What Is Fatal Familial Insomnia (FFI)?
Fatal Familial Insomnia (FFI), a highly rare form of brain disease that falls under the umbrella of Transmissible Spongiform Encephalopathies (TSE), is characterized by neurodegenerative alterations brought on by the prion protein (PrP), an abnormally constitutively produced protein 1,2. It is characterized by an inability to fall asleep (insomnia), which may start minor and degenerate with time, causing major physical and mental deteriorations1. Group of TSE are sporadic and genetic. However, (TSE), are fatal neurodegenerative diseases that affect both humans and animals2,3. This is what makes them distinctive2.

First Cases
In 1986, Lugaresi et al. introduced the term “FFI” to describe a 53-year-old patient who had myoclonus, dysarthria, tremor, progressive sleeplessness, and autonomic dysfunction3,4,5,6. Neuropathological analysis of the patient’s relatives during a five-generation period revealed that seven people had FFI, and 22 people most likely passed away from FFI, according to study4. Missense mutations in codon 178 of the PRNP gene are linked to FFI, a genetic autosomal dominant prion disease3,5,6,7. However, sporadic FFI cases without PRNP gene mutations have also been published. Pathology of the thalamus showed that it is anteroventral and mediodorsal (dorsomedial) nuclei had selectively degenerat.

What Is Going On In The Brains Of These Patients At This Time?
Polysomnography (PSG), an overnight sleep test, is one method of detecting FFI8. It measures sleep activity. An electroencephalogram (EEG) is used in PSG to record the electrical activity of the brain and sleep latency, sleep duration, eye movement, limb movement, heart rhythms, and various physiological changes that occur while patients sleep8,9.
PSG commonly indicates a steady deterioration of sleep patterns, including a decrease in sleep spindles, K complexes (they occur in the NREM2 sleep stage), and overall sleep duration10. In cases of short evolution, the most noticeable EEG indication appears after a few months (3-4), while in cases of a long evolution, it appears after a year or even longer5. After spindling stops, the EEG characteristic of wake or subwaking (a mental state midst between sleeping and waking) lasts the entire 24 hours, only being briefly broken by REM sleep or, less frequently, delta sleep that abnormally emerges from alertness5. The length of sleep is gradually reduced. Slow-wave sleep is typically impacted, and then REM sleep is reduced10.
Sporadic Familial Insomnia (sFI), PSG, and EEG findings resemble those seen in FFI10. The reduction of sleep-related EEG activity like K complexes and sleep spindles in the two disorders makes PSG recordings indistinguishable in most cases5. Importantly, all 8 of the sFI cases with PSG data that were published in the literature showed FFI-like results10.

Fatal Familial Insomnia (FFI) And Sporadic Fatal Insomnia (sFI)
A missense mutation at codon 178 of the prion protein (PrP) gene (PRNP) on chromosome 20 was found to be the cause of FFI in 199211. The mediodorsal and anterior ventral thalamic nuclei had shrunk upon autopsy verification in a patient with familial fatal insomnia (FFI)11.
When only a single copy of a mutated gene is sufficient for the disorder to appear, FFI inherited in a dominant pattern occurs. The mutated gene may be brought on by a new mutation (gene alteration) in the sick person, or it may be inherited from either parent. Regardless of the sex of the offspring, there is a 50% chance that the mutated gene will be passed from the affected parent to their offspring throughout each pregnancy12.
Without a PRNP gene variant, fatal insomnia (FI) has been reported in some people. These people are considered to have sporadic fatal insomnia (SFI), which is a non-genetic form of fatal insomnia for which there is no known cause11,12. SFI, therefore, happens at random, and far less frequently than FFI. The main distinction is that PrPSc type 2 does not exhibit the striking under-representation of the unglycosylated version of the protein that is seen in FFI. Their neuropathology is identical to that of FFI11.
Cause & Symptoms
Cause
A protein known as prion protein, or PrP, is created by the PRNP gene. The generated PrP takes on an aberrant 3-dimensional structure that can only be defined as “misfolded” as a result of the mutant gene12. The body cells, especially those in the nervous system, are hazardous when PrP is improperly folded. The thalamus, an area deep within the brain that assists in regulating a variety of biological functions like sleep, appetite, and body temperature, is where misfolded PrP is most frequently identified in FFI12,13. The symptoms of the disease are caused by a progressive degeneration of nerve cells (neurons) when the misfolded PrP accumulates in the thalamus2,5,12. On the other hand, there is no obvious cause for sFI.

Symptoms
Progressive sleeplessness is the major indicator of FFI. Progressive sleeplessness can happen earlier or later in life. Insomnia frequently starts in middle age12. Although insomnia may start mild, it progresses with time until the patient gets very little sleep. Over the subsequent months, insomnia can quickly degenerate after usually starting unexpectedly12,13. Sleeplessness causes mental and physical deterioration, and the disorder eventually escalates to coma and death.
Although insomnia is the major symptom, some people may also have progressive dementia, which worsens thought, cognitive, memory, language, and other issues5,12,13. Eventually, periods of disorientation or hallucinations may happen.
Some people who are affected may have slurred speech (dysarthria), swallowing (dysphagia), or double vision (diplopia), as well as irregular, jerky eye movements (nystagmus)12,13. Some people struggle to coordinate their voluntary motions (ataxia). Parkinson’s-like symptoms or atypical movements such as limb spasms (myoclonus) may also appear12.
The autonomic nervous system evolves to deterioration further, causing further symptoms. Fever, tachycardia, high blood pressure, increased sweating, increased tears, constipation, changes in body temperature, and sexual dysfunction are just a few of the common symptoms. Depression and anxiety are also frequent observations5,12,13.

