Fatal familial insomnia is a genetic disorder. It involves the degeneration of the thalamus, the area of the brain responsible for sleep. It involves the development of amyloid plaques, a waxy substance made of proteins associated with polysaccharides. The disease results from a protein mutation. The mutation is the addition of 178 amino acids into the normal protein, turning an asparagine acid into an aspartic acid. This makes it a part of a family of rare neurodegenerative disorders called Prion Disorders. The disease is also autosomal dominant, meaning if the FFI mutated gene is inherited, the individual will have the disease; there are no carriers. Also, both sexes are affected equally.
First, individuals with FFI have a variety of psychiatric problems, such as panic attacks and bizarre phobias. Second, individuals can have hallucinations, panic, agitation, and sweating. Weight loss and premature aging are also symptoms. Finally, suffers reach a stage similar to dementia, where they become mute and experience sudden death. Symptoms do not occur until after puberty.
1. Based
on your research into Alzheimer’s disease and your interview, how are
these two disorders alike?
Both Alzheimer's and FFI involve problems with the brain and therefore have similar symptoms, such as problems with memory, thinking and behavior. Both are also progressive diseases, where symptoms develop slowly and get worse over time, becoming severe enough to interfere with daily tasks. In addition, both diseases prevent parts of the brain cell from working correctly. As damage spreads, cells lose their ability to do their jobs and, eventually die, causing irreversible changes in the brain. Plaques, or protein deposits, develop and inhibit function.
2. What are prions?
A prion is an infectious particle composed of misfolded protein that causes progressive neurodegenerative conditions. It is therefore an abnormal form of a normally harmless protein found in the brain. Unlike other infectious particles, like viruses, it contains no nucleic acid, does not trigger an immune response, and is not destroyed by extreme heat or cold.
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?
Natural selection is the nonrandom and differential reproduction of different genotypes. It is a gradual process by which traits become either more or less common in a population based on relative fitness. It can only have an effect on inherited traits. Because FFI is a is a genetic disorder that can be inherited, it is acted upon by Natural Selection. One of Darwin's postulates is that variation exists among individuals. This variation is due to mutations that occur in the genome of the individual organism, and, therefore, these mutations can be passed to offspring. Because the disease is the result of a mutation of a gene, the gene can be passed on, and future generations can be affected. Therefore, the disease is maintained in the population.
Next, people who have a parent or sibling that developed Alzheimer's disease are tree times more likely to develop the disease than those with no family history. There it is believed it has a genetic basis. Scientists have identified two kinds of genes associated with the familial risk factor. First, a gene called ApoE4 is a "risk gene" that increases the likelihood of developing the disease. Second, a "deterministic gene" is more rare, but if inherited, the person will for sure develop Alzheimer's. Because of this genetic basis, the disease can be obviously inherited throughout the generations. Therefore, Natural Selection can act upon it and it is maintained in the population over time.
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?
Most genes
code for proteins. Therefore, a small error or mutation in a gene could lead
to
an incomplete folding of a protein, which affects its function. When studying
proteins,
one must remember that shape determines function. If a protein is
misfolded, the entire
function will be changed. Over time, more and more research has been completed
looking at the mechanisms of protein folding.
Researchers have gained a better
understanding of how the genetic blueprint of
a protein relates to its biological
function. It has also become clear that wrongly folded proteins are
involved in the
development of many diseases, such as Alzheimer's. If excessive quantities of wrongly
folded proteins begin to collect, they will form piles of unneeded material. This is
known as amyloidoses, a group of diseases in which Alzheimer's is the best-known.
These "piles" of densely packed, insoluble protein cannot be broken down by enzymes.
There are approximately 20 different proteins that can build these amyloidose plaques,
each associated with a different disease. Alzheimer's disease and FFI involve the
accumulation of plaques of insoluble b-amyloid in the brain. As previously mentioned,
the misfolding of the protein dramatically alters its properties. In normal protein,
hydrophobic amino acids are folded inward. If the protein misfolds, these hydrophobic
amino acids are exposed and bind to hydrophobic groups on other protein molecules.
This builds the plaques.
Transmissable spongiform encephalopathies (TSEs), which include mad cow disease
(bovine spongiform encephalopathy; BSE) and Creutzfeld Jakob disease (CJD) in
humans, are special forms of amyloidosis. In these diseases, the brain degenerates,
developing holes and becoming sponge like. This is a result of the aforementioned prion
misfolding. The infectious, incorrectly folded form (called PrPsc) is most likely due to a
genetic mutation. If
we can discover what kind of mutation can cause the misfolding,
then we can try to prevent said mutations.
then we can try to prevent said mutations.
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?
This is a difficult question to answer. I would want to know if I had the disease, because I would not want to have children if I did. As much as I want to be a mother, I would not allow myself to pass on the disease. However, a part of me would want to remain in "ignorant bliss" as long as I could. My quality of life would be so diminished if I knew I was going to develop these horrible symptoms after puberty. This is a question I cannot answer without being in the situation.
6. The OMIM link above [4], 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?
In the study of diseases, it is necessary to use model organisms. The disease needs to be characterized to save lives, and we cannot risk human lives with clinical studies. For example, mice are considered model organisms because they are a non-human species that can be used to understand biological phenomena. They are good examples because they are more prolific and inheritance through generations can be easily tracked. They also have a shorter generation time than humans. Mice also have a similar genome to humans, with orthologous genes, so they are good examples and comparable to humans. Therefore, we can study how gene manipulation in mice will affect humans in a much easier and more ethical way.
[3] http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/AAkroush.html
[4] http://omim.org/entry/600072
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