Down syndrome, also known as trisomy 21, is the most common identifiable form of mental retardation caused caused by an extra copy of chromosome 21 in the patient's set of chromosomes (karyotype). Nevertheless, this condition is also associated with other karyotypes as described bellow. Besides moderate to severe mental retardation, developmental abnormalities and other congenital conditions are also observed, such as heart disease (30-50% of patients), intestinal malformation (10-12%), visual or hearing impairment (50%), immunological deficiencies, and augmented predisposition to leukaemias and thyroid problems. Other characteristics include a broad short skull, broad hands with short fingers, small ears, small mouth, flattened nasal bridge, and varied degrees of altered (dysmorphic) body features. Down syndrome patients frequently develop Alzheimer's disease in early life stages. The average life expectancy of a Down's syndrome patient is about the age of 35.
In addition to trisomy 21, Down syndrome may be caused by either one of the two following types of Robertsonian translocations (breakages in chromosomes with the migration of one segment to another chromosome). First, the inheritance of two normal copies of chromosome 21 plus a translocation to chromosome 14 of an extra long arm of chromosome 21, symbolized by the formula t{21q14q}. And second, an isochromosomal translocation 21 (i.e. translocation between two complementary copies of the same chromosome), where one of the two chromosomes 21 has equal arms and the other presents an extra long arm fused to it t{21q21q}. Either of these two karyotypes is classified as a pseudotrisomy (i.e. a false trisomy). Another example of karyotype variation in Down syndrome is mosaicism, in which only certain cells have trisomy 21.
Trisomy 21 accounts for about 92.5% of the cases of Down syndrome, Robertsonian and isochromosomal translocations are implied in 4.8% of cases and the remaining 2.75% are caused by heterogenous factors, including mosaicism, double trisomies and reciprocal translocations.
Robertsonian translocations are common in acrocentric chromosomes, because their centromeres are very close to one end, dividing the chromosome in two unequal arms: one short and the other long. Common Robertsonian translocations may occur in chromosomes 13, 14, 15, 21, and 22 during meiosis. Since they usually are balanced translocations, individuals do not present disease (normal phenotype), but their offspring may inherit either a normal phenotype or a missing or extra long arm of an acrocentric chromosome, thus manifesting disease.
Records about the existence of Down syndrome date back to the Saxons, from whom we have anecdotal reports of the disorder. The first medical report of the condition was not published, however, until 1866. In that year, the British physician, J. Langdon Down (1828-1896) wrote a paper that described children with the disorder as having physical characteristics that appeared to him to be similar to certain Oriental features. Edouard Séguin's (1812-1880) text published in the same year, also carried a detailed discussion of the disorder, then known as mongolism. Although Down's classification is not considered valid anymore, the disease is currently known as Down syndrome
Credit for the most complete early description of the disorder is usually given to two British physicians, John Fraser and Arthur Mitchell. Fraser and Mitchell (19th Century) discussed 62 cases of the condition, known to them as kalmuc idiocy, and suggested that it occurred as the result of bad health conditions during pregnancy. They found no evidence to suggest that the disorder was hereditary.
Over the next half century, however, the condition was proved to be hereditary. In 1932 the Dutch physician P. J. Waardenberg suspected that it occurred because of a chromosomal abnormality. That hypothesis was later confirmed in 1959 by the French pediatrician Jerome Lejeune. and his colleagues, who found that patients with Down's syndrome have 47 autosomal chromosomes instead of the usual 46. The 47th chromosome is a third copy of chromosome 21. Because of this characteristic, Down's syndrome is also known as trisomy 21.
Scientists believe that Down syndrome is a contiguous gene syndrome because most of its phenotypic features (i.e. the set of visible features and symptoms) suggest the involvement of more than a single chromosomal region. Although the initial predictions have estimated that chromosome 21 would contain between 800 and 1000 genes, reports from the Human Genome Project and Celera, in May of 2000, have shown that it contains 225 genes and 59 pseudogenes. Present data indicates that 41% of the identified genes in chromosome 21 have no functional attributes.
Although scientists have yet to identify the genes involved in the phenotype of Down's syndrome, possible gene candidates are as follows: morphogens, ligands (i.e. molecules that activate cell membrane receptors) and their receptors, transcription regulators, and others, whose products may be either over expressed or poorly expressed. Pathophysiological studies of gene dosage effects of these and other gene candidates will be possible from now on, thanks to the recent sequencing and cataloguing of genes present in chromosome 21. Researchers are also working on the mapping of DNA regions (loci) that may play a role in specific syndrome traits.
In recent years, research and educational organizations have been very successful in helping the general public to understand more about the nature and diversity of Down syndrome patients and to see that many of them can lead long and productive lives.
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