Fatal Familial Insomnia

Fatal familial insomnia (FFI) is an inherited disease that was first documented by Lugaresi & associates in 1986.

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Figure 1. Title of a review by Aguzzi & Wiessmann (1996) dedicated to its discovery in Italy.

As implied in its name, FFI results in chronic insomnia and disregulation of slow wave sleep (SWS), which has implications in the autonomic nervous system, such as hypertension and disruptive breathing patterns. This disease also has neurological reprecussions from thalamic degradation in the brain, such as dysarthria and ataxia gait. (Benedini &et. al. 2008) The loss of SWS has also been associated with metabolic and hormonal variability. (Spiegel et. al. 2009)

Figure 2. The feelings of an insomniac. (Google images)
Figure 2. The feelings of an insomniac. (Google images)

FFI is the result of a malfunctioning prion protein and has been dubbed a prion disease, which is synonymous with the phrases ‘spongiform encephalopathies’ and ‘transmissible amyloidoses.’ The word prion comes from a combination of the phase ‘protein infection,’ and is indicative of its ability to self-replicate and propagate. Interestingly, prion neurodegenerative diseases are unique to mammals. (Xu et. al. 2011) The other two types of infectious prion diseases are Gerstmann-Straussler-Scheinker syndrome and Creutzfeldt-Jakob Disease. FFI is the result of a point mutation in the prion protein gene (PRNP). Despite its genetic encoding, FFI will occur sporadically as a function of age. (Peterson et. al. 1996) In fact, from the 28 familial pedigrees constructed, on average, the onset is 51 years of age and individuals will die roughly 18 months afterward. (Yu et. al. 2006)

FFI triggers destabilization of prion proteins and they are subsequently misshapen. In their non-native form, prion proteins become resistant to regular metabolic degradation. They can individually act as neurotoxins, or polymerize to form aggregates, which are equally as harmful to the brain. The ability of individually malformed prion proteins to-self associate has been described as a ‘seeding’ effect. (Yin et. al. 2006)

Prion diseases are thought to emerge due to oxidative stress that is typically associated with aging. Mitochondrion, the organelle that processes electrons and oxygen to produce cellular energy in a process known as oxidative phosphorylation, loses efficiency and does not recycle reactive oxygen species (ROS)  as competently as individuals get older. The resulting ROS interact with prion proteins to change their conformation into a pathogenic form. (Colombo et. al. 2009)

Figure 3. Oxidative phosphorylation process with the generation of potential free oxygen pointed out (Campbell, Biology 9th ed.)
Figure 3. Oxidative phosphorylation process with the generation of potential free oxygen pointed out (Campbell, Biology 9th ed.)

Compounds derived from acridine and phenothiazine have been used to treat malaria and psychoses for a number of years and were found to inhibit the formation of misfolded prion proteins and assist in the clearance of such from cell cultures in vitro. (Korth et. al. 2001) Under the propositions of previous work, quinacrine and chlorpromazine were hypothesized to have an impact by decreasing the infectivity of the prion disease, but were deemed ineffective. (Benito-León, 2004)

Figure 4. Chemical structures of (left to right) quinacrine, chlorpromazine, and agomelatine. (Images from sigmaaldrich.com)
Figure 4. Chemical structures of (left to right) quinacrine, chlorpromazine, and agomelatine. (Sigmaaldrich.com)

In more recent years, agomelatine, an anti-depressant, has been found to improve sleep maintenance and depth, making the patient in this case study feel less restless during nighttime and more active at daytime. Please note that this patient still died within the average time frame and that agomelatine was taken in conjunction with valproate, which could affect the conclusibility of these findings. (Frobose et. al. 2012) Since SWS has major implications in a wide variety of cellular pathways, enhancing SWS may be beneficial. While increasing SWS will not address the etymology of the disease, it could improve the symptoms and rapid physical degradation associated with habitual insomnia.

