Down's Syndrome

©istockphoto/AndreyVolodin

Down's syndrome is a genetic disorder that leads to intellectual disability, a characteristic facial appearance, and poor muscle tone in infancy. The degree of intellectual disability varies, but it is usually mild to moderate. It is a lifelong condition, present from birth and linked with an increased incidence of heart defects, leukemia and other abnormalities. About half of adults with Down's Syndrome develop Alzheimer's disease by the age of 50, a brain disorder that results in a gradual loss of memory, judgment, and ability to function.

> Down's Syndrome

> Understanding the syndrome: genetics

> Prevention and treatment

> Future research

Down's Syndrome

Down’s Syndrome is one of the most common birth defects, affecting about one in every 800 live births.¹ It is also the most common genetic cause of intellectual disabilities. The likelihood of having a baby with the condition increases with the mother’s age, from about 1 in 1,250 for a woman who gets pregnant at the age of 25, to about 1 in 100 for a woman who gets pregnant at 40.² Researchers have found that older mothers are more likely to have a baby with Down's Syndrome because the frequency of meiotic nondisjunction, where meosis does not occur correctly, increases with age.³

In meiotic nondisjunction the two halves of the chromosome do not separate fully during meiosis, leading to an imbalance of chromosomes and causing an extra chromosome. It is this extra genetic material that can be responsible for birth defects or miscarriages.

An increased understanding of Down's Syndrome and the new treatments it has brought have meant that the average life expectancy of someone with Down's Syndrome has improved from 9-12 years in the 1950s to at least 50–60 years today.⁴ Although there is no cure for the condition, there are treatments that can help patients to lead an active and independent life. Moreover, some studies suggest that it could become possible to treat a fetus in the womb in order to delay cognitive disorders and enhance motor function.

Understanding the syndrome: genetics

Down's Syndrome is usually caused by the duplication of all or part of chromosome 21, known as trisomy 21 (Ts21). It can also be caused by gene translocation, when a fragment of a gene changes its location from one region of the chrosomose to another. To investigate how Ts21 is translated into the clinical aspects of the disease, researchers have used mouse models since the 1970s. The most studied mouse model of Down's Syndrome is “Ts65Dn”, which has an extra copy of a region of chromosome 16. This region includes genes from the Down syndrome critical region (DSCR), a small segment of human chromosome 21, which contains the genes believed to be responsible for the majority of the abnormalities found in Down's Syndrome.

One of the major goals in Down's Syndrome basic research is to understand how the imbalance of certain genes translates into the specific clinical aspects of the disorder. Researchers may want to know which extra genes on chromosome 21 contribute to heart defects or leukemia, for example, and therefore use mice that have small triplicate gene segments.⁵ Scientists have created mouse models of Down's Syndrome with chromosomal abnormalities similar to those of humans to unravel the specific genes that play a significant role in Down's Syndrome, contributing to the development of medical treatments for Down's Syndrome patients.⁶

Prevention and treatment

Clinical research has made it possible to develop tests that can predict whether a child will be born with Down's Syndrome. There are two available methods, amniocentesis and chronic villus sampling. Both involve counting the chromosomes in the fetus, however they work in slightly different ways and can be performed at different stages of pregnancy. Amniocentisis involves taking a small sample of the amniotic fluid that surrounds the baby for analysis and can be carried out between 14-16 weeks. Chronic villus sampling involves taking a small sample of the tissue from the placenta for diagnosis and can be carried out bewtween 10-12 weeks. Both of these procedures are invasive and carry an average 0.5% risk of miscarriage.

There has been a push to develop noninvasive methods that can detect the syndrome early⁷ and have a reduced risk for the mother and foetus, but many of the studies are preliminary. In 2008, a group of researches at Stanford University have developed a method that only requires a sample of blood from the mother⁸, although it hasn’t been fully tested yet. Efforts have also been made to develop treatments that can prevent some aspects of the disease from developing after the child is born (increasing the cognitive, motor and sense abilities and reducing the chances of heart diseases and Alzheimer ’s disease, for example) . Treatments for adults with the syndrome are under development too.

One of the paths researchers have explored is the link between oxidative stress and Down's Syndrome patients, after a study in 1998 found high levels of oxidative stress in patients with the syndrome.⁹ Recently, researchers at Tufts Medical Centre in Boston found that 414 genes in the amniotic fluid in Down's Syndrome pregnancies are expressed differently than in those who don’t have the disorder.¹⁰ Moreover, the genes found are linked with the ability of cells to deal with oxidative stress, a process in which cells are damaged due to an abnormal level of reactive oxygen compounds. It is believed that these damaged cells can lead to abnormal brain growth, one of the symptoms of Down's Syndrome. Therefore the researchers are looking at treatments that alter the expression of these genes as they could “repair” the damaged cells.

