In fact, the cause of DS remained unknown for nearly years following Down's work. Then, in the s, researchers finally determined the source of DS: the presence of an extra copy of chromosome 21, a condition often referred to as trisomy Since the discovery of trisomy 21 , scientists have made great strides in Down syndrome research.
For instance, researchers have identified a second although less common cause of the condition that is related to chromosomal translocation , and they have also determined the complete DNA sequence of chromosome In addition, scientists have recently created mouse models of DS that possess chromosomal abnormalities similar to those of human patients.
Through the use of these models, researchers hope not only to gain a better understanding of the specific genes that play the most significant role in DS, but also to eventually develop improved medical treatments for patients with this condition. During the mids, English physician John Langdon Down Figure 1 devoted much of his professional life to children with mental retardation.
Early in his career, Down served as medical superintendent at the Royal Earlswood Asylum for Idiots, a charitable establishment dedicated to educating children with learning disabilities. As chief physician, Down noticed that the children at the facility displayed a range of symptoms, and he sought to develop a clinically useful classification scheme to describe these variations. Thus, in his classic paper of , Down noted that many children with mental retardation shared a common set of facial features, including an upward slant to the eye, a flat nose, and a large tongue.
He also noted that these children were born with their condition i. However, Down was unable to determine the cause of this condition, which we now know as Down syndrome, incorrectly attributing it to tuberculosis in an affected child's parents Down, Figure 2: Primary Down syndrome is caused by the presence of three copies of chromosome As previously mentioned, almost years elapsed between Down's medical description of DS and the discovery of the cause of this condition.
But why was this the case? It was certainly not for lack of trying. Many theories for the cause of DS were put forth in the century after Down's publication.
Some physicians even made the key observation that older mothers had a higher frequency of DS babies, and they postulated that the condition was caused by what they termed "uterine exhaustion. In fact, researchers now realize that older mothers have more babies with DS because the frequency of meiotic nondisjunction increases in women with age. The reason that cytologists in the early twentieth century failed to correctly diagnose DS is almost certainly due to technical limitations.
Chromosome 21 is the smallest human chromosome, and procedures for examining human chromosomes were still being developed during the first part of the century.
Many early cytologists had, in fact, studied chromosomes from DS patients, but none had been able to detect a supernumerary copy of chromosome A breakthrough finally occurred in , when Joe Hin Tjio and Albert Levan described a set of experimental conditions that allowed them to correctly identify the number of human chromosomes as Within three years of the publication of this groundbreaking work, Jerome Lejeune in France and Patricia Jacobs in the United States were able to identify a supernumerary copy of chromosome 21 in karyotypes prepared from DS patients Figure 2.
Because the translocations responsible for DS can be inherited, this form of the disease is sometimes referred to as familial DS. In these cases, a segment of chromosome 21 is transferred to a second chromosome, usually chromosome 14 or When the translocation chromosome with the extra piece of chromosome 21 is inherited together with two normal copies of chromosome 21, DS results.
It is possible, however, for individuals to inherit a translocation of chromosome 21 without acquiring DS. These individuals, known as translocation carriers, have inherited both products of the original translocation event. Hence, translocation carriers have two chromosomal abnormalities, but the abnormalities balance each other.
Robertsonian translocation , for example, is one of many different types of translocation that cytogeneticists have identified in DS patients over the years.
In these cases, Down syndrome is caused by a translocation of chromosomes 15 and 21 Figure 3 , in which the long arms of two acrocentric chromosomes are translocated to produce a single long chromosome, leaving a short one that fails to segregate, thus reducing the overall chromosome number.
The identification of particular translocation defects responsible for DS has been greatly facilitated by the development of banding techniques that allow cytogeneticists to distinguish different breakpoints in chromosomes. From the many karyotypes that cytogeneticists have assembled from DS patients, we now understand that even partial trisomies of chromosome 21 can cause DS. In fact, scientists are interested in determining whether there are critical regions of chromosome 21 specifically responsible for the symptoms of DS.
One could argue that the presence of extra copies of chromosome 21 in DS patients is only a correlation between an abnormality and the disease. However, scientists have developed trisomic mouse models that display symptoms of human DS, providing strong evidence that extra copies of chromosome 21 are, indeed, responsible for DS. It is possible to construct mouse models of DS because mouse chromosomes contain several regions that are syntenic with regions on human chromosome Syntenic regions are chromosomal regions in two different species that contain the same linear order of genes.
