Tag: Genetic disorder

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Definition
Down syndrome is the most common cause of mental retardation and malformation in a newborn. It occurs because of the presence of an extra chromosome.

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Chromosomes are the units of genetic information that exist within every cell of the body. Twenty-three distinctive pairs, or 46 total chromosomes, are located within the nucleus (central structure) of each cell. When a baby is conceived by the combining of one sperm cell with one egg cell, the baby receives 23 chromosomes from each parent, for a total of 46 chromosomes. Sometimes, an accident in the production of a sperm or egg cell causes that cell to contain 24 chromosomes. This event is referred to as nondisjunction. When this defective cell is involved in the conception of a baby, that baby will have a total of 47 chromosomes. The extra chromosome in Down syndrome is labeled number 21. For this reason, the existence of three such chromosomes is sometimes referred to as Trisomy 21.

In a very rare number of Down syndrome cases (about 1–2%), the original egg and sperm cells are completely normal. The problem occurs sometime shortly after fertilization; during the phase where cells are dividing rapidly. One cell divides abnormally, creating a line of cells with an extra chromosome 21. This form of genetic disorder is called a mosaic. The individual with this type of Down syndrome has two types of cells: those with 46 chromosomes (the normal number), and those with 47 chromosomes (as occurs in Down syndrome). Some researchers have suggested that individuals with this type of mosaic form of Down syndrome have less severe signs and symptoms of the disorder.

Another relatively rare genetic accident which can cause Down syndrome is called translocation. During cell division, the number 21 chromosome somehow breaks. A piece of the 21 chromosome then becomes attached to another chromosome. Each cell still has 46 chromosomes, but the extra piece of chromosome 21 results in the signs and symptoms of Down syndrome. Translocations occur in about 3–4% of cases of Down syndrome.

Down syndrome occurs in about one in every 800–1,000 births. It affects an equal number of boys and girls. Less than 25% of Down syndrome cases occur due to an extra chromosome in the sperm cell. The majority of cases of Down syndrome occur due to an extra chromosome 21 within the egg cell supplied by the mother (nondisjunction). As a woman’s age (maternal age) increases, the risk of having a Down syndrome baby increases significantly. For example, at younger ages, the risk is about one in 4,000. By the time the woman is age 35, the risk increases to one in 400; by age 40 the risk increases to one in 110; and by age 45 the risk becomes one in 35. There is no increased risk of either mosaicism or translocation with increased maternal age.

Causes and Symptoms:-
While Down syndrome is a chromosomal disorder, a baby is usually identified at birth through observation of a set of common physical characteristics. Babies with Down syndrome tend to be overly quiet, less responsive, with weak, floppy muscles. Furthermore, a number of physical signs may be present. These include:

*flat appearing face
*small head
*flat bridge of the nose
*smaller than normal, low-set nose
*small mouth, which causes the tongue to stick out and to appear overly large
*upward slanting eyes
*extra folds of skin located at the inside corner of each eye, near the nose (called epicanthal folds)
*rounded cheeks
*small, misshapen ears
*small, wide hands
*an unusual, deep crease across the center of the palm (called a simian crease)
*a malformed fifth finger
*a wide space between the big and the second toes
*unusual creases on the soles of the feet
*overly-flexible joints (sometimes referred to as being double-jointed)
*ahorter than normal height

Other types of defects often accompany Down syndrome. About 30–50% of all children with Down syndrome are found to have heart defects. A number of different heart defects are common in Down syndrome, including abnormal openings (holes) in the walls that separate the heart’s chambers (atrial septal defect, ventricular septal defect). These result in abnormal patterns of blood flow within the heart. The abnormal blood flow often means that less oxygen is sent into circulation throughout the body. Another heart defect that occurs in Down syndrome is called Tetralogy of Fallot. Tetralogy of Fallot consists of a hole in the heart, along with three other major heart defects.

