Down syndrome pathophysiology
|
Down syndrome Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Down syndrome pathophysiology On the Web |
|
American Roentgen Ray Society Images of Down syndrome pathophysiology |
|
Risk calculators and risk factors for Down syndrome pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Genetics
Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or part (such as due to translocations). The effects of the extra copy vary greatly among individuals, depending on the extent of the extra copy, genetic background, environmental factors, and random chance. Down syndrome occurs in all human populations, and analogous effects have been found in other species such as chimpanzees[1] and mice. Recently, researchers have created transgenic mice with most of human chromosome 21 (in addition to the normal mouse chromosomes).[2] The extra chromosomal material can come about in several distinct ways. A typical human karyotype is designated as 46,XX or 46,XY, indicating 46 chromosomes with an XX arrangement typical of females and 46 chromosomes with an XY arrangement typical of males.[3]
Trisomy 21
Trisomy 21 (47,XX,+21) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 21; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo now has 47 chromosomes, with three copies of chromosome 21. Trisomy 21 is the cause of approximately 95% of observed Down syndromes, with 88% coming from nondisjunction in the maternal gamete and 8% coming from nondisjunction in the paternal gamete.[4]
Mosaicism
Trisomy 21 is caused prior to conception, and all cells in the body are affected. However, when some of the cells in the body are normal and other cells have trisomy 21, it is called Mosaic Down syndrome (46,XX/47,XX,+21).[5] This can occur in one of two ways: A nondisjunction event during an early cell division in a normal embryo leads to a fraction of the cells with trisomy 21; or a Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement. There is considerable variability in the fraction of trisomy 21, both as a whole and among tissues. This is the cause of 1–2% of the observed Down syndromes.[4]
Robertsonian translocation
The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation. In this case, the long arm of chromosome 21 is attached to another chromosome, often chromosome 14 (45,XX, t(14;21q)) or itself (called an isochromosome, 45,XX, t(21q;21q)). Normal disjunctions leading to gametes have a significant chance of creating a gamete with an extra chromosome 21. Translocation Down syndrome is often referred to as familial Down syndrome. It is the cause of 2–3% of observed cases of Down syndrome.[4] It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.
Duplication of a portion of chromosome 21
Rarely, a region of chromosome 21 will undergo a duplication event. This will lead to extra copies of some, but not all, of the genes on chromosome 21 (46,XX, dup(21q)).[6] If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics. This cause is very rare and no rate estimates are available.
References
- ↑ McClure HM, Belden KH, Pieper WA, Jacobson CB. Autosomal trisomy in a chimpanzee: resemblance to Down's syndrome. Science. 1969 5 September;165(897):1010–2. PMID 4240970
- ↑ "Down's syndrome recreated in mice". BBC News. 2005-09-22. Retrieved 2006-06-14.
- ↑ For a description of human karyotype see Mittleman, A. (editor) (1995). "An International System for Human Cytogenetic Nomeclature". Retrieved 2006-06-04.
- ↑ 4.0 4.1 4.2 "Down syndrome occurrence rates (NIH)". Retrieved 2006-06-02.
- ↑ Mosaic Down syndrome on the Web
- ↑ Petersen MB, Tranebjaerg L, McCormick MK, Michelsen N, Mikkelsen M, Antonarakis SE. Clinical, cytogenetic, and molecular genetic characterization of two unrelated patients with different duplications of 21q. Am J Med Genet Suppl. 1990;7:104-9. PMID 2149934