Pathophysiology of Down Syndrome

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What is Trisomy 21?

Trisomy 21 is when there are three copies of the 21st chromosome instead of the expected two. This results in what is commonly known as Down Syndrome. The terminology of Trisomy 21 and Down Syndrome is commonly used interchangeably however in a biological context, there is a difference. Trisomy 21 occurs at the level of cell division where the expected cellular replication processes results in an unexpected amount of chromosomes and the process of this occurrence is called nondisjunction.

There are three types of trisomies that results in Down Syndrome. They are: Trisomy 21 or free trisomy, Mosaicism, and Translocation or Robertsonian translocation. The processes of each of these types of Trisomy originate differently. Some trisomies originate from the egg, sperm or zygote. To have a full understanding of how this occurs, requires a review of Grade 10 biology (for our purposes, we will cover the basics and not go into extreme detail of cellular replication and embryotic development, doing so would be to explain major concepts presented in biology 101).

Pathophysiology of Trisomy 21 Resulting in Down Syndrome

What Are Chromosomes?

The human body is made up of many cells. Cells are the basic building blocks of living things. Human cells are circular in structure and are analogous to an egg. If eggs were human cells, the whites would be called the cytoplasm and the yolk would be called the nucleus or “brain of the cell”. The nucleus is what contains genetic material in the form of chromosomes. Chromosomes themselves are small and made up of a threadlike structure that is called chromatin. The chromatin can be further examined into a double helix structure called deoxyribonucleic acid, or simply DNA. DNA is made up of nucleic acids and proteins. The arrangement of these acids and proteins form sequences and it is what makes DNA unique. Each sequence of acids and proteins make up a code that tells a cell how to look, function, and replicate. Each sequence or code is referred to as a gene and a strand of DNA has many genes in it. As you can see in the photo below, this explanation is simplistic however, provides a good visual of what is being discussed.

Chromosomes; Adapted from National Human Genome Research Institute https://www.genome.gov/18016863/a-brief-guide-to-genomics/

Every microorganism, plant, and animal have chromosomes and each one has a different amount of chromosomes. For example, dogs have 78 chromosomes and a plant has 24 chromosomes (National Human Genome Research Institute, 2015. Chromosomes. Retrieved March 17, 2017 from https://www.genome.gov/26524120/chromosomes-fact-sheet). Humans in general have 46 chromosomes in every cell, except for the reproductive cells (gametes) which have 23 chromosomes.

All Cells Undergo Cellular Replication

All cells in the human body must be able to replicate in order to replace old and damaged cells (there are some cells that do not undergo replication or unlikely to, such as brain cells, but for our purposes we will assume that all cells do). All cells in the human body except for the sex cells (gametes) replicate by a process called mitosis. In mitosis, the original cell or the parent cell, replicates to produce two cells called daughter cells. These daughter cells are exact copies of the parent cell.

In contrast, gametes are produced by a process of meiosis (the stem cells of gametes begin with mitosis just like every cell but in order for the cells to mature, they undergo meiosis). Meiosis happens in two stages. The first stage is meiosis I where the parent cell splits into two daughter cells that have half the amount of chromosomes. The chromosomes are still paired to resemble an “><” structure. Then in meiosis II, each daughter cell splits into two more cells, called the granddaughter cells. The granddaughter cells contain chromatids “>” and “<” , for a total of four granddaughter cells.

In summary, mitosis is the replication and division of body cells and meiosis is the division of the sex cells. Further, Trisomy 21 is a result of somatic (body) chromosomes (chromosomes 1-22) and not the sex-determining chromosomes (X, Y). Below is a diagram of typical meiosis and mitosis represented first by the chromosome number and then followed by the chromatid number.

Meiosis and Mitosis compared by chromosome number first, then by chromatid number. Adapted from OpenStax http://cnx.org/contents/[email protected]/Human-Biology-Chapter-134-Meio

Armed with the basic knowledge of cellular replication, seeing how Trisomy 21 occurs will be easier to understand. It is important to note that up until now, we have been looking at cellular replication within a single person’s body. Further, mitosis occurs in any cell within the human body and meiosis occurs in the sexual reproductive organs or gonads which are the ovaries in females and testes in males. This means that everything discussed thus far, has occurred before the process of fertilization between an egg and a sperm.