Malformations of the gastrointestinal tract are present in about 5–7% of children with Down syndrome. The most common malformation is a narrowed, obstructed duodenum (the part of the intestine into which the stomach empties). This disorder, called duodenal atresia, interferes with the baby’s milk or formula leaving the stomach and entering the intestine for digestion. The baby often vomits forcibly after feeding, and cannot gain weight appropriately until the defect is repaired.

Other medical conditions that occur in patients with Down syndrome include an increased chance of developing infections, especially ear infections and pneumonia; certain kidney disorders; thyroid disease (especially low or hypothyroid); hearing loss; vision impairment requiring glasses (corrective lenses); and a 20-times greater chance of developing leukemia (a blood disorder).

Development in a baby and child with Down syndrome occurs at a much slower than normal rate. Because of weak, floppy muscles (hypotonia), babies learn to sit up, crawl, and walk much later than their normal peers. Talking is also quite delayed. The level of mental retardation is considered to be mild-to-moderate in Down syndrome. The actual IQ range of Down syndrome children is quite varied, but the majority of such children are in what is sometimes known as the trainable range. This means that most people with Down syndrome can be trained to do regular self-care tasks, function in a socially appropriate manner in a normal home environment, and even hold simple jobs.

As people with Down syndrome age, they face an increased chance of developing the brain disease called Alzheimer’s (sometimes referred to as dementia or senility). Most people have a six in 100 risk of developing Alzheimer’s, but people with Down syndrome have a 25 in 100 chance of the disease. Alzheimer’s disease causes the brain to shrink and to break down. The number of brain cells decreases, and abnormal deposits and structural arrangements occur. This process results in a loss of brain functioning. People with Alzheimer’s have strikingly faulty memories. Over time, people with Alzheimer’s disease will lapse into an increasingly unresponsive state. Some researchers have shown that even Down syndrome patients who do not appear to have Alzheimer’s disease have the same changes occurring to the structures and cells of their brains.

As people with Down syndrome age, they also have an increased chance of developing a number of other illnesses, including cataracts, thyroid problems, diabetes, and seizure disorders.

Diagnosises:-
Diagnosis is usually suspected at birth, when the characteristic physical signs of Down syndrome are noted. Once this suspicion has been raised, genetic testing (chromosome analysis) can be undertaken in order to verify the presence of the disorder. This testing is usually done on a blood sample, although chromosome analysis can also be done on other types of tissue, including skin. The cells to be studied are prepared in a laboratory. Chemical stain is added to make the characteristics of the cells and the chromosomes stand out. Chemicals are added to prompt the cells to go through normal development, up to the point where the chromosomes are most visible, prior to cell division. At this point, they are examined under a microscope and photographed. The photograph is used to sort the different sizes and shapes of chromosomes into pairs. In most cases of Down syndrome, one extra chromosome 21 will be revealed. The final result of such testing, with the photographed chromosomes paired and organized by shape and size, is called the individual’s karyotype.

Two types of prenatal tests are used to detect Down syndrome in a fetus: screening tests and diagnostic tests. Screening tests estimate the risk that a fetus has DS; diagnostic tests can tell whether the fetus actually has the condition.

Screening tests are cost-effective and easy to perform. But because they can’t give a definitive answer as to whether a baby has DS, these tests are used to help parents decide whether to have more diagnostic tests.

Diagnostic tests are about 99% accurate in detecting Down syndrome and other chromosomal abnormalities. However, because they’re performed inside the uterus, they are associated with a risk of miscarriage and other complications.

For this reason, invasive diagnostic testing previously was generally recommended only for women age 35 or older, those with a family history of genetic defects, or those who’ve had an abnormal result on a screening test.

However, the American College of Obstetrics and Gynecology (ACOG) now recommends that all pregnant women be offered screening with the option for invasive diagnostic testing for Down syndrome, regardless of age.

If you’re unsure about which test, if any, is right for you, your doctor or a genetic counselor can help you sort through the pros and cons of each.

