Trisomy

21: The
Story of
Down
Syndrom
e


by Len Leshin, MD, FAAP


Copyright 1997, 2000, 2003. All rights reserved.




A Brief History
The formal story began in 1866, when a physician named John
Langdon Down published an essay in England in which he described a
set of children with common features who were distinct from other
children with mental retardation. Down was superintendent of an
asylum for children with mental retardation in Surrey, England when he
made the first distinction between children who were cretins (later to
be found to have hypothyroidism) and what he referred to as
"Mongoloids."


Down based this unfortunate name on his notion that these children
looked like people from Mongolia, who were thought then to have an
arrested development. This ethnic insult came under fire in the early
1960s from Asian genetic researchers, and the term was dropped from
scientific use. Instead, the condition became called "Down's
syndrome." In the 1970s, an American revision of scientific terms
changed it simply to "Down syndrome," while it still is called "Down's"
in the UK and some places in Europe.


In the first part of the twentieth century, there was much speculation of
the cause of Down syndrome. The first people to speculate that it
might be due to chromosomal abnormalities were Waardenburg and
Bleyer in the 1930s. But it wasn't until 1959 that Jerome Lejeune and
Patricia Jacobs, working independently, first determined the cause to
be trisomy (triplication) of the 21st chromosome. Cases of Down
syndrome due to translocation and mosaicism (see definitions of these
below) were described over the next three years.

The Chromosomes
Chromosomes are thread-like structures composed of DNA and other
proteins. They are present in every cell of the body and carry the
genetic information needed for that cell to develop. Genes, which are
units of information, are "encoded" in the DNA. Human cells normally
have 46 chromosomes which can be arranged in 23 pairs. Of these 23,
22 are alike in males and females; these are called the "autosomes."
The 23rd pair are the sex chromosomes ('X' and 'Y'). Each member of
a pair of chromosomes carries the same information, in that the same
genes are in the same spots on the chromosome. However, variations
of that gene ("alleles") may be present. (Example: the genetic
information for eye color is a "gene;" the variations for blue, green, etc.
are the "alleles.")
Human cells divide in two ways. The first is ordinary cell division
("mitosis"), by which the body grows. In this method, one cell
becomes two cells which have the exact same number and type of
chromosomes as the parent cell. The second method of cell division
occurs in the ovaries and testicles ("meiosis") and consists of one cell
splitting into two, with the resulting cells having half the number of
chromosomes of the parent cell. So, normal eggs and sperm cells only
have 23 chromosomes instead of 46.

This is what a normal
set of chromosomes
looks like. Note the 22
evenly paired
chromosomes plus the
sex chromosomes. The
XX means that this
person is a female.
The test in which blood
or skin samples are
checked for the number
and type of
chromosomes is called
a karyotype, and the
results look like this
picture.

Many errors can occur during cell division. In meiosis, the pairs of
chromosomes are supposed to split up and go to different spots in the
dividing cell; this event is called "disjunction." However, occasionally
one pair doesn't divide, and the whole pair goes to one spot. This
means that in the resulting cells, one will have 24 chromosomes and
the other will have 22 chromosomes. This accident is called
"nondisjunction." If a sperm or egg with an abnormal number of
chromosomes merges with a normal mate, the resulting fertilized egg
will have an abnormal number of chromosomes. In Down syndrome,
95% of all cases are caused by this event: one cell has two 21st
chromosomes instead of one, so the resulting fertilized egg has three
21st chromosomes. Hence the scientific name, trisomy 21. Recent
research has shown that in these cases, approximately 90% of the
abnormal cells are the eggs. The cause of the nondisjunction error isn't
known, but there is definitely connection with maternal age. Research
is currently aimed at trying to determine the cause and timing of the
nondisjunction event.
Here's the
karyotype
of a
male with
trisomy 21:




Three to four percent of all cases of trisomy 21 are due
to Robertsonian Translocation. In this case, two breaks occur in
separate chromosomes, usually the 14th and 21st chromosomes.
There is rearrangement of the genetic material so that some of the
14th chromosome is replaced by extra 21st chromosome. So while the
number of chromosomes remain normal, there is a triplication of the
21st chromosome material. Some of these children may only have
triplication of part of the 21st chromosome instead of the whole
chromosome, which is called a partial trisomy 21. Translocations
resulting in trisomy 21 may be inherited, so it's important to check the
chromosomes of the parents in these cases to see if either may be a
"carrier."
The remainder of cases of trisomy 21 are due to mosaicism. These
people have a mixture of cell lines, some of which have a normal set of
chromosomes and others which have trisomy 21. In cellular
mosaicism, the mixture is seen in different cells of the same type. In
tissue mosaicism, one set of cells, such as all blood cells, may have
normal chromosomes, and another type, such as all skin cells, may
have trisomy 21.

