Fatal insomnia

Fatal Familial Insomnia
Cranial imaging of a FFI patient. In the MRI, there are abnormal signals in the bilateral frontoparietal subcortical area. MRA showed smaller distal branches of cerebral arteries.
Specialty Psychiatry, Sleep medicine, Neuropathology
Symptoms Progressive insomnia leading to dementia and death.
Usual onset 15-60 years
Duration Long term
Causes Genetic mutation, sporadic form very rare
Risk factors Family history
Diagnostic method Brain biopsy
Differential diagnosis Creutzfeldt-Jakob disease
Prevention Genetic testing
Treatment Supportive, but all cases end in death
Prognosis Invariably fatal

Fatal insomnia is an extremely rare sleep disorder that is typically inherited and results in death within a few months to a few years after onset. The main symptom is insomnia, but the disease can also cause a range of other symptoms, such as speech and physical coordination problems and dementia.[1][2]

It is a prion disease of the brain, and is almost always caused by a mutation to the protein PrPC. It has two forms. In the autosomal dominant inherited form, it is called fatal familial insomnia (FFI). It can also develop spontaneously as a noninherited mutation variant called sporadic fatal insomnia (sFI). The first recorded case was an Italian man, who died in Venice in 1765.[3]

Fatal insomnia has no known cure and involves progressively worsening insomnia, which leads to hallucinations, delirium, confusional states like that of dementia, and eventually death.[4] The average survival time for patients diagnosed with FFI after the onset of symptoms is 18 months.[4]

The mutated protein, called PrPSc, has been found in just 40 families worldwide, affecting about 100 people. If only one parent has the gene, the offspring have a 50% risk of inheriting it and developing the disease. With onset usually around middle age, potential parents must be tested if they wish to avoid passing FFI on to their children.

Presentation

The age of onset is variable, ranging from 18 to 60 years, with an average of 50. The disease can be detected prior to onset by genetic testing.[5] Death usually occurs between 7–36 months from onset. The presentation of the disease varies considerably from person to person, even among patients from within the same family.

The disease has four stages:[6]

  1. The person has increasing insomnia, resulting in panic attacks, paranoia, and phobias. This stage lasts for about 4 months.
  2. Hallucinations and panic attacks become noticeable, continuing for about 5 months.
  3. Complete inability to sleep is followed by rapid loss of weight. This lasts for about 3 months.
  4. Dementia, during which the patient becomes unresponsive or mute over the course of 6 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 patient becomes stuck in a state of pre-sleep limbo, or hypnagogia, which is the state just before sleep in healthy individuals. During these stages, patients commonly repeatedly move their limbs as if dreaming.[7]

Cause

Idiogram of chromosome 20 showing gene PRP location

Gene PRNP that provides instructions for making the prion protein PrPC is located on the short (p) arm of chromosome 20 at position p13.[8] Both FFI patients 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."[9]

Cases

Silvano, 1983, Bologna, Italy

In late 1983, Italian neurologist/sleep expert Dr. 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. As of 2018, no cure or treatment has yet been found for FFI. Gene therapy has been thus far unsuccessful. While it is not currently possible to reverse the underlying illness, some evidence shows that treatments that focus solely upon the symptoms may improve quality of life.[10]

Michael Corke, 1991, New Lenox, Illinois

One of the most notable cases is that of Michael (Michel A.) Corke, a music teacher from New Lenox, Illinois (born in Watseka, Illinois). He began to have trouble sleeping before his 40th birthday in 1991; following these first signs of insomnia, his health and state of mind quickly deteriorated as his condition worsened. Eventually, sleep became completely unattainable, and he was soon admitted to University of Chicago Hospital with a misdiagnosis of clinical depression due to multiple sclerosis. Medical professionals Dr. Raymond Roos and Dr. Anthony Reder, at first unsure of the nature of his illness, initially diagnosed multiple sclerosis; in a bid to provide temporary relief in the later stages of the disease, physicians attempted to induce a coma with the use of sedatives – to no avail, as his brain still failed to shut down completely. Corke died in 1993, a month after his 42nd birthday, when he had been completely sleep-deprived for 6 months.[11]

Unnamed patient of Schenkein & Montagna, 2001

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.[12][10]

Diagram of a FFI experiment, showing the sleep patterns and time of the healthy control and the five infected cases

Egyptian man, 2011, Netherlands

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 4 months of these symptoms, he started having convulsions in the hands, trunk, and lower limbs while awake. The patient died at age 58, 7 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.[13]

Timeline of an FFI patient (same at the one above)

Treatments and research

Sleeping pills and barbiturates have not been found to be helpful; on the contrary, in 74% of cases, they have been shown to worsen the clinical manifestations and hasten the course of the disease.[14]

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.[15] 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.