With mapping of the human and mouse genomes now complete, researchers can identify syntenic regions in mouse and human chromosomes with great precision.
Using some genetic tricks, scientists have induced translocations involving these mouse chromosomes, producing mice that are trisomic for regions suspected to play a role in DS. Note that these are not perfect models, because the trisomic regions contain many mouse genes in addition to those that are syntenic to human chromosome 21 genes.
Additional experiments have tried to identify particularly important genes within this region by transferring smaller segments of the interval on MMU For example, the three mouse models depicted on the right in Figure 4 carry different portions of MMU16, and all display some symptoms of DS. Of the three, the most faithful model of DS is the Ts65Dn mouse, which carries genes that are syntenic with human chromosome This particular mouse demonstrates many of the symptoms of human DS, including altered facial characteristics, memory and learning problems, and age-related changes in the forebrain.
These results are both daunting and promising. On one hand, they suggest that there will be no magic bullet for treating DS, because large numbers of genes are most likely involved in the condition.
On the other hand, the results suggest that mouse models will be useful in developing treatments for the many DS patients around the world. Despite the questions raised by ongoing genetic studies of DS, one thing remains certain: Researchers have come a long way in their understanding of this condition since John Langdon Down first described its symptoms in Moreover, thanks to areas of synteny between the human and mouse genomes, researchers have also been able to use mouse models to pinpoint the specific genes on human chromosome 21 that are most likely involved in producing symptoms of DS.
So after the egg and sperm unite, the resulting cells will also have three copies of chromosome The complete extra copy of chromosome 21 is in all of the person's cells—or a complete trisomy. Almost all Down syndrome cases result from complete trisomy Not every cell in the body is exactly the same. This is called "mosaicism.
It can also occur early in development when some cells lose an extra chromosome 21 that was present at conception. The symptoms of someone with mosaic trisomy 21 may vary from those of someone with complete trisomy 21 or translocation trisomy 21, depending on how many cells have the extra chromosome. In this type of chromosomal change, only part of an extra copy of chromosome 21 is in the cells. The extra part of the chromosome gets "stuck" to another chromosome and gets transmitted into other cells as the cells divide.
This type of change causes a small number of Down syndrome cases. Other health problems. Children with Down syndrome may have thyroid problems and leukemia. They also tend to have many colds, as well as bronchitis and pneumonia. Your child should get regular medical care and stay up to date on vaccines. Learning problems. These vary widely from child to child. They can be mild, moderate, or severe. But most learning problems are mild to moderate.
Many children are helped with early intervention and special education. Some people claim that giving high-dose vitamins to children with Down syndrome will improve their learning and development problems. No studies have proved that this works. Complications of Down syndrome vary depending on the body organ affected and the severity of the problem. Problems include certain birth defects, learning problems, and facial features. How severe the complications are varies from child to child.
Treatment will also vary depending on the body organ affected and the severity of the problem. There is no reason to believe parents can do anything to cause or prevent Down syndrome in their child. For women who have had one child with Down syndrome, the chance of having another baby with Down syndrome depends on several things.
Age is one factor. Most babies with Down syndrome are born to women younger than This is because women under 35 have more babies than women over Your healthcare provider may refer you to a genetic counselor.
This expert can explain the results of chromosome tests in detail. He or she can talk about risks for future pregnancies and what tests are available to diagnose chromosome problems before a baby is born. Some medical organizations advise that all pregnant women of any age be offered screening for Down syndrome. Talk with your healthcare provider about this prenatal screening test. Children with Down syndrome can usually do most things that any young child can do.
They can walk, talk, dress themselves, and be toilet trained. But they usually do these things at a later age than other children. The exact ages of these development milestones is different for each child. Early intervention programs that begin when a child is a baby can help the child reach his or her potential.
A child with Down syndrome can go to school. Special programs beginning in the preschool years help children with Down syndrome develop skills as fully as possible.
They can also enter a regular classroom. Many children will learn to read and write. They can take part in childhood activities, both at school and in their community. Your child may need physical, occupational, and speech therapy to help with his or her development.
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