Down Syndrome: Trisomy 21 – Causes, Symptoms and Risks

The most common type of chromosomal abnormality is an aneuploidy, a chromosome mutation in which the number of chromosomes in an individual differs from that of the wild type organism. When an individual has an extra or partial extra copy of chromosome 21, Down syndrome occurs. Down syndrome is one of the most commonly occurring chromosomal abnormalities, occurring in approximately one in every 700 babies born in the United States, although the risk increases with maternal aging (1). Down Syndrome is characterized by craniofacial abnormalities, cognitive disabilities, and decreased muscle tone. Physical characteristics include upward slanted eyes, small stature, and a flat nasal bridge. Some people with Down Syndrome are also affected by certain variations of phenotypes, such as atrioventricular septal defects in the heart, acute megakaryoblastic leukemia, and acute lymphoblastic leukemia, as well as Alzheimer's and Hirschsprung Disease (2). Many studies and research have been done to analyze the effects of Down syndrome, as well as its etiology. Advances in science and medicine have allowed scientist to discover that there are three chromosomal changes that lead to Down syndrome: complete trisomy 21, mosaicism, and translocation. Throughout this essay, I will discuss the three causes of Down syndrome and the prevalence of these causes, as well as the effect maternal aging has on the occurrence of this chromosomal abnormality.

A common type of aneuploidy in humans is a trisomy, an abnormality in which there are three copies of a particular chromosome. In most cases, Down syndrome occurs because of the trisomy of chromosome 21 due to nondisjunction, a spontaneous error that occurs during cell division. Nondisjunction resulting in Down syndrome occurs when the homologous chromosomes or sister chromatids of chromosome 21 fail to separate during anaphase I or II of meiosis, resulting in an extra copy of the chromosome. While meiosis normally results in an egg or sperm with 23 chromosomes, nondisjunction causes the resulting sex cells to have 24 chromosomes instead. When the egg and sperm unite during fertilization, the zygote will have three copies of chromosome 21. This extra chromosome is replicated in every body cell as the embryo develops, resulting in a complete trisomy in which every cell contains an extra copy of the chromosome. Nondisjunction is the cause of approximately 95% cases of down syndrome (3).

Roughly 1-2% of Down syndrome cases occur due to mosaic trisomy 21, also known as Mosaicism. Mosaicism occurs when nondisjunction takes place during mitosis, usually in early cell division following fertilization. When this occurs, there is a mixture of cells containing 46 chromosomes and cells containing 47. When nondisjunction occurs during mitosis, only the cells following the nondisjunction will contain the aneuploidy, so while many of the body's cells have an extra copy of chromosome 21, not all of them do. Research has shown that generally those with mosaic trisomy 21 have fewer symptoms than those with complete or translocation trisomy 21, but these symptoms can vary based on the number of cells throughout the body containing the extra chromosome (4).

Another chromosomal change known as Robertsonian translocation is the cause of Down syndrome in about 3-4% of cases. A Robertsonian translocation, named after geneticist W.R.B. Robertson, is an unusual arrangement of chromosomes caused when two chromosomes join together (6). Chromosomes with acrocentric centromeres break apart into a large and short arm. When the long arms, containing most of the genetic material, of two chromosomes fuse together, a Robertsonian translocation occurs. In the case of Down syndrome, the long arm chromosome 21 breaks off and attaches to another chromosome. The extra genetic material from chromosome 21 causes the characteristics of Down Syndrome to the same extent of trisomy 21 due to nondisjunction. Most commonly, the broken off chromosome 21 will attach to chromosome 14, though sometimes it attaches to chromosomes 13, 15, or 22 (5). Very rarely, two different copies of chromosome 21 will attach to each other. Those with translocation Down syndrome could possibly have inherited the condition from an unaffected parent due to the parent being a Robertsonian translocation carrier with a balanced translocation. When the long arms of two chromosomes fuse, the short arms join to form a reciprocal product that is typically lost within a few cell divisions after translocation occurs, leaving behind only 45 total chromosomes. Because the parent still has two copies of each chromosome, they will not show any symptoms, but can possibly pass down the translocated chromosome resulting in a child with an unbalanced translocation and three copies of the chromosome who would then exhibit Down syndrome. A Robertsonian translocation carrier with two copies of chromosome 21 attached will always produce sperm or eggs with unbalanced chromosomes, having either two copies of a chromosome or no copies (6). Most cases of translocation Down syndrome do not result from the parent being a Robertsonian carrier, but instead from an unbalanced Robertsonian translocation occurring spontaneously even though both of the parents have normal chromosomes. Translocation Down syndrome is the only inherited form of Down syndrome, while the others occur spontaneously. Any time someone is discovered to have translocation Down syndrome, the chromosomes should be studied to see whether or not the translocation was inherited and evaluate further risks of passing down the Robertsonian translocation to more children.