There is no accepted treatment for FFI. The structural components of the misfolded prion protein have been identified by Chakroun et. al. (2010), and if the subunits can be prevented from self-polymerizing, perhaps the disease can be controlled or prevented from progressing. Recently, a lineage of FFI has successfully been modeled in mice. (Jackson et. al. 2013) This may have implications in the ability to develop treatments, which is difficult in humans because of the short period between onset and death.

The following video provides valuable insight into how physically and mentally taxing this disease can be:

Hopefully future work will allow the development of a drug that can act effectively for management, and we can simply refer to this disease as familial insomnia instead of FATAL FI!

Thank you for taking the time to consider my review.

For more in-depth details, please refer to:

The History and Metabolic Context of FFI

The Genetic and Biomolecular Basis for FFI

FFI Disease Treatment and Maintenance

What’s Up Next with FFI

For the full list of references please see:

Annotated Bibliography

6 Replies to “Fatal Familial Insomnia”

  1. This article contains a lot of scientific information, and as someone who is not familiar with scientific terms, it is difficult for me to completely understand what is being talked about. For example, I don’t know what a ‘prion’ is. While I understand that it is important to include all of these big terms in order to fully explain FFI, I wonder if it could be made even more simplified in order to appeal to a wider majority of readers.

    1. Thanks for taking the time to look my page over! I understand the difficulty you are having and I tried to go back in and rephrase some of the wording.. Much of what I discussed was to give examples or expose you to phrases that you may see in the future if you came across this material again. Some words like ‘hypertension,’ ‘neurotoxin,’ ‘pedigree,’ ‘psychoses,’ ‘malaria,’ and ‘anti-depressant,’ I assumed that the audience understood to be high blood pressure, harmful to neurons, lineage, mental confusion, infectious disease, and combating depression. Were these where you found confusion? If not, could you be more specific to what exactly was bothering you and I would be more than happy to add those words to the primer page. Under your recommendation I also added a short definition of ‘prion.’ Prion comes from the phrase ‘protein infection,’ for which I added a sentence in the second paragraph. I also found a short video from a pop-news source that gives a real life example of FFI that compliments some of the ideas I presented in this review. I hope my edits and reply are helpful to your understanding, because personally I think this disease is pretty interesting and wild! Thanks again for commenting!

  2. The author used many scientific words and phrases without attaching a link to definitions. As someone with knowledge of the basics of biology and chemistry, I expected to understand most of the terms used in this blog. However, the author did not thoroughly explain the meaning of most of the words, making the blog difficult to comprehend to an intelligent audience without advanced scientific training.

    1. Thank you for commenting on my page! I rephrased some words like ‘pedigree’ to ‘lineage’ and ‘phenotype’ to ‘symptoms.’ Can you give me examples of what else bogged down your reading experience? Some of the phrases like ‘spongiform encephalopathies’ and ‘transmissible amyloidoses’ that are synonymous with ‘prion disease,’ I included so that the audience might have an idea of what they mean if they came across them in the future.

  3. The article contained a lot of scientific words which made it a little difficult to understand. In particular, the second and third paragraph were a little confusing, especially the part on the ‘prions,’ which I am unfamiliar with. It might be useful for the non-scientific reader if you provided a short definition of what prions are, and put that definition within the body of this page, rather than in the Primer page, where definitions are hard to find.

    1. I appreciate your help! I added a quick definition of prion… It’s simply the name of the protein, similar to if we were talking about a dog and the dog’s name was ‘Billy.’ The word itself comes from the phrase ‘protein infection.’ I rephrased some of my other words.. see the reply to Jacob Dolin. The instructions provided for this assignment require that definitions of some of the more specific verbiage be located in the primer page. The best way to navigate this would be to have a second tab open in addition to this page, with the primer open. Using control+F or command+F (if mac) and typing the word you are looking for will quickly bring you to the definition. I also denoted all the definitions I listed in the primer page with the signature ‘-RPF’. I hope that was helpful and thanks again!

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