Syndrome. Journal Of Education And Training

Studies, 5(6), 97-108.

Newton, R. W., Puri, S., & Marder, L. (2015). Down Syndrome : Current Perspectives. London [England]:

Mac Keith Press.


Down Syndrome

Sterling L Holt

Salt Lake Community College