Fatal insomnia

MRI of a person with FFI showing abnormal signals in the frontoparietal subcortical areas. MRA showed smaller distal branches of cerebral arteries.
Specialty| Psychiatry, sleep medicine
Symptoms| Progressive trouble sleeping, mental health problems, poor coordination, weight loss, excessive sweating[1]
Usual onset| 40–60 years[1]
Types| Fatal familial insomnia, sporadic fatal insomnia[2]
Causes| Genetic mutation, sporadic[3]
Risk factors| Family history[3]
Diagnostic method| Sleep study, PET scan, genetic testing[1]
Differential diagnosis| Creutzfeldt–Jakob disease, Alzheimer’s disease, frontotemporal dementia, Huntington disease, dementia with Lewy bodies[3]
Treatment| Supportive care[2]
Prognosis| Life expectancy 7 months to 6 years[2]
Frequency| Rare[3]

Fatal insomnia is a rare disorder that results in trouble sleeping.[2] It typically start out gradually and worsen over time.[3] Other symptoms may include mental health problems, poor coordination, weight loss, and excessive sweating.[1] When people who are affected sleep they often have vivid dreams.[3] Death generally occurs in 6 to 36 months from the onset of symptoms.[1]

Fatal insomnia is a prion disease of the brain.[2] It is usually caused by a mutation to the protein PrPC.[2] The mutation is typically inherited from a parent in an autosomal dominant fashion, though may rarely occur as a new mutation.[1] The form due to an underlying mutation is known as fatal familial insomnia (FFI), though the disease may also occur randomly, known as sporadic fatal insomnia (sFI).[3] Diagnosis is based on a sleep study, PET scan, and genetic testing.[1]

Fatal insomnia has no known cure, with efforts directed at improving a person's symptoms.[1][3] Fatal insomnia is rare.[3] Males and females are affected equally frequently.[3] Onset is typically between the ages of 40 and 60.[1] The first recorded case was an Italian man, who died in Venice in 1765.[4]

## Contents

* 1 Signs and symptoms
* 2 Cause
* 3 Pathophysiology
* 4 Diagnosis
* 4.1 Differential diagnosis
* 5 Treatments
* 6 Prognosis
* 7 Epidemiology
* 7.1 Silvano, 1983, Bologna, Italy
* 7.2 Unnamed, Schenkein and Montagna, 2001
* 7.3 Egyptian man, 2011, Netherlands
* 8 Popular culture
* 9 Research
* 10 References
* 11 External links

## Signs and symptoms[edit | edit source]

The disease has four stages:[5]

1. The person has increasing insomnia, resulting in panic attacks, paranoia, and phobias. This stage lasts for about four months.
2. Hallucinations and panic attacks become noticeable, continuing for about five months.
3. Complete inability to sleep is followed by rapid loss of weight. This lasts for about three months.
4. Dementia, during which the person becomes unresponsive or mute over the course of six months, is the final stage of the disease, after which death follows.

Other symptoms include profuse sweating, pinpoint pupils, the sudden entrance into menopause for women and impotence for men, neck stiffness, and elevation of blood pressure and heart rate. Constipation is common as well. As the disease progresses, the person becomes stuck in a state of pre-sleep limbo, or hypnagogia, which is the state just before sleep in healthy individuals. During these stages, people commonly and repeatedly move their limbs as if dreaming.[6]

The age of onset is variable, ranging from 18 to 60 years, with an average of 50.[7] The disease can be detected prior to onset by genetic testing.[8] Death usually occurs between 7–36 months from onset. The presentation of the disease varies considerably from person to person, even among people within the same family.

## Cause[edit | edit source]

Idiogram of chromosome 20 showing gene PRP location

The gene PRNP that provides instructions for making the prion protein PrPC is located on the short (p) arm of chromosome 20 at position p13.[9] Both people with FFI and those with familial Creutzfeldt–Jakob disease (fCJD) carry a mutation at codon 178 of the prion protein gene. FFI is also invariably linked to the presence of the methionine codon at position 129 of the mutant allele, whereas fCJD is linked to the presence of the valine codon at that position. "The disease is where there is a change of amino acid at position 178 when an asparagine (N) is found instead of the normal aspartic acid (D). This has to be accompanied with a methionine at position 129."[10]

## Pathophysiology[edit | edit source]

In itself, the presence of prions causes reduced glucose use by the thalamus and a mild hypo-metabolism of the cingulate cortex. The extent of this symptom varies between two variations of the disease, these being those presenting methionine homozygotes at codon 129 and methionine/valine heterozygotes being the most severe in the later one.[11] Given the relationship between the involvement of the thalamus in regulating sleep and alertness, a causal relationship can be drawn, and is often mentioned as the cause.