Treatment
Researchers have not yet discovered a remedy for Fatal Insomnia12. Presently available therapies are palliative care, which indicates that they are intended to ease the suffering of patients who are struggling with this disorder in their last few months of life13.
Fatal Familial Insomnia -more precisely Fatal Insomnia- is an extremely rare neurodegenerative disease in the world1,2. This disease is sporadic or inheritable with autosomal dominant genetics2,3. A missense mutation at codon 178 of the prion protein (PrP) gene (PRNP) on chromosome 20 was named Fatal Familial Insomnia11. Another type, Sporadic Fatal Insomnia (sFI) is a non-genetic form of fatal insomnia for which there is no known cause11,12. This disease, which is generally seen in the middle ages, shows many symptoms psychologically (anxiety, depression, dementia) and biologically (hypertension, tachycardia, limb spasms), especially insomnia12,13. Palliative care aims to make patients’ final phases less agonizing even when there is no treatment13. This disease, which is distinctive and more dangerous than insomnia, is waiting for new remedies and solutions from researchers.
References:
- U.S. Department of Health and Human Services. (n.d.). Fatal familial insomnia – living with the disease. Genetic and Rare Diseases Information Center. Retrieved September 10, 2022, from https://rarediseases.info.nih.gov/diseases/6429/fatal-familial-insomnia/living/
- Montagna, P. (2005). Fatal familial insomnia: a model disease in sleep physiopathology. Sleep Medicine Reviews, 9(5), 339–353. https://doi.org/10.1016/j.smrv.2005.02.001
- Şevik, M. (2012, August). Patolojik Prion Proteininin Tespiti – DergiPark. Retrieved September 10, 2022, from https://dergipark.org.tr/tr/download/article-file/53556
- Manetto, V., Medori, R., Cortelli, P., Montagna, P., Tinuper, P., Baruzzi, A., … Gambetti, P. (1992). Fatal familial insomnia: Clinical and pathologic study of five new cases. Neurology, 42(2), 312–312. https://doi.org/10.1212/wnl.42.2.312
- Cortelli, Gambetti, Montagna, & Lugaresi. (1999). Fatal familial insomnia: clinical features and molecular genetics. Journal of Sleep Research, 8(S1), 23–29. https://doi.org/10.1046/j.1365-2869.1999.00005.x
- G. Almer, J. A. Hainfellner, T. Brücke, K. Jellinger, R. Kleinert, G. Bayer, O. Windl, H. A. Kretzschmar, A. Hill, K. Sidle, J. Collinge, H. Budka, Fatal familial insomnia: a new Austrian family, Brain, Volume 122, Issue 1, January 1999, Pages 5–16, https://doi.org/10.1093/brain/122.1.5
- Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., … Gambetti, P. (1986). Fatal Familial Insomnia and Dysautonomia with Selective Degeneration of Thalamic Nuclei. New England Journal of Medicine, 315(16), 997–1003. https://doi.org/10.1056/nejm198610163151605
- Akçay, G. (2020, December 17). Ölümcül Uykusuzluk Nedir? Belirtileri Nelerdir? Ölümcül Uykusuzluk Nedir? Belirtileri Nelerdir? | BilimFili.com. Retrieved September 10, 2022, from https://bilimfili.com/olumcul-uykusuzluk-nedir-belirtileri-nelerdir
- Sleep study. Johns Hopkins Medicine. (2021, August 8). Retrieved September 10, 2022, from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/sleep-study
- Cracco, L., Appleby, B. S., & Gambetti, P. (2018). Fatal familial insomnia and sporadic fatal insomnia. Handbook of Clinical Neurology, 271–299. https://doi.org/10.1016/b978-0-444-63945-5.00015-5
- Pasquale Montagna, Pierluigi Gambetti, Pietro Cortelli,Elio Lugaresi,Familial and sporadic fatal insomnia,The Lancet Neurology,Volume 2, Issue 3,2003,Pages 167-176,ISSN 1474-4422, https://doi.org/10.1016/S1474-4422(03)00323-5. (https://www.sciencedirect.com/science/article/pii/S1474442203003235)
- Fatal familial insomnia. NORD (National Organization for Rare Disorders). (2022, March 15). Retrieved September 10, 2022, from https://rarediseases.org/rare-diseases/fatal-familial-insomnia/#:~:text=Fatal%20familial%20insomnia%20(FFI)%20is,significant%20physical%20and%20mental%20deterioration.
- Summer, J., & Vyas, D. N. (2022, April 21). Fatal insomnia. Sleep Foundation. Retrieved September 10, 2022, from https://www.sleepfoundation.org/insomnia/fatal-insomnia
Figure References:
- Zwarensteyn, J. (2022, May 17). Fatal familial insomnia: Symptoms, diagnosis, and treatment. Sleep Advisor. Retrieved September 10, 2022, from https://www.sleepadvisor.org/fatal-familial-insomnia/
- What does it mean to have a genetic prion disease? (n.d.). Retrieved September 10, 2022, from http://www.prionalliance.org/2013/12/09/what-does-it-mean-to-have-a-genetic-prion-disease/
- Baldelli, L., & Provini, F. (2019). Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications. Autonomic Neuroscience.https://doi.org/10.1016/j.autneu.2019.02.007
- mc_owoblow. (2022, May 1). Fatal familial insomnia; insomnia and death: Sporadic fatal insomnia. O3schools. Retrieved September 10, 2022, from https://o3schools.com/fatal-familial-insomnia-insomnia-and-death/
- A proposal of new diagnostic pathway for fatal familial insomnia. (n.d.). Retrieved September 10, 2022, from https://www.researchgate.net/publication/258702895_A_proposal_of_new_diagnostic_pathway_for_fatal_familial_insomnia
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