Did You Know?

If you were curious to know what cells do not undergo mitosis or are unlikely to, they are: brain cells, nerve cells, muscle cells both skeletal and smooth muscles, and lens cells. Liver cells replicate rarely when stimulated and make scar tissue at the place of injury. Not to confuse you but red blood cells undergo a different process of replication called erythropoiesis. Erythropoiesis occurs in the bone marrow and further to this, mature red blood cells don’t have any chromosomes!

Recall that the process of meiosis occurs in the ovaries of females and in the testes of males. When meiosis occurs in the ovaries, it is to create a mature egg or ovum. Take note that it is a single egg that matures at a time because follicle development (the process of the ovary creating a mature ovum) occurs in a cycle in accordance to an individual female’s menstruation cycle.  Further, a female is born with more than the amount of cells that are required to create an egg from puberty to menopause. The process of creating a mature ovum is called oogenesis (not a typo).

In contrast, when meiosis occurs in the testes, it is to create mature sperm. Unlike females, males are not born with all the sperm cells they will require in life and the creation of sperm in males occurs lifelong, starting at puberty. The creation of sperm is not restricted by a cycle of fluctuating hormones as it is in females. The process of creating mature sperm is called spermatogenesis.

The process of meiosis in females and males are similar with one exception. In oogenesis, out of the four granddaughter cells that are produced, only one of the four will become a mature ovum. In spermatogenesis, out of the four granddaughter cells that are produced, all four will become mature sperm (even though we are speaking about male sperm and spermatogenesis, the term granddaughter cells in science is in reference to the product of cells in the process of meiosis and not in reference to the sex of the person where genesis of cells are occurring).

Mitosis and Meiosis of spermatogenesis and oogenesis .
Adapted from: Scanlon, V.C. & Sanders, T. (2010). Essentials of anatomy and physiology (6th ed.). Philadelphia, US: F.A. Davis Company. ProQuest ebrary, Retrieved on March 27, 2017. P: 487-487.

What Does Meisois and Mitosis Have To Do With Trisomy 21?

Trisomy 21 or Free Trisomy

95% of all Down Syndrome comes from Trisomy 21 or free trisomy. This is where non-typical cellular division occurs in either the egg or sperm, in which 90% of cases originates from the egg (Lashley, F. (2006). Essentials of Clinical Genetics in Nursing Practice. Springer Publishing Company LLC. Retrieved March 27, 2017, from http://www.mylibrary.com?ID=95797). This type of trisomy 21 is not inheritable.

In the figure below shows nondisjunction of sperm undergoing spermatogenesis in meiosis I and meiosis II, respectively.

Nondisjunction in meiosis I and II, respectively; of spermatogenesis.
Adapted from: Scanlon, V.C. & Sanders, T. (2010). Essentials of anatomy and physiology (6th ed.). Philadelphia, US: F.A. Davis Company. ProQuest ebrary, Retrieved on March 27, 2017. P: 487-487

As you can see, whether the nondisjunction occurs in either meiosis I or II, the end result is the same with four granddaughter cells, two containing 22 chromosomes and two containing 24 chromosomes. The sperm that goes on to fertilize an ovum that has the typical 23 chromosomes will form a zygote (the cell containing chromosomes both from the egg and sperm once they are united). The sperm with 22 chromosomes will form a zygote with 45 chromosomes in total and is called monosomy because one of the chromosomes will be unpaired. The sperm with 24 chromosomes will form a zygote with 47 chromosomes in total and is called trisomy because one of the chromosomes will have three copies instead of a two. If the trisomy occurs on the 21st chromosome of the zygote, then the zygote will have Trisomy 21 continuously as he/she develops. It is interesting to note that these non-typical sperm are unlikely to fertilize an egg because of their poor motility and fertilization abilities and up to 10% of sperm in normal ejaculate may not be typical. However, if 20% of sperm in ejaculate are not typical, there is an increased likelihood that it will begin to have an effect on fertility (LifeMap Discovery. (n.d.). 5. Anomalies (abnormalities) of Gametogenesis
Review of MEDICAL EMBRYOLOGY Book by BEN PANSKY, Ph.D, M.D. Retreived March 29, 2017 from http://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-5-anomalies-abnormalities-of-gametogenesis).