Another target for prenatal intervention are the brain cells that regulate the development of neurons by releasing certain proteins.¹¹ These glial cells, produce fewer proteins in Down's Syndrome patients than in normal people. Scientists therefore believe that by adding segments of the proteins in Down's Syndrome patients, they could offer protection from neuron degeneration. Researchers at the US National Institutes of Health tested this hypothesis by injecting segments of the two proteins (NAP and SAL) into the blood stream of mice pregnant with Ts21 pups, and found that neurons were protected from degeneration, with the pups showing development improvements.¹²

Researchers have found that improving the activation of neurons in the hippocampus that respond to the neurotransmitter noradenaline helps to improve cognition in engineered "Down's Syndrome" mice. In Down's Syndrome the cells which would normally release noradrenaline are damaged, but when a drug is used to replace the lost noradrenaline some of the learning function of this brain region can be restored.¹³

Future research

In recent decades scientists have made important advancements towards understanding the genetic causes of Down syndrome. However, there is still a lot of work to do in order to gain a full understanding, and research continues to search for better treatments and therapies for patients.

Some of this research involves the development of better mouse models and the testing of drug treatments that could enhance cognition and intellectual abilities. Research also aims to develop less invasive and more accurate methods for prenatal testing.

The US National Institutes of Health have developed a research plan for the next 10 years that includes exploring genetic and environmental factors that determine cognitive function; links between human and mouse cognitive studies; the impact of early intervention on motor and cognitive development, and improvement in the availability of animal models to study the syndrome.¹⁴

According to the Down Syndrome Research and Treatment Foundation, the research should focus on exploring the notion that the cognitive deficit in Down's Synodrome is caused by an extra copy of a specific gene(s). Treatments should be directed at reducing the expression of a specific gene(s) or the actions of the proteins they produce to prevent or reverse the deficit.¹⁵ DSRTF believes that the most promising and cutting-edge research involves understanding the underlying genetic, biological and neurological processes in the syndrome and how they relate to one another to cause cognitive problems.

June 2010

References

1.Roizen, N & Patterson, D (2003) “Down’s syndrome” The Lancet 361, 1281 DOI DOI:10.1016/S0140-6736(03)12987-X

2. U.S. National Institutes of Health, “Down syndrome” http://www.nichd.nih.gov/health/topics/Down_Syndrome.cfm (Accessed 29 April 2010)

3. O'Connor, C (2008) “Trisomy 21 causes Down syndrome” Nature Education http://www.nature.com/scitable/topicpage/Trisomy-21-Causes-Down-Syndrome-318 (Accessed 29 April 2010)

4. Morris, Kelly (2008) “Shift in priorities for Down's syndrome research needed” The Lancet 372 964 79 DOI:10.1016/S0140-6736(08)61321-5

5. Sietske, Heyn (2010) “The Down syndrome mouse - A historical perspective & what the future may hold” in http://dsresearch.stanford.edu/community/archive_issue_02.html (Accessed 29 April 2010)

6. Wiseman, Frances et.al. (2009) “Down syndrome—recent progress and future prospects” Human Molecular Genetics Advances 18 DOI 10.1093/hmg/ddp010

7. Dennis Lo, et.al (2007) “Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection” in Nature Medicine 13, 218 DOI:10.1038/nm1530

8. Fan HC et al (2008) “Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood” in Proceedings of the National Academy of Sciences 105 16266 DOI:10.1073_pnas.0808319105

9. Jovanovic SV, Clements D, MacLeod K (1998) “Biomarkers of oxidative research stress are significantly elevated in Down syndrome” Free Radic Biol Med. 25 1044

10. Bianchi, Diana, et.al (2009) “Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses” Proceedings of the National Academy of Sciences 106 9425 DOI: 10.1073/pnas.0903909106

11. Busciglio, Jorge et al “Protect Normal and Down's Syndrome Cortical Neurons from Oxidative Damage and Apoptosis” Current Pharmaceutical Design, 13 1091 DOI: 10.2174/138161207780618957

12. Toso, Laura et al (2008) “Prevention of Developmental Delays in a Down Syndrome Mouse Model” Obstetrics & Gynecology 112 1242 DOI: 10.1097/AOG.0b013e31818c91dc

13. Salehi, A. et. al (2009) “Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome” Sci Transl Med DOI:10.1126/scitranslmed.3000258

14. National Institute of Health “Research Plan on Down Syndrome” (2007) at http://www.nih.gov/news/health/jan2008/nichd-22.htm (Accessed 10 May 2010)

15. Down syndrome Research and Treatment Foundation, at http://www.dsrtf.org/research-faq.htm (Accessed 10 May 2010)

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Down's Syndrome

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