Screening tests include:-
*Nuchal translucency testing. This test, performed between 11 and 14 weeks of pregnancy, uses ultrasound to measure the clear space in the folds of tissue behind a developing baby’s neck. (Babies with DS and other chromosomal abnormalities tend to accumulate fluid there, making the space appear larger.) This measurement, taken together with the mother’s age and the baby’s gestational age, can be used to calculate the odds that the baby has DS. Nuchal translucency testing is usually performed along with a maternal blood test.

*The triple screen or quadruple screen (also called the multiple marker test). These tests measure the quantities of normal substances in the mother’s blood. As the names imply, triple screen tests for three markers and quadruple screen includes one additional marker and is more accurate. These tests are typically offered between 15 and 18 weeks of pregnancy.

*Integrated screen. This uses results from first trimester screening tests (with or without nuchal translucency) and blood tests with second trimester quad screen to come up with the most accurate screening results.

*A genetic ultrasound. A detailed ultrasound is often performed at 18 to 20 weeks in conjunction with the blood tests, and it checks the fetus for some of the physical traits abnormalities associated with Down syndrome.

Diagnostic tests include:-
*Chorionic villus sampling (CVS). CVS involves taking a tiny sample of the placenta, either through the cervix or through a needle inserted in the abdomen. The advantage of this test is that it can be performed during the first trimester, between 8 and 12 weeks. The disadvantage is that it carries a slightly greater risk of miscarriage as compared with amniocentesis and has other complications.

*Amniocentesis. This test, performed between 15 and 20 weeks of pregnancy, involves the removal of a small amount of amniotic fluid through a needle inserted in the abdomen. The cells can then be analyzed for the presence of chromosomal abnormalities. Amniocentesis carries a small risk of complications, such as preterm labor and miscarriage.

*Percutaneous umbilical blood sampling (PUBS). Usually performed after 20 weeks, this test uses a needle to retrieve a small sample of blood from the umbilical cord. It carries risks similar to those associated with amniocentesis.
After a baby is born, if the doctor suspects DS based on the infant’s physical characteristics, a karyotype — a blood or tissue sample stained to show chromosomes grouped by size, number, and shape — can be performed to verify the diagnosis.

Treatment:-
No treatment is available to cure Down syndrome. Treatment is directed at addressing the individual concerns of a particular patient. For example, heart defects will many times require surgical repair, as will duodenal atresia. Many Down syndrome patients will need to wear glasses to correct vision. Patients with hearing impairment benefit from hearing aids.

At one time, most children with Down syndrome did not live past childhood. Many would often become sick from infections. Others would die from their heart problems or other problems they had at birth. Today, most of these health problems can be treated and most children who have it will grow into adulthood.

Medicines can help with infections and surgery can correct heart, stomach, and intestinal problems. If the person gets leukaemia, there are medical treatments that can be very successful. Someone with Down syndrome has a good chance of living to be 50 years old or more.

A new drug, referred to as a “smart drug,” has been receiving some attention in the treatment of Down syndrome patients. This drug, piracetam, has not been proven to increase intellectual ability, despite testimonials that have been receiving attention on television and the Internet. Piracetam has not been approved for use in the United States, although it is being sold via the Internet. The National Down Syndrome Society and the National Down Syndrome Congress do not recommend the use of this drug as of 2001.

While some decades ago, all Down syndrome children were quickly placed into institutions for lifelong care. Research shows very clearly that the best outlook for children with Down syndrome is a normal family life in their own home. This requires careful support and education of the parents and the siblings. It is a life-changing event to learn that a new baby has a permanent condition that will effect essentially all aspects of his or her development. Some community groups exist to help families deal with the emotional effects of this new information, and to help plan for the baby’s future. Schools are required to provide services for children with Down syndrome, sometimes in separate special education classrooms, and sometimes in regular classrooms (this is called mainstreaming or inclusion).

Prognosis:-
The prognosis in Down syndrome is quite variable, depending on the types of complications (heart defects, susceptibility to infections, development of leukemia) of each individual baby. The severity of the retardation can also vary significantly. Without the presence of heart defects, about 90% of children with Down syndrome live into their teens. People with Down syndrome appear to go through the normal physical changes of aging more rapidly, however. The average age of death for an individual with Down syndrome is about 50–55 years.