In the figure below shows nondisjunction of an egg undergoing oogenesis in meiosis I and meiosis II, respectively.

Nondisjunction in meiosis I and II, respectively; of oogenesis.
Adapted from: Scanlon, V.C. & Sanders, T. (2010). Essentials of anatomy and physiology (6th ed.). Philadelphia, US: F.A. Davis Company. ProQuest ebrary, Retrieved on March 27, 2017. P: 487-487

Again, whether the nondisjunction occurs in either meiosis I or II, the end result is the same with four granddaughter cells, two containing 22 chromosomes and two containing 24 chromosomes. The difference is that only one of the four granddaughter cells goes on to become a mature ovum. The mature ovum with 22 chromosomes that becomes fertilized by a sperm with the typical 23 chromosomes in it, will form a zygote with 45 chromosomes in total where one of the chromosomes will be unpaired, resulting in monomy. The mature ovum with 24 chromosomes in it that becomes fertilized by a sperm with the typical 23 chromosomes in it, will form a zygote with 47 chromosomes in total where one of the chromosomes will have three copies of the same chromosome, resulting in trisomy. If the three copies of the same chromosome happen to occur on chromosome 21, then the zygote will have Trisomy 21 continuously as he/she develops.

To review, the most common form of Down Syndrome is Trisomy 21 and occurs in 95% of all cases of Down Syndrome. This form of trisomy occurs during the cellular replication of either the egg or the sperm in meiosis I or II. With this type of trisomy, it is not inheritable and is a chance-like occurrence that happens BEFORE fertilization. Further, 100% of the cells will have Trisomy 21. Next, we will look at the mosaicism type of trisomy 21 and then conclude with translocation or Robertsonian translocation.

(I did not include the following information in order to reduce confusion when discussing nondisjunction of free trisomy. Zygotes that have a total of 45 chromosomes are not typically viable and if these individuals happen to survive birth, they do not live for long because of their many complications. Unlike individuals with Trisomy 21, they do have some medical issues but these issues do not interfere with their ability to lead a happy and fulfilled life.

Mosaicism

Mosaicism is the least common form of Trisomy 21. Current rates state that there is between 1-3% of people with mosaic Trisomy 21 however, one study looked at dysmorphic features alone and concluded that the prevalence rates of mosaicism is slightly higher at 4% (Devlin, L., & Morrison, P. J. (2004). Accuracy of the clinical diagnosis of Down syndrome. The Ulster Medical Journal, 73(1), 4–12. Retrieved March 30, 2017 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475449). The possible explanation for higher prevalence rates are because dsymorphic features of mosaicsim are not always apparent. Further, those who are below normal educationally, mosaicism should be considered when there is no definitive diagnosis (Devlin L. et al. (2004)). Their study also has a higher rate of mosaicism because they included later diagnoses of mosiaicism. Interestingly, a large majority of Down Syndrome is diagnosed at day 7 after birth.