The only etiologic factor that is known to increases one's risk of having a child with Down syndrome is an increase in maternal age. Before the trisomy of chromosome 21 was identified, many scientist had already begun to recognize that Down syndrome was more prevalent in older women, especially those over age 35. Although the association between children born with Down syndrome and advancing maternal age has been recognized, scientist have speculated about the exact cause of this phenomenon for decades and, to this day, it is still unknown. While nondisjunction can occur in sperm cells, over 95% of complete trisomy 21 cases are caused due to nondisjunction within an egg, causing some scientist believe that meiosis becomes more error prone as a result of aging(7). While men are continuously producing new sperm, women are born with all of the eggs they will have, meaning the eggs will age as the woman does, possibly making these errors more prevalent. Oocytes go through periods of meiotic arrest in late prophase, continuing meiosis only at menstruation. Tetrads in prophase of meiosis must be maintained for decades, making them weaker and more at risk for errors as they age (4). The cause of increased errors in meiosis with age is still not fully understood, although studies using animal models have discovered several agents acting before or around the time of chromosomal segregation that are associated with the maternal age effect. A series of experiments that monitored the effects of aging in Drosophila oocytes showed an increase in age-related aneuploidies in situations where cohesin was disturbed. Cohesin is a multi protein complex that acts to hold sister chromatids together before cell division and maintain the connection of homologous chromosomes. The study demonstrated the effects that deficient cohesin had on homologs and suggested that the age-related decline in cohesin affects chromosomal segregation (8). Other studies have shown that decreased strength of spindle assembly checkpoints is another possible candidate for causing aneuploidies. Spindle assembly checkpoints are responsible for preventing anaphase from occurring until all of the chromosomes are properly attached to the spindle. Various experiments indicated that in both human and mice oocytes the transcripts of several loci associated with spindle assembly checkpoints were reduced as the cell aged. While this association remains true, a more recent study showed that no difference between the timing of the beginning of anaphase could be determined between young or old mice, so conformation of the relationship between spindle assembly checkpoints and maternal aging is still needed (8). Although many studies have focused on the agents above, several other factors have been linked to increased cases of nondisjunction. While the etiology of meiotic errors causing nondisjunction is still unknown, discovering that there multiple underlying mechanisms for the maternal age effect allows scientist to look at the phenomenon with a different perspective.

In humans, trisomy 21 is the most commonly occurring trisomy in which the child survives past infancy; therefore the prevalence of Down syndrome has allowed scientists to perform further research on mechanisms involved in aneuploidies (9). While there is still much research to be done on chromosomal abnormalities, much progress has been made in the last several decades by studying Down syndrome and how it occurs. Though complete trisomy 21 is the cause of almost all occurrences, its etiology is still not very well understood because of the many factors and mechanisms involved. Nondisjunction has been determined to occur during anaphase I or II of meiosis, which allows further research to focus on the mechanisms involved in segregation and recombination of chromosomes. Less common causes of Down syndrome, such as mosaicism and translocation, do not exhibit three complete copies of chromosome 21 but instead has three separate portions of genetic information from chromosome 21 that results in the same phenotypic outcome, although the characteristics expressed in mosaicism can vary. Similar to trisomy 21, mosaicism is also not an inherited abnormality. Translocation is the most well understood because its inheritance pattern is more easily studied, although a translocation is inherited in very few cases. The underlying mechanisms that cause Down syndrome can be studied due to its positive association with maternal aging. The maternal age effect allows scientists to use animal oocyte models to test various hypotheses involving possible contributing factors to nondisjunction. Although there is no single factor that causes Down syndrome or an increase in meiotic errors with age, the various associations proven, along with an expanding knowledge of chromosomal abnormalities, has provided a solid foundation on which to base further research.

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