Still, the prognosis for a baby born with Down syndrome is better than ever before. Because of modern medical treatments, including antibiotics to treat infections and surgery to treat heart defects and duodenal atresia, life expectancy has greatly increased. Community and family support allows people with Down syndrome to have rich, meaningful relationships. Because of educational programs, some people with Down syndrome are able to hold jobs.

Men with Down syndrome appear to be uniformly sterile (meaning that they are unable to have offspring). Women with Down syndrome, however, are fully capable of having babies. About 50% of these babies, however, will also be born with Down syndrome.

Prevention:-
Efforts at prevention of Down syndrome are aimed at genetic counseling of couples who are preparing to have babies. A counselor needs to inform a woman that her risk of having a baby with Down syndrome increases with her increasing age. Two types of testing is available during a pregnancy to determine if the baby being carried has Down syndrome.

Screening tests are used to estimate the chance that an individual woman will have a baby with Down syndrome. At 14–17 weeks of pregnancy, measurements of a substance called AFP (alpha-fetoprotein) can be performed. AFP is normally found circulating in the blood of a pregnant woman, but may be unusually high or low with certain disorders. Carrying a baby with Down syndrome often causes AFP to be lower than normal. This information alone, or along with measurements of two other hormones, is considered along with the mother’s age to calculate the risk of the baby being born with Down syndrome. These results are only predictions, and are only correct about 60% of the time.

The only way to definitively establish (with about 98–99% accuracy) the presence or absence of Down syndrome in a developing baby, is to test tissue from the pregnancy itself. This is usually done either by amniocentesis or chorionic villus sampling (CVS). In amniocentesis, a small amount of the fluid in which the baby is floating is withdrawn with a long, thin needle. In chorionic villus sampling, a tiny tube is inserted into the opening of the uterus to retrieve a small sample of the placenta (the organ that attaches the growing baby to the mother via the umbilical cord, and provides oxygen and nutrition). Both amniocentesis and CVS allow the baby’s own karyotype to be determined. A couple must then decide whether to use this information in order to begin to prepare for the arrival of a baby with Down syndrome, or to terminate the pregnancy.

Once a couple has had one baby with Down syndrome, they are often concerned about the likelihood of future offspring also being born with the disorder. Most research indicates that this chance remains the same as for any woman at a similar age. However, when the baby with Down syndrome has the type that results from a translocation, it is possible that one of the two parents is a carrier of that defect. A carrier “carries” the genetic defect, but does not actually have the disorder. When one parent is a carrier of a translocation, the chance of future offspring having Down syndrome is greatly increased. The specific risk will have to be calculated by a genetic counselor.

Research:-
Main article: Research of Down syndrome-related genes
Down syndrome is “a developmental abnormality characterized by trisomy of human chromosome 21″ (Nelson 619). The extra copy of chromosome-21 leads to an over expression of certain genes located on chromosome-21.

Research by Arron et al shows that some of the phenotypes associated with Down Syndrome can be related to the dysregulation of transcription factors (596), and in particular, NFAT. NFAT is controlled in part by two proteins, DSCR1 and DYRK1A; these genes are located on chromosome-21 (Epstein 582). In people with Down Syndrome, these proteins have 1.5 times greater concentration than normal (Arron et al. 597). The elevated levels of DSCR1 and DYRK1A keep NFAT primarily located in the cytoplasm rather than in the nucleus, preventing NFATc from activating the transcription of target genes and thus the production of certain proteins (Epstein 583).

This dysregulation was discovered by testing in transgenic mice that had segments of their chromosomes duplicated to simulate a human chromosome-21 trisomy (Arron et al. 597). A test involving grip strength showed that the genetically modified mice had a significantly weaker grip, much like the characteristically poor muscle tone of an individual with Down Syndrome (Arron et al. 596). The mice squeezed a probe with a paw and displayed a .2 newton weaker grip (Arron et al. 596). Down syndrome is also characterized by increased socialization. When modified and unmodified mice were observed for social interaction, the modified mice showed as much as 25% more interactions as compared to the unmodified mice (Arron et al. 596).