Like free trisomy, mosiacism is a chance event and is not inheritable. However, unlike free trisomy that occurs BEFORE fertilization, mosaicism occurs AFTER fertilization. Due to nondisjunction occurring after fertilization, it means that not all the cells in the body will have Trisomy 21. The percentage of Trisomy 21 will be different in brain cells versus muscle cells versus skins cells, etc. This is the reason why some individuals with mosaicism may not look like they have the commonly recognized features of Down Syndrome (Stanford Children’s Health. (2017). Mosaic Down Syndrome. Retrieved March 30, 2017 from http://www.stanfordchildrens.org/en/topic/default?id=mosaic-down-syndrome-90-P02133). Current studies examining the health of those with mosiacism show that the percentage of mosaicism in an individual is not an accurate predictor of health outcomes (Ibid). In other words, a lesser percentage of mosaicism does not equate to a better health outcome. This make sense because the percentages of affected cells are different in the varying tissues and it is not known how much of which tissue is affected. Further, this is related to the stage at which the nondisjuction occurred after fertilization. The sooner nondisjunction occurs, the more percentage of cells will have trisomy, the later the nondisjunction occurs, the less percentage of cells will have trisomy.

As you can see in the picture below, the zygote seen in mosaicism begins being typical like any other zygote that has 46 chromosomes. It is a chance event for whatever reason that is unknown, that triggers nondisjunction leading to some cells dividing typically and other not dividing typically. Despite the origin of this type of trisomy being different from free trisomy and translocation, the characteristics seen in Down Syndrome are nonetheless the same.

Nondisjunction in Mosaicism.
Adapted from Stanford Children’s Health. (2017). Mosaicism. Retrieved March 30, 2017 fromhttp://www.stanfordchildrens.org/en/topic/default?id=mosaicism-90-P02132

Translocation or Robertsonian Translocation

Unlike the previous two types of Trisomy 21 that were discussed, Translocation or Robertsonian Translocation is strikingly different in origin as this type is inheritable whereas the previous were not. As this is inheritable, either the mother or father is a carrier and thus translocation occurs prior to fertilization. This is to say that it happens prior to meiosis of the gametes in either spermatogenesis in males or oogenesis in females. (It occurs in the germ or stem cells of the gametes prior to meiosis). Translocation occurs at a rate of 5% (Lashley, F. (2006)).

Translocated Cells Present in the Carrier’s Germ cells of the gamete prior to meiosis

Someone who is a carrier is called a balanced translocation carrier. A balanced translocation carrier has 45 chromosomes instead of 46 chromosomes. You may be asking why does a balanced translocation carrier have 45 chromosomes and is otherwise normal compared to other zygotes that form to have 45 chromosomes and are not viable, further cells in mosiacism that have 45 chromosomes die. How is this possible? To answer this, is to understand how translocation comes about.

All chromosomes have pairs that are the homologous or the same. In translocation a small part of one chromosome gets attached to another part of another chromosome. Five chromosomes of the twenty-three chromosomes in a cell are acrocentric chromosomes, that is they have short arms and have no unique genes (Unique. (2005). Robertsonian Translocations. Retrieved March 30, 2017 from http://www.rarechromo.org/information/other/robertsonian%20translocations%20ftnw.pdf).  They are chromosomes 13, 14, 15, 21, and 22. Translocation happens when the short arms breaks off of two acrocentric chromosomes and are lost. Then the two long arms of the affected acrocentric chromsomes are fused together, creating an extra long chromosome. There are different combinations that can be fused together within the acrocentric chromosomes. The most common that occur is 14 attaching to 21. The fused chromosome is referred to as chromosome 14/21. (The two short arms are lost but does not affect the individual because the genetic material from the lost short arms can be found in the short arms of the other unaffected acrocentric chromosomes). Therefore, a balanced translocation carrier who has 45 chromosomes, their chromosomes can be represented as 14, 14/21, and 21. That is because they are missing one chromosome due to the fusion of 14/21.

The picture below makes this concept clearer. It contrasts the karyotype of a translocation trisomy 21 to a free trisomy 21.

Translocation or Robertsonian Karyotype contrasted to Trisomy 21 or Free Trisomy.
Adapted from New Health Advisior. (2014). Down Syndrome Karotype. Retrieved March 30, 2017 from http://www.newhealthadvisor.com/down-syndrome-karyotype.html
Translocated germ Cells of the gamete Undergo Meiosis

Recall during meiosis that there are four granddaughter cells that are created. When the germ cells of the gamete in either male or female that are balanced translocation carriers undergo meiosis, there are a possibility of six different combinations of gametes that can be present in any of the four granddaughter cells.

