Editorial Cite This: ACS Chem. Neurosci. 2017, 8, 2570−2572
pubs.acs.org/chemneuro
Genetic and Rare Disease of the CNS. Part I: Fatal Familial Insomnia (FFI)
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stands for scrapie, a prion disease known in sheep and goats).1,2,6−13 Once misfolded, the aberrant PrPSc then templates “good” PrPC into more toxic PrPSc that then spreads throughout the brain, killing healthy neuronal populations.1,2,6−13 FFI is an autosomal dominant prion disease caused by a D178N (aspartic acid to arginine) mutation in PRNP, in combination with a methionine at codon 129 on the mutated allele (Figure 1) of the same gene (referred to as a D178N-129 M halotype). While all prion diseases are thus related, they can be differentiated based on the brain region affected. For FFI, the region most affected is the thalamus, the brain region that modulates the sleep−wake cycle.1,2,6−13 Interestingly, CJD bares the same D178N mutation in PRNP, but possess a valine at codon 129. Historically, patients diagnosed as either “thalamic atrophy or dementia” or “thalamic form of CJD” actually had FFI.1,2,6−13 FFI shows no gender bias, affecting males and females equally, with a typical onset between 36 and 62 years of age, with a mean of 51 years. As mentioned previously, there is no treatment for FFI (standard sleep agents worsen disease), and the outcome is fatal. The disease progresses through four stages. In stage 1, insomnia begins and worsens over the span of 3−6 months. During this stage, psychiatric symptoms may appear along with panic attacks and paranoia. When able to sleep, vivid dreaming has been reported. In stage 2 (5−9 months), the psychiatric and mood symptoms become more pronounced and severe. Patients also enter a period of sympathetic hyperactivity, wherein cortisol levels (stress hormone), heart rate, blood pressure, body temperature, breathing, and perspiration all increase.1,2,6−13 Making matters worse, this stage is also characterized by anxiety/depression, movement disorders, and gait changes (see videos above).12,13 Complete disruption of the sleep−wake cycle occurs in stage 3, with total insomnia lasting ∼3 months. Finally, in stage 4, the prolonged inability to sleep leads to rapid dementia, an inability to speak (akinetic mutism), coma, and finally death. Stage 4 can last up to 6 months, but had also been documented to be much shorter.1,2,6−13 In terms of sleep architecture, FFI is characterized by a disrupted sleep pattern involving a loss of slow wave sleep and sleep spindles, as well as enacted dreams during REM sleep (again, see the videos).1,2,6−13 Brain imaging studies (MRI and CT) of FFI patients display dilation of ventricles and cerebellar atrophy. PET studies with [18F]-2-fluorodeoxy-D-glucose indicated severe thalamic hypometabolism, as well as widespread brain hypometabolism. A defining hallmark of FFI is hypometabolism of the thalamus and the cingulate cortex; moreover, brain regions showing hypometabolism correlated with deposition of PrPSc.1,2,6−13 Neuropathological features are found primarily in the thalamus, with severe pathology in the ventral and mediodorsal nuceli (50−80% neuronal loss) as well
magine a disease that prevents you from being able to sleep. If you have ever pulled all-nighters, you are well aware of your mental state and cognitive performance the next day. Now imagine months on end of never being able to sleep, and the toll that will take on your mind and body. Sadly, there is a real disease that destroys the thalamus and prevents carriers from sleeping. The disease was coined Fatal Familial Insomina (FFI) in 1986,1,2 though it has been known for centuries, yet has afflicted very few. Due to the terminal nature of the disease and current stories in the lay press, FFI will be the first genetic and rare disease of the CNS that we will cover monthly over the next 5 years.3,4 While I am far from an expert on prion diseases or FFI, this series of editorials is designed to provide a general overview of a genetic and rare disease with the aim to raise awareness and hopefully encourage experts in the field to draft the definitive manuscripts and publish with ACS Chemical Neuroscience. FFI can be traced back to a single family, and perhaps a patient zero, two centuries ago in the Veneto region outside of Venice, Italy (detailed in the book, “The Family That Couldn’t Sleep”).5 For members of this family, they suffered with an inherited prion disease that manifested in the prime of their lives (usually late 40s to early 50s) and prevented them from sleeping. The lack of sleep quickly led to mood and behavioral disturbances, before succumbing to death within ∼18 months.1,2,5−11 While the risk of FFI to the general population is on the order of one in 30 million, for this family, with an autosomal dominant disease (Figure 1), the child of a parent with FFI has a 50 percent chance of inheriting the disease.1,2,6−11 As of today, there is no treatment or cure for FFI, and death usually follows within 18 months of the emergence of symptoms. Currently, it is estimated that are just under 30 families (∼100 individuals) in the world with, or are carriers of, FFI across Europe, America, Japan, China, and Australia. Truly, a rare (orphan disease).3,4 While I will walk through the stages and neuropharmacology of FFI, there are several excellent videos that show patient stories and define the disease in ways that text simply cannot, and I encourage you to watch the videos (https://www.youtube.com/watch?v= nIeTVVAEFn8 and https://www.youtube.com/watch?v=34QySd1CtM) to fully understand the horror of FFI,12,13 as well as a story of great hope, as a young carrier sets out to cure her own disease.14 Fatal Familial Insomnia (FFI) is a very rare, genetic neurodegenerative prion disease. Caused by infectious proteins, there are several prion diseases: bovine spongiform encephalopathy (ie., mad cow disease), chronic wasting disease in American deer and elk, Creutzfeldt−Jakob disease (CJD), and Gerstmann−Sträussler−Scheinker syndrome (GSS).1,2,6−13 All mammals have prion protein (PrP) which is encoded by the PRNP gene, found on the short arm of chromosome 20.1,2,6−13 In most instances, PrP is well behaved and exists in a properly folded cellular form referred to as PrPC; however, PrP can misfold into an infectious, toxic form designated PrPSc (Sc © 2017 American Chemical Society
Published: December 20, 2017 2570
DOI: 10.1021/acschemneuro.7b00463 ACS Chem. Neurosci. 2017, 8, 2570−2572
ACS Chemical Neuroscience
Editorial
Figure 1. Fatal familial insomnia, an autosomal dominant rare CNS disease. If an affected person (carrying the mutation, in this case a D178N) has children with an unaffected (normal) mate, half of the offspring will carry the mutation and be affected. In FFI, there is a mis-sense GAC to AAC mutation at codon 178 of the prion-protein gene (PRNP) that leads to a D178N substitution (aspartic acid to arginine). FFI is distinguished from other prion diseases by the codon-129 polymorphism (methioinine-valine) on the mutated allele. In all FFI cases, methionine is expressed, whereas in another prion disease, Creutzfeldt−Jakob disease (CJD), valine is expressed. The codon-129 polymorphism determines the brain region of disease and clinical symptoms resulting from the codon-178 mutation (D178N) in PRNP. Thus, FFI has also been thought of as a thalamic form of CJD.
