HTT & Its CAG Repeats

The scenario:  You are faced with a genetic dilemma. Your maternal grandfather died at age 65 of a known, inherited neurodegenerative disease. The HTT gene, that when

containing extra CAG repeats, encodes this disease. Currently, there is no cure for this disease. Presence of the repeat is easily detected by genetic testing. You have 3 other siblings: a brother who is 30, a brother who is 15, and a sister who is 18. What should one do? What are the basics one should know of the HTT gene and its incurable disease? 

Upon finding out that my maternal grandfather died at the age of 65 of a known, inherited neurodegenerative disease, I would inform my siblings that he died from Huntington’s disease that is caused by CAG expanded repeats in the exon 1 region of the HTT gene. This region encodes for a polyglutamine tract that starts from the N-terminus, which is located 17 residues away (Kraub 2013).

The Huntington Disease and Patient Counseling

The HD is a neuro degenerative genetic disease. It is characterized by lack of coordination and involuntary movements. Cognitive problems appear in later stages of disease and patients’ quality of life deteriorates up to the point where they need 24 hour assistance. Depression is common among people suffering from the disease. 

The Genetic Disorder and Mechanisms of Disease

This genetic defect on chromosome 4 causes excessive CAG repeats. Usually this repeat occurs 10 to 28 times, however those with this defect causes CAG to be repeated 36 to 120 times. (URAC 2013) This disease is characterized by progressive neuronal cell death. It progresses over time becoming fatal which lead to his death. It is a disorder passed down through families in which parts of the brain degenerate. (URAC 2013)

HD is inherited as a dominate trait so those who inherit homozygous HTT have similar signs as with those who are heterozygote for HTT including the symptoms, signs, or age of onset. (Kraub 2013)

Although in most cases the age of onset is 35 to 50, it is inversely correlated with the length of CAG expanded repeats. The CAG repeats bind to translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. These repeats are translated into elongated polyQ stretches (Tobin 2000).

The size of the CAG repeat grows when MID1 binds to protein phosphatase 2A protein complex. This also stimulates the translation of the CAG expansion, protein phosphatase 2A and mammalian target of rapamycin- dependent manner. The MID1 complex may serve as a therapeutic target for the treatment of CAG repeat expansion. (Tobin 2000)

The higher the repeat numbers the lower the ages of onset for individuals. Those with 35 repeats of HTT or fewer do not develop HD. Individuals with 35 to 39 repeats may or may not develop Huntington’s disease. Repeats of 40 to 60 develop into HD when the individual reaches adulthood. In more severe cases, people who have 60 or greater repeats have onset before 20 years of age. (Kraub 2013)

Symptoms of those living with HD show altered energy metabolism in brain and muscle. (Kraub 2013).

Clinical symptoms and Quality of Life

Huntington’s disease causes motor, cognitive, and behavioral dysfunction. Choreatic movements are usually the first sign of Huntington’s disease. These are irregular, unpredictable, purposeless, rapid movements that flow randomly from one body part to another. The first signs also include motor dysfunction of the toes, fingers, and face. Eye movement abnormalities soon follow with slow saccades. (Tobin 2000)

It is relentlessly progressive where death occurs 15-20 years after symptom onset. Juvenile onset includes symptoms such as seizers, and rapidly progressive dementia. (Tobin 2000)

Diagnosis and Treatment

The treatment of HD consists mainly in treating and alleviating the symptoms and trying to preserve the quality of life as long as possible. The goal is to slow down the symptoms and help the person function and live a normal life. Supervision and treatment (such as DOPA blockers which aid in decreasing abnormal behaviors and movements) might be needed since depression and suicide are very common among person with HD. (URAC 2013)

Epidemiology and Prevention

The risk of getting HD from one parent suffering from HD is 50 percent. Inheriting the HTT gene from a parent will guarantee that the child will develop the disease at some point in their lives which will be passed on to their children. (URAC 2013)