Possible six combinations of granddaughter cells after meiosis in a balanced translocation carrier.
Adapted from Knowledge. (n.d.). Genetics. Retrieved March 30, 2017 from http://clinicalgate.com/genetics
Translocated gamete Cells fertilize with a typical 46 chromosomal parent

When a balanced translocation carrier parent’s egg or sperm meets with another parent’s egg or sperm that has 46 chromosomes, a possible six combinations of zygotes can occur.

Zygote combinations of a Balanced Translocation Carrier and Typical 46 Chromosomal Parent.
Adapted from Knowledge. (n.d.). Genetics. Retrieved March 30, 2017 from http://clinicalgate.com/genetics

From these combinations, the “Normal” zygote will go on to have 46 chromosomes, will not be a carrier, and be healthy. The “Translocation carrier” will become another balanced translocation carrier that has 45 chromosomes and will be otherwise healthy or “normal”. The “Monosomy 14”, “Trisomy 14”, and “Monosomy 21” zygotes are sadly not compatible with life and will miscarry (Lashley, F. (2006)). “Translocation Down Syndrome” is one of the most common of the trisomies that are compatible with life and will have some medical issues but otherwise can lead healthy and happy lives.

It is interesting to note that the balanced translocation carrier that is female will have a higher percentage chance of having a child with Down Syndrome, 10-15%, compared to a male balanced translocation carrier who will have a 5-8% chance of having a child with Down Syndrome. This is despite that the processes of having a baby with Down Syndrome is the same in balanced translocation carriers both male and female (Lashley, F. (2006)) and despite that theoretically the chance should be 33% (1 of 3 being 33% as the other 3 zygotes are miscarried naturally). Also, someone can be a balanced translocation carrier and not know it until they are trying to seek out reasons as to why it is difficult for them to conceive. These carriers will have difficulty with fertility and women will have miscarriages. Some key points to remember about balanced translocation carriers are that they are not contagious and that there is no cure for their predisposition. There is no cure because their predisposition is genetic and is present in every single cell of their being. This is only a small part of them as they are otherwise completely like every other typical chromosomal people. This means that they are not limited, for example, they can still donate blood.

How Do the Different Types of Trisomy Affect the Characteristics of Down Syndrome That Are Seen?

As discussed, there are three different ways in which trisomy 21 occurs on a microscopic level. How these different genes are displayed is in the syndrome that is called Down Syndrome. In no way, does the different types of trisomy 21 affect the characteristics of Down Syndrome. All three types of individuals with Trisomy 21 would be impossible to discern from each other unless a karyotype is done. As to why does some individuals with Down Syndrome have more characteristics or more health issues compared to others with Down Syndrome that seem to be otherwise completely “normal” despite their chromosomal number? Despite the advances in science, it does not know why despite identical physiologic processes that some  people with Down Syndrome are more severe than others. Or the flip-side, science does not know why despite identical physiologic processes that some people with Down Syndrome are less severe than others.

There is a cultural bias that stems from longer than thirty years ago where people with Down Syndrome were treated poorly, institutionalized and/or had medical care withheld from them, resulting in short life expectancies or failure to thrive. This cultural bias is very recent in our history since the discovery of Down Syndrome. When these individuals are treated well, integrated and become a part of a welcoming society, and have access to medical treatment and care; they thrive for a long time. Today’s life expectancy of someone with Down Syndrome is up to 60-70 years old. Their medical complications are manageable and are similar to medical complications that other people have. It is true that they are more likely to have certain complications however, these complications are not devastating and dire. Further, they do not cause depression or chronic pain in these individuals. People with Down Syndrome are happy and do not suffer. One may be surprised to know that there is actually a waiting list in Alberta, Canada, where people are waiting to adopt babies and children with Down Syndrome. To learn more about Down Syndrome from a medical perspective that is respectful of individuals with Down Syndrome and current of today’s changing 21st century medical and cultural view , please visit my New Parent’s Handbook and my other blog posts.

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