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Instructions: Read the article below and answer the following questions
May 2009
Trisomy 21: The Story of Down Syndrome by Len Leshin, MD, FAAP
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.
Chromosomes Errors
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.
Three to four percent of all cases of trisomy 21 are due to 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 remains 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.
Toward the Next Century
You can think of the over-expressed 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.
Answer the following questions in the space provided
1a) What is a non-disjunction chromosomal error?
b) How many people with Downs Syndrome have this type of chromosomal error?
2. Explain what is meant by a chromosomal translocation error.
3. What is mosaicism?
4. Describe the size of chromosome 21.
5. In the last paragraph, describe the relevance of over-expressed genes