## Diagnosis[edit | edit source]

Diagnosis is suspected based on symptoms.[1] Further work up often include a sleep study and PET scan.[1] Confirmation of the familial form is by genetic testing.[1]

### Differential diagnosis[edit | edit source]

Other diseases involving the mammalian prion protein are known.[12] Some are transmissible (TSEs, including FFI) such as kuru, bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle, and chronic wasting disease in American deer and American elk in some areas of the United States and Canada, as well as Creutzfeldt–Jakob disease (CJD). Until recently, prion diseases were only thought to be transmissible by direct contact with infected tissue, such as from eating infected tissue, transfusion, or transplantation; research suggests that prions can be transmitted by aerosols, but that the general public is not at risk of airborne infection.[13]

## Treatments[edit | edit source]

Treatment involves supportive care.[2] Sleeping pills, including barbiturates, have not been found to be helpful; on the contrary, they have been suggested to worsen the symptoms.[14][disputed - discuss]

## Prognosis[edit | edit source]

Similar to other prion diseases, the disease is invariably fatal.[15][2] Life expectancy ranges from seven months to six years,[2] with an average of 18 months.[15]

## Epidemiology[edit | edit source]

Hypnogram comparing the sleep pattern of a healthy control with five FFI patients, who display decreased sleep efficiency and disrupted sleep cycles. [W: wake; R: REM; N1-3: NREM sleep stages].

In 1998, 40 families were known to carry the gene for FFI globally: eight German, five Italian, four American, two French, two Australian, two British, one Japanese, and one Austrian.[16] In the Basque Country, Spain, 16 family cases of the 178N mutation were seen between 1993 and 2005 related to two families with a common ancestor in the 18th century.[17] In 2011, another family was added to the list when researchers found the first man in the Netherlands with FFI. While he had lived in the Netherlands for 19 years, he was of Egyptian descent.[18] Other prion diseases are similar to FFI and could be related, but are missing the D178N gene mutation.[6]

As of 2016, 24 cases of sporadic fatal insomnia have been diagnosed.[1] Unlike in FFI, sFI sufferers do not have the D178N mutation in the PRNP-prion gene; they all have a different mutation in the same gene causing methionine homozygosity at codon 129.[19][20]

### Silvano, 1983, Bologna, Italy[edit | edit source]

In late 1983, Italian neurologist Ignazio Roiter received a patient at the University of Bologna hospital's sleep institute. The man, known only as Silvano, decided in a rare moment of consciousness to be recorded for future studies and to donate his brain for research in hopes of finding a cure for future victims.[21]

### Unnamed, Schenkein and Montagna, 2001[edit | edit source]

One person was able to exceed the average survival time by nearly one year with various strategies, including vitamin therapy and meditation, using different stimulants and hypnotics, and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day. He managed to write a book and drive hundreds of miles in this time, but nonetheless, over the course of his trials, the person succumbed to the classic four-stage progression of the illness.[22][21]

### Egyptian man, 2011, Netherlands[edit | edit source]

Timeline of an FFI patient (same as the one above this one)

In 2011, the first reported case in the Netherlands was of a 57 year-old man of Egyptian descent. The man came in with symptoms of double vision and progressive memory loss, and his family also noted he had recently become disoriented, paranoid, and confused. While he tended to fall asleep during random daily activities, he experienced vivid dreams and random muscular jerks during normal slow-wave sleep. After four months of these symptoms, he began to have convulsions in his hands, trunk, and lower limbs while awake. The person died at age 58, seven months after the onset of symptoms. An autopsy revealed mild atrophy of the frontal cortex and moderate atrophy of the thalamus. The latter is one of the most common signs of FFI.[18]

## Popular culture[edit | edit source]

* Charlie Huston's 2010 novel Sleepless concerns an epidemic of a fatal insomnia that is frequently compared to FFI by characters in the story.
* FFI is a central plot element in In Another Life Archived 2020-11-23 at the Wayback Machine, a short story published in 2015.
* In Something's Killing Me with BD Wong, November 2017 (season one, episode five), "Family Curse", FFI is the topic.[23]
* Nancy Kress's novelette Pathways concerns research into FFI.[24]
* The 2019 movie, A Score to Settle, starring Nicolas Cage, uses FFI as a plot element.
* The 2019 movie, Awoken, uses FFI as a major plot element.[citation needed]
* FFI is a major plot element and is described in detail in the Lewis episode “Falling Darkness”.
* In the first episode of the 2020 TV series Next, one of the main characters confesses to have the disease and says "It's a real thing, look it up."
* Fatal familial insomnia induced by genetic engineering is part of the backstory of Destiny 2: Beyond Light.[25]

## Research[edit | edit source]

Still with unclear benefit in humans, a number of treatments have had tentative success in slowing disease progression in animal models, including pentosan polysulfate, mepacrine, and amphotericin B.[1] As of 2016[update], a study investigating doxycycline is being carried out.[1][26]

In 2009, a mouse model was made for FFI. These mice expressed a humanized version of the PrP protein that also contains the D178N FFI mutation.[27] These mice appear to have progressively fewer and shorter periods of uninterrupted sleep, damage in the thalamus, and early deaths, similar to humans with FFI.