As of 2016, studies are investigating whether doxycycline may be able to slow or even prevent the development of the disease.[16][17][18]

Epidemiology

It was reported in 1998 that 25 families in the world are known to carry the gene for FFI: 8 German, 5 Italian, 4 American, 2 French, 2 Australian, 2 British, 1 Japanese, and 1 Austrian.[19] In the Basque Country, 16 family cases of the 178N mutation were seen between 1993 and 2005 related to 2 families with a common ancestor in the 18th century.[20] 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.[13] Other prion diseases are similar to FFI and could be related, but are missing the D178N gene mutation.[7]

Only 9 cases of sporadic fatal insomnia have ever been diagnosed as of July 2005.[21] Unlike in FFI, sFI sufferers do not have the D178N mutation the in the PRNP-prion gene; they all have a different mutation in the same gene causing methionine homozygosity at codon 129.[22][23]

Other diseases involving the mammalian prion protein are known.[24] 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; new research now suggests that prion diseases can be transmitted by aerosols, but that the general public is not at risk of airborne infection.[25]

In an episode of Law & Order: Special Victims Unit, a witness to an attempted murder is dying of FFI, which was why he was out in the early morning hours. He had taken to wandering around the city, because he reasoned that if he could not sleep, he might as well occupy his time with something else.

In Rooster Teeth's show Day 5, character Bill Beavers suffers from this disease. Ironically, this means he would end up being one of the last living humans.

In Something's Killing Me with BD Wong, November 2017 (season one, episode five), "Family Curse", FFI is the topic.[26]

In the Lewis episode "Falling Darkness", anger over inheriting FFI is the motivation for the murders.

References

  1. ↑ "What is fatal familial insomnia?". Healthline. Retrieved 4 May 2018.
  2. ↑ "Fatal Insomnia". Merck Manual. Retrieved 4 May 2018.
  3. ↑ Max, D. T. (2007). The Family that Couldn't Sleep: A medical mystery. New York: Random House Trade Paperbacks. p. 4.
  4. 1 2 Schenkein J, Montagna P (2006). "Self management of fatal familial insomnia. Part 1: what is FFI?". MedGenMed. 8 (3): 65. PMC 1781306. PMID 17406188.
  5. ↑ Max, D.T. (May 2010). "The Secret of Sleep". National Geographic Magazine. p. 74.
  6. ↑ Turner, Rebecca. "Dying To Sleep: Fatal Familial Insomnia (FFI)". www.world-of-lucid-dreaming.com. Retrieved 22 March 2018.
  7. 1 2 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.
  8. ↑ Reference, Genetics Home. "PRNP gene". Genetics Home Reference. Retrieved 22 March 2018.
  9. ↑ "About FFI". Perpetual Summer.
  10. 1 2 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.
  11. ↑ "10 Amazing things people's brains have done". HowStuffWorks. 15 December 2010. Retrieved 30 June 2017.
  12. ↑ "Dying without sleep: Insomnia and its implications". triplehelixblog.com. 16 June 2011. Retrieved 22 March 2018.
  13. 1 2 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. Blackwell Publishing Ltd. 37 (5): 549–553. doi:10.1111/j.1365-2990.2010.01126.x. Retrieved 16 October 2015.
  14. ↑ Turner, Rebecca. "The man who never slept: Michael Corke". World of Lucid Dreaming. Retrieved 20 May 2011.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ Robson, David (19 January 2016). "The tragic fate of the people who stop sleeping". BBC. Retrieved 20 May 2016.
  18. ↑ "Dying for sleep: Could there be a cure for fatal familial insomnia?". ResearchGate. 29 February 2016. Retrieved 20 May 2016.
  19. ↑ Gambetti and Lugaresi 1998
  20. ↑ 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.
  21. ↑ My Shocking Story - Dying to Sleep (documentary)|format= requires |url= (help). Discovery Channel.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ Panegyres, Peter; Burchell, Jennifer T. (2016). "Prion diseases: Immunotargets and therapy". ImmunoTargets and Therapy: 57. doi:10.2147/ITT.S64795. ISSN 2253-1556.
  25. ↑ Mosher, Dave (13 January 2011). "Airborne prions make for 100 percent lethal whiff". Wired. Retrieved 20 May 2011.
  26. ↑ "Something's Killing Me". TVGuide.com. Retrieved 22 March 2018.

Further reading

  • Akroush, Ann M. "Fatal Familial Insomnia". University of Michigan.
  • Online Mendelian Inheritance in Man (OMIM) Fatal Familial Insomnia; FFI -600072
  • 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.
  • Almer G, Hainfellner JA, Brücke T, et al. (1999). "Fatal familial insomnia: A new Austrian family". Brain. 122 (1): 5–16. doi:10.1093/brain/122.1.5. PMID 10050890.
Classification
  • Schadler, Jay; Viddy, Laura. "Medical mystery: When sleep doesn't come, death does". ABC News.
  • "AFIFF Fatal Familial Insomnia Families Association".
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