Introduction

Trisomy 21, often known as "Down Syndrome" after a British physician John Langdon Down who published an essay in 1866 about children with characteristic features and mental retardation, is the most common chromosomal abnormality which affects 1 in 700-800 births in the U.S. Some people might have heard of it as "mongolism" but this term is no longer in scientific use because of implication of negative ethnic bias.

Etiology

In order to understand this disease, it is essential to have basic knowledge of human cell structure and how the cells divide.

DNA and Chromosomes

As we all know, DNA is the ultimate source of genetic inheritance. In spite of such important and complex function, the molecular structure of DNA is quite simple; it is a long chain of sugar(deoxyribose) and phosphate group and attached to each sugar molecule is one of four types of nitrogenous bases. Two chains of DNA twist around each other forming the familiar shape of double helix. The sequence of bases dictates the type of protein the cell synthesizes, and ultimately, passes down the unique set of genes of the living form.
Within the cell nucleus, the twisted chain of DNA is wound around histone proteins. This long string of DNA and protein is now called chromatin, which is the largely uncoiled chromosomes, and this thread-like structure is dispersed throughout cell nucleus, some of them inactive and condensed (heterochromatin), some of them active, synthesizing RNA (euchromatin).

Cell Division and Chromosomes
There are two types of cell division; most cells divide and grow through mitosis, and only the cells in testes and ovaries are produced by meiosis. For both processes, cells prepare for the division by replicating its DNA. At this point, the chromosome consists of two identical strands, or chromatids, joined at the center.

Each of these chromosomes have a pair that has identical structure and they are called homologous chromosomes. As you can see in the following picture, karyotype is a process in which homologous chromosomes are lined up and numbered from largest to smallest.

Human cells uniquely contain 46 chromosomes, or 23 pairs. During meiosis, one member of the homologous pair is pulled to one side and the other member to the other side, producing two daughter cells with 23 chromosomes in each. The two daughter cells go through second meiotic division in which two strands, or chromatids, of each chromosomes are now separated. The resulting four daughter cells still contain total of 23 chromosomes, and when conception occurs by joining of sperm and egg, the zygote will have total of 46 chromosomes again.

Something Goes Wrong
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.

What about the other 5%?
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.

Trisomy 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. At this point, the question of exactly which genes do what remains speculative.

Signs and Symptoms

Children with Down syndrome have a characteristic facial appearance; most frequently they include upward-slanting eyes, broad and flat nose, protruding tongue, short and thick neck, hypotonic extremities, low-set ears, and a simian crease on the palms.

This is Mary Abigail. You can see her photos and read her stories by clicking this link.
All children with Down syndrome have some degree of intellectual impairment, ranging from low normal intelligence to severe cognitive impairment. They are also prone to upper respiratory infections, and many children have congenital heart defects. Other associated health problems include hypothyroidism and increased incidence of leukemia.
The life expectancy for persons with Down syndrome has improved in recent years but still remains lower than that of general population. Over 80% of those afflicted survive to age 30 years and beyond. Down syndrome is associated with earlier aging.

Prevention

Recent research has shown that in nondisjunction 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, especially for women over 35 years of age. Research is currently aimed at trying to determine the cause and timing of the nondisjunction event.

Links For More Information

Genetic Fact Sheets This webpage contains detailed information on Down syndrome with useful statistics
CDC Genomics and Disease Prevention Here's an interesting study on Down syndrome and maternal smoking
Trisomy 21 Online This is a helpful online community, especially if you have a child with Down syndrome
Medline