Down Syndrome: The Effects of an Extra 21st Chromosome

Down syndrome, also known as trisomy 21, is one of the most prevalent genetic syndromes in the U.S., affecting 1 out of every 1200 people. [1] Six thousand babies with Down syndrome are born every year.[2] While most people are familiar with the outer physical traits of Down syndrome, such as small stature, upward eye slant, and low muscle tone, the inner traits associated with Down syndrome are far less known. Yet,  most people do not know the effects that Down syndrome can have on the body throughout one’s lifetime. 

Down syndrome is a genetic condition that results in three copies of the 21st chromosome.[3] This is why, scientifically, Down syndrome is referred to as Trisomy 21. This third copy can cause dysregulation throughout the immune system, resulting in higher inflammation throughout the body.[4] This can lead to disease development and poor vaccine responsiveness.[5] As a result, during the Covid-19 pandemic, Down syndrome should have been considered “high risk” due to these risk factors associated with a third 21st chromosome. There needs to be more wide-spread awareness of Down Syndrome’s effects on the immune system and disease development. 

It is important to be familiar with the 21st chromosome to understand why Down syndrome can lead to increased risk of disease and poor vaccine response.  The 21st chromosome contains genes that activate interferons, which are part of the immune system’s inflammatory factors that are used to fight off viruses and bacteria.[6] People with Down syndrome have an extra copy of the 21st chromosome. With this, they will have overexpression of these inflammatory genes and interferons. This leads to an elevated baseline inflammation level, which causes chronic inflammation and a dysregulated immune system.[7] This higher chronic inflammation level in people with Down syndrome underlies all other disease development associated with the syndrome.[8]

Down syndrome is associated with the development of a multitude of diseases common with high levels of inflammation, like higher rates of cancer, heart disease, higher rates of autoimmune disease, epilepsy, and Alzheimer’s. Alzheimer’s disease is one of the most prevalent diseases associated with Down syndrome — by the age of 40, almost all people with Down syndrome will have developed plaque in their brain, which is a key feature associated with Alzheimer’s disease.[9] Moreover, two-thirds of those with Down syndrome will have fully developed Alzheimer’s disease by age 60.[10]

The increased risk for Alzheimer’s is in part a result of the chronic inflammation. Immune cells are present everywhere in the body, including the brain. When the immune cells in the brain are constantly activated like they are in those with Down syndrome, a type of toxic protein called beta-amyloid 42 is released in higher concentration and accumulates in the brain. This protein causes plaques to form and disrupt the space between neurons, which is the main characteristic of Alzheimer’s disease development.[11]  To combat this devastating development, researchers are currently trying to better understand the etiology of Alzheimer’s disease in people with Down syndrome through conducting cohort studies and clinical trials.[12] The hope of these researchers is to delay the onset of Alzheimer’s disease in people with Down syndrome or prevent it altogether.[13]

Another pertinent example of Down syndrome’s effects on health is the Covid-19 pandemic and how a third copy of the 21st chromosome can impact vaccine responsiveness. In a study containing 8 million adults from the United Kingdom, people with Down Syndrome had a 19.4% increased chance of dying from Covid-19 compared to the control group.[14] The researchers estimated a 10-fold increased risk of death from Covid-19 in people with Down syndrome, in addition to a 4-fold increased risk of hospitalization from Covid-19.[15] While these results are not causal, researchers believe that this increased risk might be the result of the constant immune activation associated with Down syndrome; making the immune system unable to fight off threats like Covid-19.[16]

People with Down syndrome also have a poorer vaccine response than the general population. They often have a beneficial initial response to vaccines where their immune system creates antibodies at first. However, this immunity wanes quickly due to a lower number of memory B-cells, which are the cells that retain the immune response to a particular pathogen.[17] The Covid-19 vaccine provided immunity to those with Down syndrome at first, but their immunity waned more quickly than other groups. With this, it is important that people with Down syndrome are considered for early Covid-19 booster shots to combat their weakened vaccine response.

Dr. Christina Gavegnano, an Assistant Professor of Human Health at Emory University and Director of the Gavegnano Group, says that people with Down syndrome have poor vaccine responsiveness, in part due to the elevated level of chronic inflammation in their bodies. Dr. Gavegnano and other have demonstrated that this chronic inflammation causes “immune exhaustion”, which causes people with Down syndrome to be unable to mount a durable vaccine response compared to individuals with exhausted and inflamed immune systems. Dr. Gavegnano is currently in the beginning stages of researching ways to halt the inflammatory response right before a person with Down syndrome is vaccinated in an attempt to allow their immune system to recover and work properly in order to create a long-lasting response. Dr. Gavegnano notes that people with Down syndrome were not identified as a “high-risk group” early on in the Covid-19 pandemic, despite the aforementioned dysregulation of their immune systems. This placed them at high risk for infection, without early access to vaccination. Dr. Gavegnano says that there must be more awareness of the health risks of this group in the future to provide equity and awareness for people with Down syndrome.