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as the inferior olives, and all are accompanied by astrogliosis.1,2,6−13 Overall, there is significant neuronal loss, glial changes, changes in inflammatory markers, abnormal sertoninergic function, and a decline in mitochondrial and protein synthesis machinery in affected brain regions.1,2,6−13 Finally, FFI can also manifest spontaneously in patients without an inherited mutation (sporadic fatal insomnia, sFI), and is very rare. 1,2,6−13 Clinical features of sFI are indistinguishable from FFI, but there is no mutation in PRNP, yet PrPSc deposition is similar to that of FFI. All sFI patients to date were homozygous for methionine at codon 129. For both FFI and sFI, mouse models have been generated.1,2,6−13 This is a disease that needs innovation. This series of editorials is by no means meant to be a comprehensive review of a rare and genetic disease of the CNS, but rather a vignette to catalyze awareness, discussion, and, hopefully, additional studies toward treatment options. I encourage experts in the prion disease (or FFI) field to consider submissions on the topic of FFI (neuropharmacology, imaging studies, emerging treatments, and/or case studies from the clinic) as Reviews, Viewpoints, Letters, and Articles. As always, ACS Chemical Neuroscience has no publication charges, no fee for color, and flexibility with page length/number of figures/tables and is eager for author ideas for cover art!
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REFERENCES
(1) Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., Tinuper, P., Zucconi, P., and Gambetti, P. (1986) Fatal familial insomnia and dysautonomia with slectvie degeneration of thalamic nuclei. N. Engl. J. Med. 315, 997−1003. (2) Medori, R., Tritschler, H.-J., LeBlanc, A., Villare, F., Manetto, V., Chen, H. Y., Xue, R., Leal, S., Montagna, P., Cortelli, P., Tinuper, P., Avoni, P., Mochi, M., Baruzzi, A., Hauw, J. J., Ott, J., Lugaresi, E., Autilio-Gambetti, L., and Gambetti, P. (1992) Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N. Engl. J. Med. 326, 444−449. (3) Lindsley, C. W. (2017) Embarking on a 5 year journey to highlight genetic and rare diseases of the central nervous system. ACS Chem. Neurosci. 8, 2349. (4) https://rarediseases.info.nih.gov/GARD. (5) Max, D. T. (2006) The Family That Couldn’t Sleep, Random House, Inc., New York. (6) Montagna, P., Gambetti, P., Cortelli, P., and Lugaresi, E. (2003) Familial and sporadic fatal insomnia. Lancet Neurol. 2, 167−176. (7) Peng, B., Zhang, S., Dong, H., and Lu, Z. (2015) Clinical, histopathological and genetic studies in a case of fatal familial insomnia. Int. J. Clin. Exp. Pathol. 8, 10171−10177. (8) https://health.howstuffworks.com/mental-health/sleep/ disorders/fatal-familial-insomnia1.htm. (9) http://www.cureffi.org/2012/12/03/introduction-to-fatalfamilial-insomnia/. (10) https://www.npr.org/templates/story/story.php?storyId= 6525243. (11) Llorens, F., Thune, K., Schmitz, M., Ansoleaga, B., FrauMendez, M. A., Cramm, M., Tahir, W., Gotzmann, N., Berjaoui, S., Carmona, M., Silva, C. J., Fernandez-Vega, I., Zarranz, J. J., Zerr, I., and Ferrer, I. (2016) Identification of new molecular alterations in fatal familial insomnia. Hum. Mol. Genet. 25, 2417−2436. (12) https://www.youtube.com/watch?v=nIeTVVAEFn8. (13) https://www.youtube.com/watch?v=-34QySd1CtM.
Craig W. Lindsley, Editor-in-Chief AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS. 2571
DOI: 10.1021/acschemneuro.7b00463 ACS Chem. Neurosci. 2017, 8, 2570−2572
ACS Chemical Neuroscience
Editorial
(14) https://news.harvard.edu/gazette/story/2016/03/strength-inlove-hope-in-science/.
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DOI: 10.1021/acschemneuro.7b00463 ACS Chem. Neurosci. 2017, 8, 2570−2572