The 21st Chromosome and Down Syndrome
The chromosomes are holders of the genes, those bits of DNA that
direct the production of a wide array of materials the body needs. This
direction by the gene is called the gene's "expression." In trisomy 21,
the presence of an extra set of genes leads to overexpression of the
involved genes, leading to increased production of certain products.
For most genes, their overexpression has little effect due to the body's
regulating mechanisms of genes and their products. But the genes that
cause Down syndrome appear to be exceptions.
Which genes are involved? That's been the question researchers have
asked ever since the third 21st chromosome was found. From years of
research, one popular theory stated that only a small portion of the
21st chromosome actually needed to be triplicated to get the effects
seen in Down syndrome; this was called the Down Syndrome Critical
Region. However, this region is not one small isolated spot, but most
likely several areas that are not necessarily side by side. The 21st
chromosome may actually hold 200 to 250 genes (being the smallest
chromosome in the body in terms of total number of genes); but it's
estimated that only a small percentage of those may eventually be
involved in producing the features of Down syndrome. Right now, the
question of which genes do what is highly speculative. However, there
are some suspects.
Genes that may have input into Down syndrome include:
Superoxide Dismutase (SOD1)-- overexpression may cause
premature aging and decreased function of the immune
system; its role in Senile Dementia of the Alzheimer's type or
decreased cognition is still speculative
COL6A1 -- overexpression may be the cause of heart defects
ETS2 -- overexpression may be the cause of skeletal
abnormalities
CAF1A -- overexpression may be detrimental to DNA
synthesis
Cystathione Beta Synthase (CBS) -- overexpression may
disrupt metabolism and DNA repair
DYRK -- overexpression may be the cause of mental
retardation
CRYA1 -- overexpression may be the cause of cataracts
GART -- overexpression may disrupt DNA synthesis and repair
IFNAR -- the gene for expression of Interferon, overexpression
may interfere with the immune system as well as other organ
systems
Other genes that are also suspects
include APP, GLUR5, S100B, TAM, PFKL, and a few others. Again, it
is important to note that no gene has yet been fully linked to any
feature associated with Down syndrome.
One of the more notable aspects of Down syndrome is the wide variety
of features and characteristics of people with trisomy 21: There is a
wide range of mental retardation and developmental delay noted
among children with Down syndrome. Some babies are born with heart
defects and others aren't. Some children have associated illnesses
such as epilepsy, hypothyroidism or celiac disease, and others don't.
The first possible reason is the difference in the genes that are
triplicated. As I mentioned above, genes can come in different
alternate forms, called "alleles." The effect of overexpression of genes
may depend on which allele is present in the person with trisomy 21.
The second reason that might be involved is called "penetrance." If
one allele causes a condition to be present in some people but not
others, that is called "variable penetrance," and that appears to be
what happens with trisomy 21: the alleles don't do the same thing to
every person who has it. Both reasons may be why there is such
variation in children and adults with Down syndrome.

Toward the Next Century
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 second-most heavily mapped human chromosome.
Research is focusing on trying to identify genes and their effects when
overexpressed.
However, it would be a mistake to assume that the clinical features of
Down syndrome are only due to a handful of genes being
overexpressed. You can think of the overexpressed gene products
interacting with a number of normal gene products, each product
individualized by the person's unique genetic makeup, and thus being
thrown "out of genetic balance." This would then make the person
more susceptible to other genetic and environmental insults, leading to
the features, diseases and conditions associated with Down syndrome.
It is this complex arrangement that scientists will be addressing in the
second century of Down syndrome research.


Related links:
Dr. Langdon Down's original paper: Observations on an Ethnic
Classification of Idiots
(ethnically incorrect but historically interesting)
Risk and Recurrence of DS, by Dr. Paul Benke (includes a
more detailed discussion of translocation)
My essay on Mosaic Down Syndrome

References:
1. Coleman, Mary and Rogers, PT. Medical Care in Down
Syndrome: A Preventative Medicine Approach. Marcel Dekker,
Inc, NY, 1992.
2. Korenberg, JR et al. Down syndrome phenotypes: The
consequences of chromosomal imbalance. Proc. Natl. Acad.
Sci. USA, 91: 4997-5001, 1994.
3. Patterson, D. The integrated map of human chromosome 21.
In Etiology and Pathogenesis of Down Syndrome, Wiley-Liss,
1995, p 43-55.
4. Hernandez D and Fisher EMC. Down syndrome genetics:
unravelling a multifactorial disorder. Hum. mol. Genet., 5:
1411-1416, 1996.
5. Shapiro, BL. Whither Down syndrome critical regions? Hum
Genet 99: 421-423, 1997.