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