The Prion Alliance was established by husband and wife duo Eric Minikel and Sonia Vallabh after Vallabh was diagnosed with the fatal disease.[28] They conduct research at the Broad Institute to develop therapeutics for human prion diseases. Other research interests involve identifying biomarkers to track the progression of prion disease in living people.[29][30]

## References[edit | edit source]

1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 "Fatal familial insomnia". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Archived from the original on 15 April 2019. Retrieved 17 May 2019.
2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Fatal Insomnia - Neurologic Disorders". Merck Manuals Professional Edition. Archived from the original on 17 May 2019. Retrieved 17 May 2019.
3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 "Fatal Familial Insomnia". NORD (National Organization for Rare Disorders). Archived from the original on 19 May 2019. Retrieved 17 May 2019.
4. ↑ Max, D. T. (2007). The Family that Couldn't Sleep: A medical mystery. New York: Random House Trade Paperbacks. p. 4.
5. ↑ Turner, Rebecca. "Dying To Sleep: Fatal Familial Insomnia (FFI)". www.world-of-lucid-dreaming.com. Archived from the original on 23 February 2018. Retrieved 22 March 2018.
6. ↑ 6.0 6.1 Cortelli, Pietro; Gambetti, Pierluigi; Montagna, Pasquale & Lugaresi, Elio (1999). "Fatal familial insomnia: clinical features and molecular genetics". Journal of Sleep Research. 8: 23–29. doi:10.1046/j.1365-2869.1999.00005.x. PMID 10389103.
7. ↑ "Episode 25: Fatal Insomnia". Obscura: A True Crime Podcast. Archived from the original on 2018-12-19. Retrieved 2018-12-19.
8. ↑ Max, D.T. (May 2010). "The Secret of Sleep". National Geographic Magazine. p. 74.
9. ↑ Reference, Genetics Home h. "PRNP gene". Genetics Home Reference. Archived from the original on 26 June 2018. Retrieved 22 March 2018.
10. ↑ "Zalan Khan; Pradeep C. Bollu, Fatal Familial Insomnia". NCBI Bookshelf. Archived from the original on 2020-11-12. Retrieved 2019-11-01.
11. ↑ Cortelli., P. (1 July 1997). "Cerebral metabolism in fatal familial insomnia: Relation to duration, neuropathology, and distribution of protease-resistant prion protein". Neurology. 49 (1): 126–133. doi:10.1212/WNL.49.1.126. PMID 9222180. S2CID 31614281. Archived from the original on 2 November 2019. Retrieved 1 November 2019.
12. ↑ Panegyres, Peter; Burchell, Jennifer T. (2016). "Prion diseases: Immunotargets and therapy". ImmunoTargets and Therapy. 5: 57–68. doi:10.2147/ITT.S64795. ISSN 2253-1556. PMC 4970640. PMID 27529062.
13. ↑ Mosher, Dave (13 January 2011). "Airborne prions make for 100 percent lethal whiff". Wired. Archived from the original on 24 May 2011. Retrieved 20 May 2011.
14. ↑ Turner, Rebecca. "The man who never slept: Michael Corke". World of Lucid Dreaming. Archived from the original on 4 January 2019. Retrieved 20 May 2011.
15. ↑ 15.0 15.1 Schenkein J, Montagna P (2006). "Self management of fatal familial insomnia. Part 1: what is FFI?". MedGenMed. 8 (3): 65. PMC 1781306. PMID 17406188. Archived from the original on 2017-09-12. Retrieved 2012-03-12.
16. ↑ Montagna P, Gambetti P, Cortelli P, Lugaresi E (2003). "Familial and sporadic fatal insomnia". Lancet Neurol. 2 (3): 167–76. doi:10.1016/S1474-4422(03)00323-5. PMID 12849238. S2CID 20822956.
17. ↑ Zarranz JJ, Arteagoitia JM, Atarés B, Rodríguez-Martínez AB, Martínez-de-Pancorbo M, et al. (2007). "Las encefalopatias espongiformes o enfermedades por priones en el País Vasco". GacMedBilbao. 104 (2): 64–69. doi:10.1016/S0304-4858(07)74572-9. PMID 10371520.
