Down syndrome

  Down syndrome was first described in 1866. The cause of Down syndrome (trisomy 21) was discovered in 1959. Down syndrome is relatively well known, with distinctive characteristics such as mental retardation, distinguishing facial features, and other traits. In the United States, Down syndrome occurs in 1 in 800 live births, and approximately 6000 children are born with Down syndrome each year. About 85% of infants with Down syndrome survive 1 year, and 50% of people with Down syndrome live longer than 50 years.

The Genetics of Down Syndrome – Trisomy 21

Down syndrome is a genetic disorder caused by extra genetic material (DNA) (ie, presence of an extra 21st chromosome). Chromosomes, which are microscopic thread-like structures that are present in every cell of the body except red blood cells, carry genes. Genes are necessary for development. Human cells normally have 46 chromosomes that can be arranged in 23 pairs. One set of 23 chromosomes comes from the mother (egg cell or ovum) and the other half of the 23 pairs comes from the father (sperm cell).

Trisomy 21

In Down syndrome, 95% of all cases are caused by either the sperm or the egg cell having 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 time the abnormal cells are the eggs. The cause of the extra chromosome isn't known, but there is definitely connection with the mother's age.

Robertsonian translocation and partial trisomy 21

A different kind of genetic error occurs in 3-4% of cases of Down syndrome. In this case, the genetic material (genes carried on chromosomes) is rearranged so that some of the 13th, 14th, or 15th chromosome is replaced by an extra copy of genetic material from the 21st chromosome. The overall number of chromosomes remains normal (46 chromosomes in 23 pairs), but there are 3 copies of the 21st chromosome material. Sometimes the extra genetic material only comes from part of the long arm of the 21st chromosome (21q), and this is called partial trisomy 21.

Mosaicism and trisomy 21

Mosaicism causes the remaining cases of Down syndrome. In these cases, people have a mixture of cells (cell lines). Some cells have a normal set of chromosomes, and other cells 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 Effects of Trisomy 21 – Symptoms of Down Syndrome

In trisomy 21, there is extra genetic material from chromosome 21. This extra material means that there are more genes expressed than normal. For most genes, this overexpression has little effect because the body regulates genes and their products. But the genes that cause Down syndrome appear to be exceptions.

Scientists have been trying to determine exactly which genes are involved in Down syndrome ever since the third 21st chromosome (trisomy 21) was found. Current research has led to a theory that only certain areas of chromosome 21 need to be tripled to get the effect of Down syndrome. These regions are called the Down syndrome critical region. Exactly which genes cause Down syndrome when tripled is not known, but some genes are suspected.

Genes that may have input into Down syndrome include:

• SOD1 (superoxide dismutase 1 gene) overexpression may cause premature aging and decreased function of the immune system.
  
• COL6A1 (alpha-1 collagen VI gene) overexpression may be the cause of heart defects.
  
• ETS2 (ETS2 oncogene) overexpression may be the cause of skeletal abnormalities.
  
• CAF1A (chromatin assembly factor 1, p60 subunit) overexpression may cause problems with DNA synthesis.
  
• CBS (cystathione beta synthase) overexpression may disrupt metabolism and DNA repair.
  
• DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) overexpression may be the cause of mental retardation.
  
• CRYA1 (alpha-1 crystallin) overexpression may be the cause of cataracts.
  
• GART (glycinamide ribonucleotide synthetase) overexpression may disrupt DNA synthesis and repair.
  
• IFNAR (interferon alpha receptor) overexpression may interfere with the immune system as well as other organ systems.

Remember that no gene has yet been fully linked to any feature associated with Down syndrome.

Figuring out which genes may be associated with Down syndrome is difficult because, although there are certain characteristics associated with Down syndrome, people with Down syndrome have a wide variety of features and a wide range of mental retardation and developmental delay is possible. Some babies are born with heart defects and others aren't. Some children have associated illnesses such as hypothyroidism, and others don't. There are some possible explanations for this variability.

Genes come in different versions (alleles). For example, one allele for eye color produces blue eyes and one allele produces brown eyes. The variety of features in Down syndrome may be related to which version (allele) of a gene is present in triplicate. Also, some alleles cause a condition in some people but not in others, which is called reduced or incomplete penetrance. Reduced penetrance appears to occur with trisomy 21: the extra alleles don't do the same thing to every person who has them. Both the type of allele and the penetrance of the allele may be why there is such variation in children and adults with Down syndrome.

Down Syndrome Treatment

There is no specific treatment for Down syndrome. Early intervention programs, such as physical therapy, occupational therapy, and speech therapy, are helpful. Special education and training is offered in most communities for mentally handicapped children. Because the risk of vision problems, hearing loss, infection, and hypothyroidism (low thyroid hormone) is increased, screening and treatment may be necessary.

Timely surgeries for cardiac and gastrointestinal anomalies are necessary to prevent serious complications. Digitalis and diuretics are usually needed for the medical management of cardiac anomalies along with prophylaxis for subacute bacterial endocarditis.