Although there is no cure or no way to stop the disease from getting worse, it is crucial for family members to have their DNA tested for HD because as the gene is passed down through family generations, the number of repeats get larger and the risks of developing HD symptoms at a younger age increases. (URAC 2013)

For my brother that is 30 years of age, will develop symptoms in his mid 30s and 40s. This is the most common form of HD which is in adult onset. (URAC 2013)

For my 18 year old brother and 15 year old sister, it will be less likely that they will develop early onset form of HD there are only a small number of cases that begins in childhood or 

adolescence. (URAC 2013)

Once I have informed my siblings of our grandfather’s disease, I would encourage them to get tested and screened for risk of developing HD.

If any of my siblings were to have high risk or have the disease I would encourage them to get supportive counseling after the DNA testing whether or not they are symptomatic.

It is difficult to take the right steps in the pathogenic pathways of HD since there is no cure for the disease, as of yet. There are however, therapeutic interventions that target early steps in a pathogenic chain of events of those with HD. I would make sure that they are well informed and supported throughout the process.

Kraub, Syllibe, Susann Schweiger, Erich Wanker, Stephanie Dorne, Rainer Schneider, Nadine Griesche, Ewa Jastrzebwa, Desiree Rutschow, and Changwei Chen. "Translation of HTT MRNA with Expanded CAG Repeats Is Regulated by the MID1–PP2A Protein Complex." Translation of HTT MRNA with Expanded CAG Repeats Is Regulated by the MID1–PP2A Protein Complex (2013): 1723-2041. Nature. 26 Feb. 2013. Web. 10 Oct. 2013.

Tobin, Allan J., and Ethan R. Signer. "Trends in Cell Biology - Huntington's Disease: The Challenge for Cell Biologists." Huntington's Disease: The Challenge for Cell Biologists 10.12 (2000): 531-36. Trends in Cell Biology - Huntington's Disease: The Challenge for Cell Biologists. Web. 9 Oct. 2013.

URAC. "Huntington's Disease: MedlinePlus Medical Encyclopedia." Huntington's Disease (n.d.): n. pag. Medline Plus. U.S. National Library of Medicine, 22 Mar. 2013. Web. 11 Oct. 2013.

 *I do not own these images, they were found on various tumblr sites. Please let me know if any are yours and I will give you credit for them. Thanks so much!

Governments Role in Scientific Research

The role of the governments is to represent and protect the people. But most importantly the role of government is to make sure that human life is safe and people's dignity is preserved. In general people in various countries agree with, support, and even demand that their governments carry out the majority of these roles. In other cases they are deeply divided. Although it may lead to breakthrough discoveries that can save many lives, using embryonic stem cells for research is one of government roles that has deeply divided the constituency in two groups those that are in favor and the ones that adamantly are against embryonic stem cell research.

The opponents of stem cell research are convinced that embryonic cells are human beings and although in their earliest stages of development, their lives should be protected. In fact, if embryos are considered as living human beings they constitute the most vulnerable segment of populations the rights of which a good government should protect first.

There is a considerable number of people that have strong religious views or other reasons that make them feel offended if the government, that represents them and their ideals as well as their morals, instituted polices favoring the use of embryonic stem cells. Education, social status, and more importantly religious beliefs seem to heavily influence people opinions. The fact that embryonic stem research is banned in countries like Italy, Portugal, Ireland, Germany, Austria with their populations predominately Roman Catholics reflects the power that religious education and faith has on this matter.

Those who support the use of stem cells in scientific research believe that such research will lead to making organs from stem cells that can be transplanted into sick patients. But, by what means will this noble act be conducted?

This brings us to another topic that is closely related to stem cell research, organ transplantation and the market for organs. Today people have to endure long waiting periods for organ recipients and this shortage of organs puts their lives in danger everyday.This unavoidably can lead to instances where the rich in need for organs are willing to pay for these organs. In less developed countries there is evidence that the poor sell their organs. Then, there are worse cases in which illegal trafficking of organs are taken from individuals without their consent. (Anecdotal information has indicated that such events have occurred in some recent civil wars).

