Case Study Questions: Fatal Familial Insomnia and How It Relates to Alzheimer's Disease

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

Fatal familial insomnia (FFI) is a genetic disorder. We are still not completely sure about the cause of Alzheimer’s disease but it is likely that genetics plays a large role in causing early-onset Alzheimer’s. Both diseases usually occur in an individual’s later stages of life (The average age of the onset of FFI is 49 and the average age of an Alzheimer’s patient is 65+).

Over time FFI degenerates the thalamus of the brain. Alzheimer’s also decays parts of the brain but is not specific to the thalamus, in fact, it can spread through the entire brain as it progresses. Because of this the progression of the disease can affect several functions of the brain. Likewise, as FFI progresses its symptoms are directly related to the malfunction of the responsibilities of the thalamus.

Plaques are abnormal structures that responsible for damaging nerve cells. These structures are found in an Alzheimer’s patient’s brain and are a result of FFI disease.

Also both diseases develop in stages. Alzheimer’s involves an abnormal aging of the brain and moves through 7 stages, and FFI involves the affects of a mutated protein and moves through 4 main stages

Alzheimer’s disease is a widespread form of dementia. As FFI progresses, following insomnia other common symptoms include poor reflexes and dementia. Both diseases lead into other serious problems as they progress; eventually leading to death. Also, no cure has been found for either disease.

2. What are prions?

A prion is a pathogen or disease-causing agent that contains no genetic material. It is a protein that is usually normal and harmless, but by folding into an unusual shape, the normal prion turns into a harmful agent. It then invites other normal prions to become harmful. This infectious protein particle is like a virus but lacks a nucleic acid (DNA/RNA). Prions have been held responsible for a number of degenerative brain diseases. Prion diseases have both infectious and hereditary components. The gene that codes for prions can mutate and be passed on to the next generation.

Here’s a video that shows how prions are made.

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?

Genes can be activated at any point during a human’s life time. This is why we see the development of diseases such as cancer and other degenerative diseases. Natural selection will never get rid of this disease due to its dominate expression. As long as those who hold the gene are able to reproduce it will constantly be maintain in a specific population. Unless the disease is cured it will maintain at a consistent level in populations. Since the direct mechanism of Alzheimer’s is unknown it is hard to predict whether it will rise in frequency or decline. However since both of these disorders result in malformation of proteins and the aggregation of plaques it can be inferred that they may share similar genetic pathways.

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 miss-folding help in understanding diseases like these?

These missfoldings of proteins are the result of single mutations in amino acids. Since the structure of a protein is determined by such specific encoding the potential knowledge for protein manipulation and correction is nearly endless. The study of similar diseases in lower vertebrates could also help us understand the evolution and early stages of homologous genetic mutations. This knowledge could provide new technology to eliminate genetic defects and degenerative diseases. The fact that a single position in the chain can mutate to cause two separate diseases also demonstrates the diversity of the genetic code. If one position can code for multiple protein malformation, it is possible many similar pathologies could be linked on a single mutation point with separate amino acids.

With further research, we could see if other neurodegenerative diseases, like Alzheimer ’s disease, are caused by missfolding proteins. By identifying a common cause they might be able to figure out a cure to not just one neurodegenerative disease, but hopefully all prion related diseases. The ability to suppress the missfolding of these proteins could lead to a delay or loss of symptoms, which would allow patients to stabilize the disease, making it possible to live longer.

5. This disease was discussed last week on Medical Mysteries: 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?

I would definitely want to know if I had a disease like this so I could at least make my family aware of it too so they would not have to go through the process of wondering what is causing the problems that a disease like this can cause. Plus, if I had children I would want them to be prepared for something like this, that way it can go a little bit smoother for everyone involved. If you are aware of a disease like FFI before the onset of symptoms you could raise awareness and hopefully find a cure so your children do not have to suffer as well. (Margaret Cameron)

I would not bother being tested for this disease because I would not enjoy that hanging over my life. I choose to live everyday a new and know something like that would only create fear and dread. That is no way to live and I think one should just live the time they have and enjoy because it ends no matter what. (Price Heins)

I would probably choose to be tested for the mutation. Although the symptoms and end result of the disease are depressing, I would still want to know if I had the disease. The fact that the disease is in my genetics would be on my mind all the time and I would worry about it my whole life. Having that information would make me feel more aware and I could prepare myself and my family for what would be coming in the future. (Kristine Makhamreh)

6. The NCBI 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?

Mice are easy a specimen to study because they are small, reproduce quickly and their life spans are relatively short in comparison to humans. Also, the moral dilemmas that doctors face when trying to work on a disease that affects the brain is much less applicable when dealing with mice. If the mice develop a similar disease this provides vital information on the origins of a degenerative disease that could have been passed on between species over the generations. In theory if another mutation occurs that leads to a new strain of a particular disease, researchers can go back and see where the strain changed during its lifetime. Since many of the same genes code for the same proteins, limbs, etc, all similar genetic mutations can be compared across species. Since it is the expression, timing, and environmental factors that have a direct affect on gene expression; the more we know about how the genes evolved over time the more can be understood about genetic coding. Eventually it might lead to the testing of potential cures for the disease.