Down Syndrome

What Causes Down Syndrome?

How Does Down Syndrome Affect a Child?

Medical Problems Associated with Down Syndrome
Prenatal Screening and Diagnosis
Screening tests include:

Diagnostic tests include:

Integrated Ultrasound and Biochemical Screening for Trisomy 21 Using Fetal Nuchal Translucency, Absent Fetal Masal Bone, Free b-hCG and PAPP-A at 11 to 14 Weeks At 11 to 14 weeks' gestation, the method of combining maternal age, fetal nuchal translucency thickness, and maternal levels of free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) will detect trisomy 21 90% of the time, with a false-positive rate of 5%. A study of 100 trisomy 21 pregnancies, compared with 400 normal pregnancies, confirms that an absent nasal bone occurs in approximately 70% of affected fetuses, independent of the other markers. Adding this observation to the previous tests increases the detection rate to 90.5% with a reduction in false-positives to 0.5%; maintaining a false-positive rate of 5% increases the detection rate to 97%.
Cicero S, Bindra R, Rembouskos G, et al. Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency, absent fetal masal bone, free b-hCG and PAPP-A at 11 to 14 weeks. Prenat Diagn 2003;23:306-310.


Translocation Down Syndrome.
All individuals with Down syndrome have three copies of chromosome 21. About 95% have three freestanding copies of chromosome 21. Approximately 1% of individuals are mosaic with some normal cells. Approximately 4% of Down syndrome individuals have a translocation involving chromosome 21. Translocations account for 9% of the children with Down syndrome born to mothers younger than 30 yr of age. Half the translocations arise de novo in the affected individual,
whereas half are inherited from a translocation carrier parent. Parents who are carriers of a translocation involving chromosome 21 produce three types of viable offspring: normal phenotype and karyotype, a phenotypically normal translocation carrier, and the translocation trisomy 21. The majority of translocations that give rise to Down syndrome are fusions at the centromere between chromosomes 13, 14, 15, or 21, for example, t(13q,15q) or t(21q,21q). The phenotype in translocation Down syndrome is not distinguishable from regular trisomy 21 Down syndrome ( Chromosome studies must be performed on every Down syndrome individual. If a translocation is identified, parental studies must be performed to identify normal individuals who are translocation carriers with a high recurrence risk for a chromosomally abnormal child and who may also have other family members at risk.

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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.

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 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

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Down syndrome was first described by John L. H Down. There is a history of this syndrome. Down distinguished the heterogenous nature of mental retardation and described The Mongolian type of Idiocy k/a Downs syndrome. He first tried to classified mental retardation on the basis of the physical appearances and suggested that various forms of mental retardation represent the regression to earlier racial forms. Later on he abandoned his idea and classified mental retardation into 3types depending on the etiology: Congenital, Developmental and Accidental