Down syndrome does not receive the attention it deserves. Given its association with immune system dysregulation, chronic inflammation, chronic disease development, and poor vaccine response, Down syndrome should be more widely recognized as a high-risk condition, especially during the Covid-19 pandemic. With more knowledge, awareness, and research, the physical effects of Down syndrome can be reduced.

References:

[1] National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. (2020). “Data and Statistics on Down Syndrome”. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/birthdefects/downsyndrome/data.html 

[2] National Down Syndrome Society. (2022).  “What is Down Syndrome?”. National Down Syndrome Society. https://www.ndss.org/about-down-syndrome/down-syndrome/

[3] National Down Syndrome Society. (2022).  “What is Down Syndrome?”. National Down Syndrome Society. https://www.ndss.org/about-down-syndrome/down-syndrome/

[4] Wilcock, D.M., & Griffin, W.S.T. (2013). Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation 10, 864. https://doi.org/10.1186/1742-2094-10-84

[5] Wilcock, D.M., & Griffin, W.S.T. (2013). Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation 10, 864. https://doi.org/10.1186/1742-2094-10-84

[6] Sullivan, K. D., Lewis, H. C., Hill, A. A., Pandey, A., Jackson, L. P., Cabral, J. M., Smith, K. P., Liggett, L. A., Gomez, E. B., Galbraith, M. D., DeGregori, J., & Espinosa, J. M. (2016). Trisomy 21 consistently activates the interferon response. eLife, 5, e16220. https://doi.org/10.7554/eLife.16220

[7] Wilcock, D.M., & Griffin, W.S.T. (2013). Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation 10, 864. https://doi.org/10.1186/1742-2094-10-84

[8] Sullivan, K. D., Lewis, H. C., Hill, A. A., Pandey, A., Jackson, L. P., Cabral, J. M., Smith, K. P., Liggett, L. A., Gomez, E. B., Galbraith, M. D., DeGregori, J., & Espinosa, J. M. (2016). Trisomy 21 consistently activates the interferon response. eLife, 5, e16220. https://doi.org/10.7554/eLife.16220

[9] Wiseman, Frances. (2021). “Understanding neuroinflammation in Down syndrome dementia”. Alzheimer’s Society. https://www.alzheimers.org.uk/research/our-research/research-projects/understanding-neuroinflammation-down-syndrome-dementia

[10] Wiseman, Frances. (2021). “Understanding neuroinflammation in Down syndrome dementia”. Alzheimer’s Society. https://www.alzheimers.org.uk/research/our-research/research-projects/understanding-neuroinflammation-down-syndrome-dementia

[11] Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018). Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & dementia (New York, N. Y.), 4, 575—590. https://doi.org/10.1016/j.trci.2018.06.014

[12] Ryan, L. & Silverberg, N. (2021). “Teaming up to expand Alzheimer’s and Down syndrome research”. National Institute on Aging. https://www.nia.nih.gov/research/blog/2021/06/teaming-expand-alzheimers-and-down-syndrome-research.

[13] Ryan, L. & Silverberg, N. (2021). “Teaming up to expand Alzheimer’s and Down syndrome research”. National Institute on Aging. https://www.nia.nih.gov/research/blog/2021/06/teaming-expand-alzheimers-and-down-syndrome-research.

[14] Clift, A.K., Coupland C.A.C., Keogh, R.H., & Hemingway, H. (2020). COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study of 8 Million Adults. Annals of Internal Medicine. https://doi.org/10.7326/M20-4986

[15] Clift, A.K., Coupland C.A.C., Keogh, R.H., & Hemingway, H. (2020). COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study of 8 Million Adults. Annals of Internal Medicine. https://doi.org/10.7326/M20-4986

[16] Wadman, Meredith. (2020). “COVID-19 is 10 times deadlier for people with Down syndrome, raising calls for early vaccination”. Science. https://www.science.org/content/article/covid-19-10-times-deadlier-people-down-syndrome-raising-calls-early-vaccination

[17] Valentini, D. et al. (2022). Safety and Long-Term Immunogenicity of BNT162b2 Vaccine in Individuals with Down Syndrome. Journal of Clinical Medicine 11, no. 3: 694. https://doi.org/10.3390/jcm11030694