18. ↑ 18.0 18.1 Jansen, C.; Parchi, P.; Jelles, B.; Gouw, A. A.; Beunders, G.; van Spaendonk, R. M. L.; van de Kamp, J. M.; Lemstra, A. W.; Capellari, S.; Rozemuller, A. J. M. (13 July 2011). "The first case of fatal familial insomnia (FFI) in the Netherlands: a patient from Egyptian descent with concurrent four repeat tau deposits". Neuropathology and Applied Neurobiology. 37 (5): 549–553. doi:10.1111/j.1365-2990.2010.01126.x. PMID 20874730.
19. ↑ Mehta LR, Huddleston BJ, Skalabrin EJ, et al. (July 2008). "Sporadic fatal insomnia masquerading as a paraneoplastic cerebellar syndrome". Arch. Neurol. 65 (7): 971–973. doi:10.1001/archneur.65.7.971. PMID 18625868.
20. ↑ Moody KM, Schonberger LB, Maddox RA, Zou WQ, Cracco L, Cali I (2011). "Sporadic fatal insomnia in a young woman: A diagnostic challenge". Case report. BMC Neurol. 11: 136. doi:10.1186/1471-2377-11-136. PMC 3214133. PMID 22040318.
21. ↑ 21.0 21.1 Schenkein J, Montagna P (2006). "Part 2: Case report". MedGenMed: Medscape General Medicine. Self-management of fatal familial insomnia. 8 (3): 66. PMC 1781276. PMID 17406189. Archived from the original on 2012-09-13. Retrieved 2011-12-21.
22. ↑ "Dying without sleep: Insomnia and its implications". triplehelixblog.com. 16 June 2011. Archived from the original on 23 March 2018. Retrieved 22 March 2018.
23. ↑ "Something's Killing Me". TVGuide.com. Archived from the original on 3 November 2017. Retrieved 22 March 2018.
24. ↑ "Pathways". isfdb.org. Archived from the original on 9 December 2018. Retrieved 9 December 2018.
25. ↑ "Mysterious Logbook". Destinypedia. Archived from the original on 2 November 2020. Retrieved 3 November 2020.
26. ↑ Forlonia, Gianluigi; Tettamantia, Mauro; Luccaa, Ugo; Albanesea, Yasmin; Quaglioa, Elena; Chiesaa, Roberto; Erbettab, Alessandra; Villanib, Flavio; Redaellib, Veronica; Tagliavinib, Fabrizio; Artusoc, Vladimiro; Roiterc, Ignazio (21 May 2015). "Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases". Prion. 9 (2): 75–79. doi:10.1080/19336896.2015.1027857. PMC 4601344. PMID 25996399.
27. ↑ Jackson W, et al. (2009). "Spontaneous beneration of prion infectivity in fatal familial insomnia Knockin mice". Neuron. 63 (4): 438–450. doi:10.1016/j.neuron.2009.07.026. PMC 2775465. PMID 19709627.
28. ↑ Clancy, Kelly (2019-01-15). "One Couple's Tireless Crusade to Stop a Genetic Killer". Wired. ISSN 1059-1028. Archived from the original on 2019-01-21. Retrieved 2019-01-21.
29. ↑ "Sonia Vallabh". Broad Institute. 2015-08-20. Archived from the original on 2019-01-21. Retrieved 2019-01-21.
30. ↑ "Prion Alliance". www.prionalliance.org. Archived from the original on 2019-01-21. Retrieved 2019-01-21.

## External links[edit | edit source]

Classification|

* ICD-10: A81.9
* ICD-9-CM: 046.72
* OMIM: 600072
* MeSH: D034062
* DiseasesDB: 32177

|

* "AFIFF Fatal Familial Insomnia Families Association". Archived from the original on 2016-10-21. Retrieved 2013-01-26.

* v
* t
* e

Prion diseases and transmissible spongiform encephalopathy

Prion diseases
in humans|

| inherited/PRNP:|

* fCJD
* Gerstmann–Sträussler–Scheinker syndrome
* Fatal familial insomnia

|

sporadic:|

* sCJD
* Sporadic fatal insomnia
* Variably protease-sensitive prionopathy

acquired/
transmissible:|

* iCJD
* vCJD
* Kuru

Prion diseases
in other animals|

* Bovine spongiform encephalopathy
* Camel spongiform encephalopathy
* Scrapie
* Chronic wasting disease
* Transmissible mink encephalopathy
* Feline spongiform encephalopathy
* Exotic ungulate encephalopathy

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