Case Study on FFI

1. Based on your research into Alzheimer’s disease and your interview, how are these two disorders alike?

Both Alzheimer’s and Fatal Familial Insomnia are diseases that onset later in life after the person has most likely already had children which involves degeneration of the brain as well as the formation of amyloid plaques. Both of theses disease have stages in which the disease progresses little by little over time and eventually leads to death. Dementia, as well, is an outcome of both diseases. There is also no cure for either disease.

2. What are prions?

A prion is a protein that is associated with brain tissue and is the protein that is mutated in FFI and Alzheimer’s.  The protein being mis-folded causes the mutation and is named an amyloid fold. This protein can not multiply but it can affect the structure of the tissue because it acts like a template that other proteins start to follow and create the abnormal protein. Due to the number of abnormal templates increasing, there is a substantial increase in the amount of abnormal proteins because there are the more conversions that occur from normal to abnormal.

3. FFI is an autosomal dominant disease, meaning that if an individual inherits just one dominant allele from either parent, they will develop the disease.  However, this disease does not manifest itself phenotypically until after reproductive age.  So can this disorder be acted on by natural selection?  What about Alzheimer’s? What is maintaining these disorders in the population?

It is hard for natural selection in nature to act on FFI because the mutation does not occur during reproduction, it occurs within cells in the brain during and after the reproductive age of the person. It can although be acted on natural selection within the cells because it is the competition between the cells that can result in the disease to arise. A high entropy system promotes survival while a lower entropy system can not as readily adapt to changes. Alzheimer’s is also an autosomal dominant disease that does not show symptoms until later in life. This later onset of symptoms is what is keeping these two diseases in the population. Unless the person has some type of gene mapping done they will not know they have either of these diseases until at least 50 years old when they could have already passed on the gene to their children without knowing it.

4. FFI is caused by a single mutation that, in the presence of methionine at amino acid position 129, changes aspartic acid to asparagine.  This same mutation, in the presence of valine at position 129, causes a separate prion-disease called Creutzfeldt-Jacob syndrome.  In cattle, the homologous syndrome is Mad Cow disease.  How can studying protein folding and mis-folding help in understanding diseases like these?

The abnormal protein folding within the cow can actually be passed onto humans if beef they eat is contaminated with the affected central nervous system tissue. Due to Creutzfeldt-Jacob syndrome and Mad Cow disease being homologous diseases, but in different species, this allows researchers to compare and contrast the diseases.  This is an advantage in the research process because this allows the researchers to examine the different effects in the species that may allow them to make discoveries that were not otherwise possible. Protein folding plays a central role in cell biology so it is inevitable that it will lead to malfunctioning of biology process therefore causing a disease. The number of diseases that are now known to incorporate mis-folding are increasing so it is a very important topic in research so that hopefully a cure can be found before it becomes a much more potent problem.

5. This disease was discussed on Medical Mysteries a few years ago: (https://www.youtube.com/watch?v=Co94aQDs3ek)

The two sisters in this story lost their mother to FFI.  One sister chose to be tested for the mutation, while the other sister did not.  Would each of you want to know whether or not you had a disease such as this, or would you rather remain unaware?

Eric: Using genetic testing to determine the risks one has for different diseases is a relatively hot topic right now, some would never do it, and some are all for it. However, if it was up to me, and I knew I had a 50/50 chance of being diagnosed with FFI, I would want to get tested to see if I have those genes. I would want this first of all so that I wouldn't pass it on to any children, which would be the most important thing for me. Secondly, if I knew I was going to have this disease, I believe I would try to do what I could to fight the disease before it was too late, even if there was only a slim chance of the treatment working. Finally, I would use my family history to try to determine when it would likely progress so that I could prepare as needed for my family and friends. In order to prevent passing on the disease and try to give myself time to enjoy life before it was too late, I think I would rather be tested than not for this disease

Brandi: I do not think I would not want to get tested to see if I had such a disease. There is a risk of passing it on to my children but it is not a for sure thing. Because there is not a cure I feel as if you are finding out you have a fatal disease and yet there is nothing you can do about it. With this being the case I feel like I would be living my life just waiting to die. I rather not know and be able to go about my life not waiting for a death sentence I know is going to occur. Although it would be relieving to know if I did not have the disease and not have to worry about it, I do not think it would be worth it. There are so many different things in life that can kill you; I believe that everyone should live their life to the fullest every day because you never know what can happen in the next instance.

Raunak: I think I would eventually want to know if I am going to get this disease. Not now, but probably when I am older and have maybe started a family. If I had a family history of the disease, like the two women did in the video, then I would probably want to know sooner. If I knew about it in time, then I might be able to make proper arrangements for my family and loved ones. I would rather be prepared for it than get me by surprise

Kush: Personally, I would want to know if I had a disease such as FFI.  I would chose this because my awareness of my condition would allow me to plan accordingly for my future i.e. buying a life insurance policy, saving for retirement, planning my mortgage payments, etc.  I would also want to know so I can appreciate each day if I knew I were to die in a short period of time.  It would allow me to shift my focus away from a career and more towards my family, friends, and experiences. Although it would be difficult to live with the knowledge that an illness will kill me, I would rather know about it and have a chance to plan my life so it is still personally fulfilling.

6. The OMIM link above, under “Animal Model”, discusses a phenotype in mice that is similar to that of FFI in humans.  Why, from an evolutionary standpoint, might it be informative for scientists or doctors to study conditions in mice when investigating human diseases like FFI?

This discovery is very important because it is not only the prion that is abnormally folded, but it also have the same sleeping altercations which is different from previous diseases that have been mentioned like Alzheimer’s and Mad Cow Disease. Human studies are very hard to get passed because of FDA regulations. Other animal species, such as mice, have easier access to have a study/experiment passed. Also non-human animals have fewer regulations in which have to be implicated within the study so it is usually easier to be able to perform experiments on the mice than it would be to on humans. With this, more progress is likely to be made in the mice that could then lead to an experiment on humans being endorsed that could hopefully lead to a cure.

http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/AAkroush.html

Further reading:  http://omim.org/entry/600072