The genes that may be responsible for the phenotypes associated may be located proximal to 21q22.3. Testing by Olson et al. in transgenic mice show the duplicated genes presumed to cause the phenotypes are not enough to cause the exact features. While the mice had sections of multiple genes duplicated to approximate a human chromosome-21 triplication, they only showed slight craniofacial abnormalities (688-690). The transgenic mice were compared to mice that had no gene duplication by measuring distances on various points on their skeletal structure and comparing them to the normal mice (Olson et al. 687). The exact characteristics of Down Syndrome were not observed, so more genes involved for Down Syndrome phenotypes have to be located elsewhere.

Reeves et al, using 250 clones of chromosome-21 and specific gene markers, were able to map the gene in mutated bacteria. The testing had 99.7% coverage of the gene with 99.9995% accuracy due to multiple redundancies in the mapping techniques. In the study 225 genes were identified (311-313).

The search for major genes that may be involved in Down syndrome symptoms is normally in the region 21q21–21q22.3. However, studies by Reeves et al. show that 41% of the genes on chromosome-21 have no functional purpose, and only 54% of functional genes have a known protein sequence. Functionality of genes was determined by a computer using exon prediction analysis (312). Exon sequence was obtained by the same procedures of the chromosome-21 mapping.

Research has led to an understanding that two genes located on chromosome-21, that code for proteins that control gene regulators, DSCR1 and DYRK1A can be responsible for some of the phenotypes associated with Down Syndrome. DSCR1 and DYRK1A cannot be blamed outright for the symptoms; there are a lot of genes that have no known purpose. Much more research would be needed to produce any appropriate or ethically acceptable treatment options.

Recent use of transgenic mice to study specific genes in the Down syndrome critical region has yielded some results. APP is an Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties. Another gene, ETS2 is Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have “demonstrated that over-expression of ETS2 results in apoptosis. Transgenic mice over-expressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome.”

Vitamin supplements, in particular supplemental antioxidants and folinic acid, have been shown to be ineffective in the treatment of Down syndrome.

Sociological and cultural aspects:-
Advocates for people with Down syndrome point to various factors, such as additional educational support and parental support groups to improve parenting knowledge and skills. There are also strides being made in education, housing, and social settings to create environments which are accessible and supportive to people with Down syndrome. In most developed countries, since the early twentieth century many people with Down syndrome were housed in institutions or colonies and excluded from society. However, since the early 1960s parents and their organizations (such as MENCAP), educators and other professionals have generally advocated a policy of inclusion, bringing people with any form of mental or physical disability into general society as much as possible. In many countries, people with Down syndrome are educated in the normal school system; there are increasingly higher-quality opportunities to move from special (segregated) education to regular education settings.

Despite these changes, the additional support needs of people with Down syndrome can still pose a challenge to parents and families. Although living with family is preferable to institutionalization, people with Down syndrome often encounter patronizing attitudes and discrimination in the wider community.

The first World Down Syndrome Day was held on 21 March 2006. The day and month were chosen to correspond with 21 and trisomy respectively. It was proclaimed by European Down Syndrome Association during their European congress in Palma de Mallorca (febr. 2005). In the United States, the National Down Syndrome Society observes Down Syndrome Month every October as “a forum for dispelling stereotypes, providing accurate information, and raising awareness of the potential of individuals with Down syndrome.” In South Africa, Down Syndrome Awareness Day is held every October 20.[49] Organizations such as Special Olympics Hawaii provide year-round sports training for individuals with intellectual disabilities such as down syndrome.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://www.answers.com/topic/down-syndrome-diagnosis
http://kidshealth.org/parent/medical/genetic/down_syndrome.html
http://www.charliebrewersworld.com/page4.htm
http://en.wikipedia.org/wiki/Down_syndrome

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