Those that willingly sell their organs such as a kidney to receive money to feed their family may do so without being fully informed of the consequences of such a procedure.

These examples stated above are considered illegal because the lives of those people whose organs are taken or sold are put in danger. It is the government’s job to protect the population against such actions. This is a valid argument that those who oppose stem cell research have and can use to defend their views about the role of government in protecting the lives of embryos.
Restricting guidelines and limitations on scientific research may therefore be necessary in order to maintain the safety of the population.

Egg donation in my opinion is different with regard to ethical aspect. Even though financial transactions are most of the time involved it is still justified. Two arguments can be used to support this view. The first relates to the question, is life destroyed in that act? The answer is no. In fact even though failure rates may be high the intention is to procreate. The second aspect of egg donation is the financial aspect of it. Women that donate eggs are being paid a sum of about $10,000. These are mostly related to the time or restriction in their lives to harvest the eggs and finally the intervention to capture the egg from the women' body.

Scientific research is the key to finding cures, conquering diseases, and to ultimately create a better future for mankind. Restricting research may make achieving such goals more difficult, but these challenges fund the research to take place in the most safe and cautious way possible.

I believe in scientific research and the promises it holds but I also believe that there will be future advancements in science that will make it possible for scientists to produce organs that will save lives without the use of embryos. Is it right to destroy embryos for others to live? We should respect the beliefs of those who oppose the use of embryos and continue to improve scientific technology so that one day scientists might be able to do such things without destroying human embryos.
  *I do not own these images, they were found on various tumblr sites. Please let me know if any are yours and I will give you credit for them. Thanks so much!

Eugenics Movement & Sterilization Practices

The eugenics movement strove to genetically improve the human population. The process consisted of identifying unfit individuals in society such as homosexuals, promiscuous women, mentally ill, and the impoverished and an elimination process was set forth. Many of these individuals and their family members were sterilized. This movement led to a new form of discrimination. Proponents of that movement believed that the power of science could solve the social problems that they faced at that time and Eugenics was their solution. The problem with the movement was multifaceted. Based on their race, health status or the state of carrying certain diseases (deafness, blindness, or other), or their behavior, people were grouped in certain categories some of which were stigmatized as unfit for the human race.

 
Ideological and scientific bases of Eugenics were unsupported and their philosophy including their methods were wrong, violating people’s rights and freedom to procreate and reproduce, the right to live, and have a family. Eugenics was ultimately a violation of human rights.

Proponents of eugenics and their leaders such as the board members failed to take into account the effects of social, political and environmental factors that have powerful influences on human behavior.

For instance, the son of a criminal is raised by a single mother working two jobs and shows her unconditional love for her son in every way possible. The son, therefore, through a strong parental figure, a home to come to, and unconditioned love, can decide that his father is far from the man he wants to become. Instead, the social failure, his father, becomes the sons motivation and drive to become a valuable member of society.
The example stated above, is just one possible instance out of many that occur in the world and social communities.  Although, such unfit individuals may overcrowd our hospitals, jails, or commit horrific crimes, they make people appreciate the value of an education, importance of role models, and significance of compassion towards others.

Instead of using the states money to sterilize and eliminate those that were unfit or social failures, they should have provided resources towards these individuals and their families that would give them the opportunity to become a valuable member in society that the life they were born into never gave them.

Francis Galton and his eugenics movement in essence strove to achieve something innately that we all want for ourselves- to be intelligent, healthy, athletically fit, and to ultimately live longer. In the end we are all still human. We are complex organisms, where our DNA is constantly changing creating errors in the process. It is our body’s age that prevents some of these genetic mutations in our DNA to be eliminated which can lead to cancer or disease.  We ourselves are not perfect beings so we cannot expect to sterilize people for the possibility of giving birth to a child that might become an unfit member of society.

 

 *I do not own these images, they were found on various tumblr sites. Please let me know if any are yours and I will give you credit for them. Thanks so much!